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Vol.

32

No. 1

January-March 2009

Drugs and Pharmaceuticals


Current R & D Highlights
(Diabetes)

Contents
R& D Technology

Introduction
Diabetes

Features
Diabetes: Cure by Nature
4
Development of the Thiazolidinediones as
PPAR Agonists for the Treatment
of Type 2 Diabetes
22
Exploring Role of 5-Hydroxytryptamine in
Diabetes Mellitus and Cardiovascular
Complications
31
System Biology Enables Novel Strategies for
the Management of Type 2 Diabetes
40
Overview of Diabetes Mellitus Management 51

News & Views

64

R&D Highlights
Cell-based Treatments for Diabetes

Current R&D Highlights, Jan.-Mar. 2009

72

Risk Factors and Complications of


Diabetes

New Leads

89
100

Natural Products
Withania coagulans: Role in Diabetes
Marine Biota and Diabetics

106
113

Biotechnology
Latent Autoimmune Diabetes in Adults
(LADA)

Patents
CDRI Publications

119
123
129

Introduction

Diabetes
Diabetes is not a disease but a disorder, affecting 10% of the human population where the body does
not produce insulin or does not properly use insulin due to which the glucose concentration remains high in
the blood stream.

Glucose, Insulin and Diabetes


Like any engine, our body needs fuel to keep it going and this fuel is glucose. Glucose is derived from
all sorts of foods that we consume. After every meal a large part of our food is converted into glucose,
thereby increasing the blood glucose levels. Pancreas, a small gland below the stomach secretes a hormone
called insulin. The insulin released carries the blood glucose present in the blood stream to cells that need
extra energy. The cells do not and can not use glucose without the help of insulin. Once inside the cells, the
glucose produces heat and energy. But if the insulin is not helping, then the glucose is not of use to body
and in fact it is bad for body to have too much of unused glucose. In a normal individual, body manages to
maintain a ideal level of glucose concentration. But in diabetes insulin is either not produced or not utilized
properly, and hence the glucose remains in the blood causing the condition Diabetes.
The problem in people with diabetes is that either they dont produce enough insulin, or the insulin
they do produce does not work properly, or their cells dont respond properly to insulin (insulin resistance).
The net result is that glucose is not cleared from their blood stream and they have high blood glucose
levels which the body tries to clear by various compensatory methods, such as increased urination.

Types of Diabetes
Diabetes due to absence of insulin
This is frequently seen in childhood and hence called, Juvenile Onset or Childhood Diabetes. In this
diabetes which is called Type 1, the patient has failed to produce insulin and the only remedy to overcome
this is to go in for Insulin injections. The problem can happen in any age of the individual, though majority
are from childhood. The injected insulin, the frequency and dose is decided by the medical expert. The
synthesized insulin is injected and it mimics the natural insulin and the individual can lead a normal life.
Diabetes due to ineffective insulin
This is commonly seen in adults and called as Type 2. Though the body produces insulin it has trouble
using it, that is body is resistant to its own insulin. High blood sugar is found in the blood without being
transported to the cells. Routine checkups with dietary restrictions and healthy life style along with regular
affordable physical and mental activities are the only solution. There are medicines available which make
insulin more effective in such individuals and a combination of medicines and calorie control can help the
patients a lot in keeping the disorder under control.

Diabetes Management
Both types of diabetes have different treatment options and in general population the Type 2 diabetes

Current R&D Highlights, Jan.-Mar. 2009

Introduction
is more prevalent than Type 1. More than 80% of the patients have Type 2 which means it is a problem of
ineffective insulin.
In case of Type 1, the objective of treatment is to give adequate insulin, in right intervals so that the
patient will not have Hypo or Hyper sugar levels. This requires frequent monitoring for sugar levels
and require higher frequency of medical supervision and intervention.
In case of Type 2, the objective of treatment is to make insulin more effective and reduce the
consumption of unwanted food materials. This is achieved by reduction in quantity of food or
modifications in type of food, increase in physical exercises or avoid sedentary life styles and also take
such medicines which improve the action of insulin. This requires less often blood sugar monitoring,
compared to Type 1, but requires constant and periodic medical monitoring and supervision.
Diabetes is a manageable disease if one knows how to control the sugar levels. But uncontrolled
diabetes can give rise to so many health complications such as Heart Disease, Kidney Disease, Blindness,
Brain Failure and Amputations of legs or Limbs.

How to Control?
Some manage it well but a lot of people with diabetes struggle continuously. It requires a lot of will
power to change the lifestyle and also to follow disciplined day to day activities. Specialists advise diabetic
patients to adopt following guidelines to live healthy with the disease:

Do not skip medicines if they are advised.


Avoid temptations of eating such foods which are to be avoided.
Keep increasing the physical activity of the body.
Reduce weight and then maintain a constant weight.
Avoid Sugar, Rice, Potato and fruits in excess.
Avoid smoking.
Avoid or minimize alcohol.
Keep monitoring the sugar level at certain intervals.
Monitor periodically lipid profiles.
Monitor cardiac parameters at least once in a year

Views expressed in the journal are those of the authors and the
Editorial Board/Publisher takes no responsibility for the same. We are
a secondary abstracting service and the veracity of information is of
the source quoted and not our primary responsibility.
Editor

Current R&D Highlights, Jan.-Mar. 2009

Feature

Diabetes: Cure by Nature


Akanksha and Rakesh Maurya*
Medicinal and Process Chemistry Division,
Central Drug Research Institute, Lucknow

Introduction
During evolutionary process of life on the
earth, microorganisms, plants and animals get
originated. All the living organisms are
interdependent in so many ways, as for food,
shelter etc. Some are parasitic saprophytic or
mutualists too. Plants possess innumerable
number of compounds, having innumerable
pharmacological profiles. By its wide range of
pharmacologically active compounds, plants
protect themselves from various diseases. At
the same time, animals are dependent on plants
for their food either directly or indirectly.
Animals taking food directly from plant get
cured from various diseases. Humans take
medication to cure or prevent diseases. From
very ancient time, wide range of plants is
reported to treat various diseases and
complications in various ancient medicinal
systems. In Ayurveda a number of plants are
reported to be used in curing diabetes.
Diabetes mellitus, arising as a global problem,
can be defined as a metabolic disorder, which
is most prevalent. Number of diabetic patients
is rising steadily day by day. Diabetes mellitus
is caused by the abnormality of carbohydrate
metabolism either by low blood insulin level
or insensitivity of target organs to insulin 42.
Diabetes can be defined as a group of
syndromes characterized by hyperglycemia,
altered metabolism of lipids, carbohydrates
and proteins. In type 1 diabetes, the pancreas
stops producing insulin due to autoimmune
destruction of pancreatic beta cells. In case of
type 2 diabetes, body cells do not respond to
4

insulin. In absence of insulin, body cells dont


get the required glucose for producing ATP,
body starts breaking down the muscle tissue
and fat for producing energy hence, causing
fast weight loss. Dehydration is also usually
observed due to electrolyte disturbance. In
advanced stages, coma and death is also
reported. In both types of diabetes, signs and
symptoms are more likely to be similar as the
blood sugar is high, either due to less or no
production of insulin, or insulin resistance.
Common symptoms of diabetes are increased
fatigue, polydipsia, polyuria, polyphagia,
blurred vision, poor wound healing, quick
exhaustion, drowsiness. Synthetic drugs for
diabetes treatment are costly and they have
many side effects too. Natural products have
safer side over synthetic drugs having less or
no side effects. Effective treatment includes
controlling hyperglycaemia as well as
secondary complications. About 800 plants
have been reported possessing anti-diabetic
potential.1 Since antiquity, diabetes has been
treated with medicines derived from plants.
Biological activities of various plants have
been proved by phytochemical studies. Below
are the briefs of some plants having
hypoglycaemic and/or antihyperglycemic
potential.
Acacia arabica (Lam.) Muhl. ex Willd.
(Family: Mimosaceae)
Common name is Babul in Hindi and
Indian Gum Arabic tree in English. Acacia has
been used to treat high cholesterol, diabetes,
cancer, gingivitis, stomatitis (mouth sores) and
Current R&D Highlights, Jan.-Mar. 2009

Feature
pharyngitis. The powdered seeds of A. arabica
were administered in doses of 2, 3 and 4 gm/kg
body-weight to normal and alloxan-diabetic
rabbits. 2, 4, 6 and 8 hours after the
administration the blood glucose levels were
estimated. It exerted a significant (p<0.05)
hypoglycemic effect in normal rabbits. It acts
through release of insulin from pancreatic beta
cells8.
Aegle marmelos (L.) Correa ex Roxb.
(Family: Rutaceae)
Commonly known as Bael in Hindi.
Administration of an oral dose of 250 mg/ kg
of alcoholic leaf extract of A. marmelos
showed significant improvements in ability to
utilize the external glucose load in glucose
induced hyperglycemic rats. Efficacy of A.
marmelos was 71% of glybenclamide. This
increase in glucose utilization can be attributed
either by direct stimulation of glucose uptake
or by enhanced insulin secretion64. Aqueous
extract of fruits of A. marmelos is known to
exhibit hypoglycaemic effect in streptozotocininduced diabetes in rats. At the dose of 125
and 250 mg/ kg twice a day for 4 weeks
resulted in significant reductions in blood
glucose, plasma thiobarbituric acid reactive
substances, hydroperoxides, ceruloplasmin and
-tocopherol and a significant elevation in
plasma reduced glutathione and Vitamin C.
The effect of the extract at a dose of 250 mg
kg1 was more effective than glibenclamide35.
The effect of methanolic extract of A.e
marmelos has been studied on a battery of
targets
glucose
transporter
(Glut-4),
peroxisome proliferator activator receptor
gamma (PPAR) and phosphatidylinositol 3
kinase (PI3 kinase) involved in glucose
transport. It was found active at 100 ng/ml
dose
comparable
with
insulin
and
rosiglitazone5.
Aerva lanata (L.) Juss. ex Schult. (Family:
Amaranthaceae)
It is commonly known as Sunny khur. Its
alcoholic extract reduced the increase in blood
Current R&D Highlights, Jan.-Mar. 2009

sugar in alloxanized rats by 42% at 375 mg/kg


and 48% at 500 mg/kg body weight. The
extract also reduced blood sugar level of
alloxanized rats significantly upon chronic
administration for 2 weeks48.
Allium cepa L. (Family: Liliaceae)
Commonly known as Pyaj in Hindi and
Onion in English. It has been used to treat
diabetes and is reputed to lower blood sugar
levels.
Oral
administration
of
the
hypoglycaemic fraction to alloxan-diabetic
rabbits improved their glucose tolerance. After
7 days treatment, the more active
hypoglycaemic fraction was about half as
active as Phenformin in lowering the fasting
blood sugar of alloxan-diabetic rabbits43. Smethyl cysteine sulfoxide (SMCS) isolated
from Allium cepa was investigated for its lipid
lowering action in SD rats, in comparison to
the hypolipidemic drug gugulipid. SMCS at a
dose of 200 mg/kg body weight for 45 days
enhanced the hyperlipidemic condition.
Concentrations of cholesterol, triglyceride and
phospholipids were significantly reduced with
respect to control38.
S
H 2N

S O
OH

O
S-methyl cysteine sulfoxide (SMCS)

The effects of two dietary doses of freezedried onion powder, i.e., onion low (ONL;
0.5%) and onion high (ONH; 2.0%) on
streptozotocin (STZ)-induced diabetes rat
model was studied. After 4 weeks on the
experimental diets, fasting blood glucose
levels for both onion-fed groups were found
elevated. Serum insulin concentrations and
insulin resistance were dose-dependently
increased in the onion-fed groups. The ONH
group had significantly higher lipid
concentrations, ONL group showed a similar
hyperlipidemic trend to a lesser extent31.
5

Feature
Allium sativum L. (Family: Alliaceae)
Commonly known as Lahasun in Hindi
and Garlic in English. Ethanolic extract of
garlic at the doses of 0.1, 0.25 and 0.5 g/kg
body weight was orally given to normal and
streptozotocin-induced diabetic rats for 14
days. The level of serum glucose, total
cholesterol, triglycerides, urea, uric acid,
creatinine, aspartate amino transferase (AST)
and alanine amino transferase (ALT) were
found decreased. The antidiabetic effect of the
extract was found more active than that of
glibenclamide18. The antidiabetic effect of
garlic is thought to be due to the formation of a
colloidal type suspension in the stomach and
intestines when the mucilaginous fiber of

garlic is hydrated, therefore affecting gastrointestinal transit and slowing glucose


absorption47. S-allyl cysteine sulphoxide, a
sulphur containing amino acid which is the
precursor of allicin and garlic oil, has been
found to show significant antidiabetic effects
in alloxan diabetic rats at a dose of 200 mg/kg
body weight. It increased significantly liver
and intestinal HMG CoA reductase activity
and liver hexokinase activity (Sheela &
Augusti, 1992). Allicin (thio-2-propene-1sulfinic acid S-allyl ester), isolated from garlic,
produced significant blood glucose lowering
activity in experimental diabetic animals48.

S
S O

H 2N
OH
O

H 2C CHCH 2S SCH2 CH CH 2
O
Allicin

S-allyl cysteine sulphoxide

Aloe vera (L.) Burm.f. (Family: Aloaceae)


Commonly known as Ghee Kunwar or
Kumar panthu in Hindi. Aloes have long been
used all over the world for their various
medicinal properties. Separate experiments on
three groups of rats, namely, non-diabetic
(ND), type I (IDDM) and type II (NIDDM)
diabetic rats were carried out. A. vera leaf pulp
and gel extracts were ineffective on lowering
the blood sugar level of ND rats. Leaf pulp
extract showed hypoglycaemic activity on
IDDM and NIDDM rats. Whereas, leaf gel
extract showed hyperglycaemic activity on
NIDDM rats. This study directed that the pulps
of A. vera leaves devoid of the gel could be
useful in the treatment of non-insulin
dependent diabetes mellitus54.
Andrographis paniculata
Acanthaceae)

Nees

(Family:

Commonly known as Kalmegh in Hindi


6

and
King
of
bitters
in
English.
Andrographolide, a principle present in
O
HO

HO
H 3C CH2OH
Andrographolide

Andrographis paniculata is suggested to


increase glucose utilization in peripheral tissue
via an insulin-dependent mechanism80.
Annona squamosa L. (Family: Annonaceae)
Commonly known as Sharifa or Sitafal in
Hindi and Sugar apple or Custard apple in
English. Aqueous leaf extract has shown
hypoglycemic activity in streptozotocinCurrent R&D Highlights, Jan.-Mar. 2009

Feature
nicotinamide induced diabetic rats. At the dose
of 350 mg/kg ethanolic leaf extract has been
found to possess hypoglycemic as well as
antihyperglycemic potential in normal,
streptozotocin- diabetic rats and alloxanized
rabbits48
Areca catechu L. (Family: Arecaceae)
Commonly known as Supari in Hindi and
Betelnut in English. Subcutaneous
O
OCH 3
N
CH 3
Arecoline

administration of alkaloid fraction at the dose


0.05-0.5 mg/kg in alloxanized rabbits showed
significant hypoglycemic effect15. Arecoline,
isolated from A. catechu is reported to have
hypoglycemic activity48.
Artemisia pallens Wall. ex DC. (Family:
Compositae)
Commonly known as Davana in Hindi.
Oral administration of the methanol extract of
the aerial parts of Artemisia pallens, led to
significant blood glucose lowering effect in
glucose-fed hyperglycaemic and alloxaninduced diabetic rats. This effect of the extract
was dose dependent and significant at 100
mg/kg level in glucose-fed rats. In fasted
normal rats, the extract caused a moderate
hypoglycaemic effect at 1000 mg/kg74.
Azadirachta
Meliaceae)

indica

A.

Juss.

(Family:

Commonly known as Neem. Studies


showed that petroleum ether extract of neem
seed kernel (NSK) and husk (NSH) showed
significant protection against the oxidative
damage induced by STZ in heart and
erythrocytes of rats. NSK and NSH may act as
cardioprotective and free radical scavenger
agent. Serum creatine phosphokinase (CPK)
increased in diabetic rats was significantly
Current R&D Highlights, Jan.-Mar. 2009

decreased on insulin, NSK and NSH


treatments. The decrease in activities of
superoxide dismutase (SOD) and catalase
(CAT) and increase in lipid peroxidation
(LPO) of erythrocytes as observed in diabetes
was regained after insulin, NSH and NSK
treatments. Results suggest that NSH and NSK
prevent oxidative stress caused by STZ in
heart and erythrocytes25. Pretreatment with A.
indica leaf extract, blocked the depressive
effect of epinephrine in diabetic rabbits as well
as in normal ones. In in vitro trials, A. indica
leaf extract, failed to alter the hepatic
glycogen, but it partially blocked epinephrine
action on hepatic glycogen both in normal and
diabetic rabbits12. A. indica leaf extract blocks
significantly the inhibitory effect of serotonin
on insulin secretion mediated by glucose14.
Barleria
lupulina
Acanthaceae)

Lindl.

(Family:

Commonly known as Snake bush in


English. The methanol extract of aerial parts
of Barleria
lupulina Lindl.
showed
a
pronounced blood-glucose-lowering potential
in streptozotocin hyperglycemic rats. The
extract at dose of 200 mg/kg body weight
exhibited a maximum activity (p<0.001) at 12
h after administration. The most significant
activity (15.35% blood glucose reduction) was
observed for the group administered 300
mg/kg body weight at 12 h after
administration, while the standard drug
glibenclamide (10 mg/kg body weight) showed
an 18.80% reduction of blood glucose at the
same time interval73.
Beta vulgaris L. (Family: Chenopodiaceae)
It is known as Chukander in Hindi and
Garden beet in English. Beta vulgarosides IIIV, isolated have been shown to ameliorate
glucose tolerance in OGTT conducted in rats.
Uncontrolled induced
diabetes
caused
significant
increases
in
nonenzymatic
glycosylation of skin proteins, lipid
peroxidation
and
blood
glucose.
Administration of B. vulgaris extract inhibited
7

Feature
these effects except the increase in lipid
peroxidation. These findings indicated that the
use of B. vulgaris may decrease the
development of some diabetic complications23.

STZ administration, urine volume per day and


UAE levels were significantly higher
(P<0.0005) in diabetic controls as compared to
normal controls24.

Biophytum sensitivum (L.) DC. (Family:


Oxalidaceae)

Caesalpinia bonducella (L.) Roxb. (Family:


Cesalpinaceae)

It is commonly called as Lajjalu in Hindi


and Life plant in English. Leaf extract has
been proved to show antihyperglycemic effect
in alloxan diabetic male rabbits. It was found
ineffective in severe diabetes23.

Commonly known as Kantkarej or


Kantikaranja in Hindi and Fever nut or Bonduc
nut in English. In normal rats, aqueous and
50% ethanolic extracts of C. bonducella seeds
exhibited hypoglycaemic activity at a dose of
100 mg/kg after 4 hour of administration. The
hypoglycaemia produced by the aqueous
extract was of prolonged duration as compared
to ethanolic extract. In diabetic rats, both the
extracts produced significant (p<0.01)
antihyperglycaemic effect from day 5
onwards66.

Boerhavia
diffusa
Nyctaginaceae)

L.

(Family:

Commonly known as Punarnava in Hindi.


Oral administration of B. diffusa leaf extract at
200 mg/kg of body weight for 4 weeks resulted
in significant reduction in serum and tissue
cholesterol, free fatty acids, phospholipids, and
triglycerides. It was found to be more effective
than glibenclamide in the treatment of diabetic
rats57.

HO
HO

HO
O

Camellia
Theaceae)

OH O
Shamimin

Brassica juncea
Brassicaceae)

(L.)

Czern.

(Family:

Common name is Rai in Hindi and Indian


mustard in English. Study was made on the
effects of daily oral feeding of 10% powder of
seeds of Brassica juncea for 60 days on serum
glucose concentrations and kidney functions in
streptozotocin diabetic rats. After 60 days of
8

(Family:

OH
OH

OH

Millsp.

OH

Common name is Semul in Hindi and Red


silk cotton tree in English. Shamimin, a
flavonol glucoside known as Shamimin,
isolated from the leaves of the plant has been
reported to possess significant hypoglycemic
activity at dose of 500 mg/kg in rats65.
HO

(L.)

Common name is Tuvar in Hindi and Red


gram in English. Oral administration of graded
doses of aqueous extract of C. cajan leaves in
streptozotocin induced type 2 diabetic rats
showed significant increase in 14.3 % in
fasting blood glucose levels of normal rats.
The dose of 1000 mg/kg showed the maximum
rise of 17.1, 71.2 and 50.7 % in blood glucose
levels of normal, sub and mild diabetic rats
respectively in glucose tolerance test32.

Bombax ceiba L. (Family: Bombacaceae)

OH

Cajanus cajan
Fabaceae)

sinensis

Kuntze

(Family:

Commonly known as Tea in English. The hot


water extract of C. sinensis significantly
reduced the blood glucose level and was found
to possess both preventive and curative effects
on experimentally produced diabetes in rats.
The green tea as well as black tea both possess
antidiabetic activity20.
Capparis decidua (Forsk.) Edgew. (Family:
Capparidaceae)
Commonly known as Keekar, Karir, Kirir,
Karril, etc. in Hindi and Caper plant in
Current R&D Highlights, Jan.-Mar. 2009

Feature
English. Oral feeding of diet containing (30%)
C. decidua fruit powder for 3 weeks to
alloxanized diabetic rats showed significant
hypoglycemia23.
Casearia
esculenta
Flacourtiaceae)

Roxb.

(Family:

Commonly known as Saptarangi in Hindi.


The plant root extract exhibited significant
hypolipidaemic and antiperoxidative activity in
red blood cells of streptozotocin diabetic rats48.
Cassia
auriculata
Cesalpinaceae)

L.

(Family:

Common name is Tanners Cassia. Extract


of flowers of C. auriculata suppressed the
elevated blood glucose and lipid levels in
diabetic rats at doses of 0.15, 0.30 and 0.45
g/kg body weight for 30 days. At the dose of
0.45 g/kg was found to be comparable to
glibenclamide. Extract significantly reduced
the levels of serum and tissue lipids56.
Catharanthus roseus (L.) G. Don. / Vinca
rosea (Family: Apocynaceae)
Commonly called as Sadabahar in Hindi
and Madagascar periwinkle in English.
Administration of aqueous extracts of V. rosea
flower and leaf have been found to regulate the
blood sugar level in alloxan diabetic male
albino rats19. Ethanol extract of V. rosea
promotes significant wound healing and
closure in diabetic rats compared with
mupirocin At the dose of 100 mg/kg body
weight, it significantly reduced (p<0.001)
wound size in streptozotocin induced diabetic
rats53. Alkaloids isolated catharanthine,
vindoline and vindolinine lower blood sugar
level48.
O
HO HO
O
N

O
N
N
H
O

Catharanthine

Common name is Indryan in Hindi and


Bitter apple in English. Oral administration of
300 mg/kg of aqueous extract produced
significant reduction in plasma glucose after 1
hour and highly significant after 2,3 and 6 hour
in normal rabbits. The glycosidic extract at a
oral dose of 50 mg/kg significantly lowered
the fasting glucose levels after 2 and 3 hour
and highly significant after 6 hour. The
saponin extract at the same oral dose
significantly lowered the fasting glucose levels
after 1 and 2 hour and highly significant
(p<0.001) after 3 and 6 hour1.
Coccinia indica Wight & Arn. (Family:
Cucurbitaceae)
Common name is kundru. It have been
used in the traditional treatment of diabetes
mellitus. Toluene, chloroform, ethyl acetate
and n-butanol fractions of the dried alcoholic
extract of the aerial part were fed to alloxan
treated diabetic rats orally, twice daily at a
dose of 150 mg/kg. The toluene fraction
prevented the elevation of lipid profile
significantly (p<0.001) in comparison to
control diabetic rats16. Ethanol extract of C.
grandis showed significant triglyceride (TG)
and
cholesterol-lowering
effects
in
dyslipidemic hamster model. Activity was
proved to be concentrated in chloroformsoluble fraction. Chloroform soluble fraction
on
repeated
column
chromatography,
furnished a polyprenol characterized as C60polyprenol. It significantly decreased serum
TG by 42%, total cholesterol (TC) 25% and
glycerol (Gly) 12%, accompanied HDL-C/TC
ratio 26% in highfat diet (HFD)-fed
dyslipidemic hamsters at the dose of 50 mg/kg
body weight. Results are comparable to
standard drug fenofibrate at the dose of 108
mg/kg70.

H
O

Vindoline

N
H
O

Vindolinine

Citrullus colocynthis (L.) Schrad. (Family:


Cucurbitaceae)
Current R&D Highlights, Jan.-Mar. 2009

Feature
Curcuma longa (Family: Zingiberaceae)

Gentiaceae)

Commonly known as Haldi in Hindi and


Turmeric in English. Ethanol extract of
rhizome significantly suppressed an increase in
blood glucose level in type 2 diabetic mice.
The extract stimulated human adipocyte
differentiation in a dose-dependent manner and
showed human peroxisome proliferatoractivated receptor (PPAR)- ligand-binding
activity in a GAL4-PPAR- chimera assay
(Kuroda et al., 2005). Ferulic acid (4-hydroxy3-methoxycinnamic acid) is found in many
plants, isolated from Curcuma too. It has
shown hypoglycemic activity in both type of
diabetes48.

Commonly known as Chhota chirata in


Hindi and Whitehead in English. At the dose
of 1.5 g/100g body weight/day of aqueous
extract of E. littorale increased HDL levels
and decreased serum cholesterol, triglyceride,
LDL, VLDL, LDL/HDL ratio in rats fed with
hypercholesterolaemic diet. It showed a
decrease in activities of erythrocyte catalase,
superoxide dismutase and lipid peroxidation
levels, with an increase in reduced glutathione
levels. It also showed decrease in liver and
kidney cholesterol levels and triglyceride
levels76.

HO
OH

O
O
Ferulic acid

Cynodon dactylon (Family: Poaceae)


Commonly known as Doob in Hindi. At a
dose of 500 mg/kg, aqueous extract lowered
blood glucose level around 31% after 4 hour of
administration in normal rats. During glucose
tolerance test (GTT) of mild diabetic rats, the
same dose produced a fall of 23% in blood
glucose level within 1 hour. This dose has
almost similar effect as that of standard drug
tolbutamide at the dose of 250 mg/kg body
weight. A significant reduction of 59% was
observed in fasting blood glucose level of
severely diabetic rats at same dose given for 14
days. It reduced urine sugar level. In severely
diabetic rats total cholesterol (TC), low density
lipoprotein (LDL) and triglyceride (TG) levels
were decreased by 35, 77 and 29%,
respectively, whereas, cardioprotective, high
density lipoprotein (HDL) was increased by
18%. These results suggested antidiabetic
potential of aqueous extract along with
significant hypoglycemic and hypolipidemic
effects70,71.
Enicostemma
10

littorale

Blume

(Family:

Eucalyptus
Myrtaceae)

globulus

Labill.

(Family:

Commonly known as Safeda in Hindi. In


diabetic rats, the repeated oral administration
of E. globulus aqueous leaf extract
significantly increased the basal plasma insulin
concentrations (p<0.05)27. An aqueous extract
of E. globulus at the dose of 0.5 g/L
enhanced 2-deoxy-glucose transport by 50%,
glucose oxidation by 60% and incorporation of
glucose into glycogen by 90% in mouse
abdominal muscle.
In
acute,
20 min
incubations, administration of 0.25-0.5 g
showed stepwise 70-160% enhancement of
insulin secretion from the clonal pancreatic cell line21.
Eugenia uniflora L. (Family: Myrtaceae)
Commonmly known as Surinam Cherry or
Brazilian Cherry in English. Ethanolic extract
of the leaves of E. uniflora inhibited the
increase in plasma glucose level and plasma
triglyceride level48.
Ficus bengalensis (Family: Moraceae)
It is known as bargad in Hindi and Banyan
in English. 50 mg/kg of hot water extract of F.
bengalensis was given orally to normal rabbits
and rabbits with alloxan induced alloxanrecovered, mildly diabetic and severely
diabetic states daily for three days. After a gap
of five days, the water extract was
Current R&D Highlights, Jan.-Mar. 2009

Feature
readministered for three days at the same dose
level. There was no significant change in
fasting blood glucose (FBG), or glucose
tolerance test (GTT) in normal rabbits. There
was no fall in FBG but improvement in
glucose tolerance in alloxanrecovered rabbits.
In mildly diabetic rabbits there was 55.8% fall
in FBG values and an improvement in glucose
tolerance. The extract produced 68% fall in
FBG values in severely diabetic rabbits69. The
bark and aerial roots ethanolic extracts at a
dose of 100 mg/kg

chlorobenzoic acid derivative and nicotinic


acid
derivative
showed
potent
antihyperglycemic activity at 100 mg/kg body
weight52.
Glycyrrhiza glabra L. (Family: Fabaceae)
Commonly
known
as
Licorice.
Glycyrrhizin, isolated from licorice root, is
composed of one molecule of glycyrrhetinic
acid and two molecules of glucuronic acid.
After oral administration, glycyrrhizin has
been shown to be hydrolyzed by the
glucuronidase of intestinal bacteria to its
COOH
O
H

HO

significantly (p<0.001), (p<0.01) lowered the


blood sugar level of hyperglycemic rats
respectively. Barks exhibited better activity
than aerial roots17. Leucodelphinidin, isolated
from the bark of F. bengalensis has been
reported for its hypoglycemic activity.
Ficus racemosa (Family: Moraceae)
It is commonly known as Gular in India.
-amyrin acetate, isolated from the fruits of F.
racemosa at the dose of 100 mg/kg body

O
O
-amyrin acetate

weight, lowered the blood glucose levels by


18.4 and 17.0% at 5 and 24 hour, respectively,
in sucrose challenged streptozotocin induced
diabetic rat (STZ-S) model. Its pCurrent R&D Highlights, Jan.-Mar. 2009

H
18-glycyrrhetinic acid

principal aglycone, 18-glycyrrhetinic acid.


18-glycyrrhetinic acid when administered
orally at 100mg/kg of bodyweight, showed
potential antihyperglycemic effect that is
comparable with glibenclamide34.
Gymnema montanum
Asclepiadaceae)

Hook.f.

(Family:

G. montanum leaf extract possess


antihyperglycemic and antiperoxidative effect.
Oral administration of 200 mg/kg body weight
of the alcoholic extract of the leaf for 3 weeks
resulted in a significant reduction in blood
glucose and an increase in plasma insulin. The
decrease in lipid peroxides and increase in
reduced glutathione (GSH), ascorbic acid
(Vitamin C) and -tocopherol (Vitamin E)
showed its antioxidant properties6.
Gymnema sylvestre
Asclepiadaceae)

R.

Br.

(Family:

G. sylvestre leaf extract lowers the blood


11

Feature
glucose level in normal fasting, glucose-fed
hyperglycemic and diabetic rats compared
with placebo-treated animals. The maximum
glucose suppression occurred after 2 hour of
treatment by the effective dose of 200 mg/kg,
PO, of the extract 12,13.
Helicteres isora L. (Family: Sterculiaceae)
Administration of the bark extract of H.
isora at the doses of 100 and 200 mg/kg body
weight for 21 days resulted in significant
reduction in serum and tissue cholesterol,
phospholipids,
free
fatty
acids
and
triglycerides in STZ diabetic rats. Significant
(p< 0.05) decrease in high-density lipoprotein
(HDL) whereas significant increase (p<0.05)
low-density lipoprotein (LDL) and very lowdensity lipoprotein (VLDL) were observed in
STZ diabetic rats. The bark extract possesses
definite
hypotriglyceridemic
and
antiatherogenic properties in STZ diabetic rats
after 3 weeks of treatment39.
Hibiscus rosa-sinensis (Family: Malvaceae)
Commonly known as Gudhal in Hindi and
shoe flower in English. In streptozotocin
induced diabetic rats, oral administration of an
ethanol flower extract of Hibiscus rosa
sinensis lowered the total cholesterol and
serum triglycerides by 22 and 30%,
respectively. Maximal diminution in blood
glucose (4146%) and insulin level (14%) was
noticed after 21 days. The hypoglycemic
activity of this extract is comparable to that of
glibenclamide63 .
Hygrophila
Acanthaceae)

auriculata

(Family:

It is a wild herb widely used in


Ayurveda as Rasayana drug for treatment
of various disorders. aerial parts of H.
auriculata extract possesses significant
antidiabetic activity along with potent
antioxidant potential in diabetic conditions.
Treatment of diabetic rats at the doses of 100
and 250 mg/kg body weight for 3 weeks
showed significant reduction in blood glucose,
12

thiobarbituric acid reactive substances


(TBARS) and hydroperoxide in both liver and
kidney78.
Indigofera mysorensis (Family: Fabaceae)
In insulin resistant db/db mice extract of
the whole shrub of Indigofera at 300 mg/kg for
10 days, produced a 63% reduction in plasma
glucose, 41% reduction in plasma triglyceride
and 77% reduction in plasma insulin levels,
which is better than insulin sensitizer,
troglitazone (400 mg/kg). Study showed that
the antidiabetic effect of the ethanolic extract
of Indigofera is due to its insulin sensitizing
property and is clearly different from that of
sulfonylurea or acarbose10.
Ipomoea batatas (Family: Convolvulaceae)
Commonly known as sweet potato. Whiteskinned sweet potato is useful in the
prevention and improvement of
diabetic
symptoms by stimulating human immunity. It
increased phagocytic activity and phagosomelysosome fusion in neutrophils and monocytes
in a dose-dependent manner46.
Lantana camara (Family: Verbenaceae)
In Hindi, it is known as Caturang.
Administration at the dose of 1500 mg/kg/day
for 14 days showed significant hypoglycemic
effect in rats23.
Lactuca indica (Family: Asteraceae)
Commonly known as Indian Lettuce.
Lactucain C and lactucaside have shown
significant hypoglycemic activity48.
O

O
OHH
O

O
O

HO

H
O

OH

OH

H HO

H
O
O

HH
O

OH
O

HO

OHO

OH

OH
O

Lactucain C

Lactucaside

Mangifera
indica
Anacardiaceae)

L.

(Family:

It is known as Aam in Hindi and Mango in


Current R&D Highlights, Jan.-Mar. 2009

Feature
English. Aqueous leaf extract at the dose of 1
g/kg p.o. showed hypoglycemic effect when
given 60 mins prior to glucose administration
in streptozotocin-induced diabetic rats2. The
chronic intraperitoneal administration of
mangiferin, a xanthone glucoside isolated from
the leaves of Mangifera indica at the doses of
10 and

stimulates glycogen storage by the liver and


improves
peripheral
glucose
uptake62.
Charantin, a steroidal saponin isolated have
hypoglycemic potential.

OH
HO
HO

O
O
OH

Charantin

Momordica cymbalaria Fenzl ex Naudin


(Family: Cucurbitaceae)

20 mg/kg once daily for 28 days exhibited


antidiabetic activity by significantly lowering
fasting plasma glucose level at different time
intervals in STZ-diabetic rats. At the same
doses,
mangiferin
showed
significant
antihyperlipidemic
and
antiatherogenic
activities as evidenced by significant decrease
in plasma total cholesterol, triglycerides, lowdensity lipoprotein cholesterol (LDL-C) levels
coupled together with elevation of highdensity lipoprotein cholesterol (HDL-C) level
and diminution of atherogenic index in
diabetic rats50.
Memecylon umbellatum Burm. f. (Family:
Melastomataceae)
Commonly known as Anjani in Hindi. Oral
administration of alcoholic extract of the
leaves of M. umbellatum (250 mg/kg) caused a
significant reduction in the serum glucose
levels in normal and alloxanized rats at 30, 60
and 90 min after administration23.
Momordica
charantia
Cucurbitaceae)

L.

(Family:

Common name is karela in Hindi and


bittergourd in English. The anti-diabetic
potential of Momordica charantia is well
established in streptozocin or alloxan induced
diabetic animals. Momordica charantia
displays insulin-like properties, remarkably
Current R&D Highlights, Jan.-Mar. 2009

Commonly known as Kadavanchi in


Hindi. It exhibited both hypoglycemic as well
as hypolipidemic properties. Its powdered fruit
exhibited significant reduction in fasting blood
glucose levels in alloxanized rats23.
Morus alba L. (Family: Moraceae)
Commonly known as Shetut in Hindi and
White Mulberry in English. Hot water extract
of leaves of M. alba showed hypoglycemic
activity in fasted and non-fasted STZ diabetic
mice at the dose of 200 mg/kg23.
Mucuna pruriens
Leguminosae)

(L.)

DC.

(Family:

It is called as Kavach in Hindi and


Cowitch in English. In normal rats, at the the
oral administration of 100 and 200 mg/kg body
weight, the aqueous extract of the seeds of M.
pruriens significantly reduced the blood
glucose levels after an oral glucose load from
127.53.2 to 75.64.8 mg %. It also
significantly lowered the blood glucose in STZ
diabetic rats from 240.57.2 to 90.65.6 mg %
after 21 days of daily oral administration of the
extract (Pb0.001)9.
Murraya koeingii (L.) Spreng. (Family:
Rutaceae)
One month oral administration of M.
koenigii aqueous leaves extract in STZ induced
severe diabetic rats, at the dose of 300 mg/kg
body weight fasting blood glucose (FBG)
levels reduced by 48.2% after 30 days
13

Feature
treatment with the aqueous leaves extract. A
fall of 19.2 and 30.8% in total cholesterol (TC)
and 22.97 and 37.1% in triglyceride (TG)
levels were also observed in the case of treated
normal as well as diabetic rats, respectively.
Feeding the extract increased the HDLcholesterol level by 16 and 29.4% in normal
and diabetic rats, respectively, as compared
with their initial values. In the normal rats after
1 month of oral administration of the extract
serum glutamate oxaloacetate and pyruvate
transaminases (SGOT and SGPT) levels were
decreased by 21.7 and 25.0%. Serum alkaline
phosphatase values of the treated normal
animals were also reduced by 33% while
negligible change was observed in the normal
control animals. In the case of diabetic rats,
SGOT and SGPT levels were reduced by 36.7
and 32.2%, respectively, whereas phosphatase
(ALKP) levels decreased by 39.7%. The serum
creatinine levels decrease in normal as well as
in the diabetic animals by 17.75 and 18.2%,
respectively, as compared to initial values. In
the diabetic control animals the urinary sugar
remains at +4 level but there was a decrease of
75% in urine sugar in the case of treated
diabetic rats 37.
Musa sapientum L. (Family: Musaceae)
Commonly known as Kela in Hindi and
Banana in English. Oral administration of
0.15, 0.20 and 0.25 g/kg of chloroform extract
of the M. sapientum flowers for 30 days
resulted in a significant reduction in blood
glucose, glycosylated haemoglobin and an
increase in total haemoglobin, but in the case
of 0.25 g/kg the effect was highly significant.
It also prevents decrease in body weight. There
was a significant improvement in glucose
tolerance in treated animals and the effect was
compared with glibenclamide57.
Nelumbo
nucifera
Nymphaeaceae)

Gaertn.

(Family:

This is aquatic plant known as Kamal in


Hindi and Lotus in English. Ethanolic extract
of the rhizome of N. nucifera suppressed blood
14

glucose levels in normal, glucose-fed


hyperglycemic, insulin-treated and diabetic
rats. The extract improved glucose tolerance
and potentiated the action of exogenously
injected insulin, The hypoglycemic potential of
the extract was comparable with that of
tolbutamide in normal and diabetic rats. It was
observed that in normal and diabetic rats, the
activity of the extract was 73 and 67%
compared with that of tolbutamide,
respectively49.
Nigella sativa (Family: Ranunculaceae)
Nigella sativa seeds, commonly known as
Black cumin have been used traditionally for
treating diabetes. The aqueous extract of N.
sativa at 0.1 pg/ml to 100 ng/ml, exerted dosedependent inhibition of sodium-dependent
glucose transport across isolated rat jejunum.
Chronic N. sativa treatment improved glucose
tolerance as efficiently as metformin. It also
reduced body weight without any toxic
effect45.
Ocimum sanctum (Family: Lamiaceae)
Common name is tulsi in Hindi and Basil
in English. The hypoglycemic effect of the
alcoholic extract of leaves of Ocimum sanctum
was investigated in both normal and alloxaninduced diabetic rats. Alcoholic extract of
leaves of O. sanctum reduced blood sugar
levels 204.48 11.0 to 131.43 7.86 in
normal rats and 73.54 3.7 to 61.44 2.3 in
diabetic rats significantly (p<0.001). In
addition, the extract also showed a favorable
effect on glucose disposition in glucose fed
hyperglycemic rats77.
Phyllanthus
amarus
Schumach.
&
Thonn./Phyllanthus
niruri
(Family:
Euphorbiaceae)
Commonly known as Jangli Amla in
Hindi. Oral administration of 5 g/day of a
preparation of the whole plant for 10 days
reduces blood glucose in diabetic as well as
nondiabetic subjects23.
Picrorrhiza kurroa Royle ex Benth. (Family:
Current R&D Highlights, Jan.-Mar. 2009

Feature
Scrophulariaceae)

be the possible target for their activity75.

Alcoholic extract of P. kurroa at the dose


of 75 mg/kg reduced serum glucose by 43 %
and at 150 mg/kg reduced by 60%33.

Pterocarpus
Fabaceae)

Pongamia pinnata (Family: Fabaceae)


Commonly known as Karanja in Hindi.
The oral administration of ethanolic extract of
Pongamia pinnata flowers at a dose of 300
mg/kg body weight showed significant
antihyperglycemic, and antilipidperoxidative
effects and enhancement in antioxidants
defense system in alloxan induced diabetic
rats. It considerably reduced the blood glucose
concentration in a similar extent to that of the
reference drug glibenclamide (600 g/kg body
weight) in alloxan induced diabetic rats60.
Antidiabetic potential of the compounds
pongamol and karanjin isolated from
Pongamia
have
been
proved.
In
streptozotocin-induced diabetic rats, single
dose treatment of pongamol and karanjin
lowered the blood glucose level by 12.8%
(p<0.05) and 11.7% (p<0.05) at 50mg /kg dose
and 22.0% (p<0.01) and 20.7% (p<0.01) at
100 mg/kg dose, respectively after 6 h postoral administration. The compounds also
significantly lowered blood glucose level in
db/db mice with percent activity of 35.7
(p<0.01) and 30.6 (p<0.01), respectively at 100
mg/kg dose after consecutive treatment for 10
days. The compounds were observed to exert a
significant inhibitory effect on enzyme protein
tyrosine phosphatase-1B. The results showed
that pongamol and karangin isolated from the
O

OCH3

OH

pongamol

O
Karanjin

fruits of P. pinnata possesses significant


antihyperglycemic activity in Streptozotocininduced diabetic rats and type 2 diabetic db/db
mice and protein tyrosine phosphatase-1B may
Current R&D Highlights, Jan.-Mar. 2009

Roxb.

(Family:

Common name is Vijaysar in Hindi and


Indian Malabar in English. Pterostilbene
(trans-3,5-dimethoxy-4-hydroxystilbene),
a
constituent derived from wood of Pterocarpus
marsupium caused hypoglycemia in dogs (at
the dose of 10 mg/kg IV). Higher dose (20, 30
and 50 mg/kg) caused initial hyperglycemia
followed by hypoglycemia lasting for nearly
5h26. (-) Epicatechin, Marsupsin, Pterosupin,
Pterostilbene, isolated from the bark and
heartwood of the plant possess blood sugar
lowering activity (Mukherjee et al., 2006).
OH
HO

HO

OH
CH2

OH
OCH 3 O

OH
OH

OH
M arsupsin

(-) Epicatechin

OH
HO

OH

H 3 CO

Glc
OH

OH

Pterosupin

OCH 3
Pterostilbene

Punica granatum L. (Family: Punicaceae)


Commonly known as Pomegranate. 50%
ethanolic extract of flower showed blood
glucose lowering activity in glucose fed and
alloxanized hyperglycemic rats. At the doses
of 150, 300, 600 mg/kg showed hypoglycemic
activity 12 hour after administration in STZdiabetic rats48.
Ricinus communis (Family: Euphorbiaceae)

O
OCH3

marsupium

Commonly known as Eranda or


Gandharva hasta in Hindi and Castor in
English. 50% ethanolic extract of roots of R.
communis at the dose of five-hundred
milligram per kilogram body weight caused
maximum lowering of the fasting blood
glucose, both in normal as well as type 1
diabetic animals. It was considered as effective
dose. Administration of the effective dose to
15

Feature
the diabetic rats for 20 days showed favorable
effects not only on fasting blood glucose, but
also on total lipid profile and liver and kidney
functions on 10th and 20th day68.
Rosmarinus officinalis (Family: Labiatae)
Commonly
known
as
Rosemary.
Hypoglycaemic effects of oral administration
of various doses (50, 100 and 200 mg/kg) of
the extract were examined in normoglycaemic
and glucose-hyperglycaemic rabbits. Optimal
effect was observed in both of the animal
groups with a dose of 200 mg/kg of the extract
and this activity was independent from the
effects of insulin. Acute effect of various doses
of the R. officinalis extract on blood glucose
and serum insulin levels was studied in
alloxan-induced diabetic rabbits. Of the three
doses of extract, the highest dose (200 mg/kg)
significantly lowered blood glucose level and
increased serum insulin concentration in
alloxan-diabetic rabbits. At the doses of 100
and 200 mg/kg, antihyperglycaemic effect of
extract was accompanied by a significant
increase in serum insulin levels in diabetic
rabbits. Furthermore, during 1 week of
treatment of diabetic rabbits with a dose of 200
mg/kg of the extract showed that the extract
possessed a capability to inhibit the lipid
peroxidation and activate the antioxidant
enzymes7.
Salacia oblonga Wall. (Family: Celastaceae)
S. oblonga root is an Ayurvedic medicine
with anti-diabetic and anti-obese properties.
Chronic oral administration of the water
extract from the root of S. oblonga to Zucker
diabetic fatty rats, a genetic model of type 2
diabetes and obesity, lowered plasma
triglyceride and total cholesterol levels,
increased plasma high-density lipoprotein
levels and reduced the liver contents of
triglyceride, non-esterified fatty acids and the
ratio of fatty droplets to total tissue. By
contrast, the extract had no effect on plasma
triglyceride and total cholesterol levels in
fasted Zucker diabetic fatty rats29.
16

Salacia
reticulata
Celastaceae)

Wight.

(Family:

Commonly known as Kothala himbutu.


Aqueous extracts of Kothala himbutu stems
decreases fasting blood glucose levels. Results
demonstrate that it exerts its effect by
gluconeogenic gene regulation in traditional
diabetic medicine30.
Scoparia
dulcis
Scrophulariaceae)

L.

(Family:

Commonly known as Sweet Broomweed.


The administration of an aqueous extract of . S.
dulcis at a dose of 200 mg/kg body weight
significantly decreased the blood glucose with
significant increase in plasma insulin level in
streptozotocin diabetic rats at the end of 15
days treatment. S. dulcis plant extract protected
against streptozotocin- mediated cytotoxicity
(88%) and NO production in rat insulinoma
cell line (RINm5F). Results suggest its glucose
lowering effect to be associated with
potentiation of insulin release from pancreatic
islets41.
Sida cordifolia L. (Family: Malvaceae)
Commonly known as Bala. It is used in
Ayurvedic medicine. S. cordifolia extracts of
the aerial and root parts showed good
analgesic,
antiinflammatory
and
hypoglycaemic activities. The methanol
extract of root was found to possess significant
hypoglycaemic activity36.
Swertia chirayita (Roxb. ex Fleming) H.
Karst. (Family: Gentianaceae)
Hexane fraction of S. chirayita at the dose
of 250 mg/kg body weight induced significant
fall in blood sugar in albino rats. Daily
administration for 28 days resulted in
significant lowering of blood sugar and
increase in plasma IRI along with a significant
rise in liver glycogen. Intestinal absorption of
glucose was not inhibited by hexane fraction.
It is suggested that hexane fraction of S.
chirayita possibly acts through its insulin
releasing effect11. A xanthone was isolated
Current R&D Highlights, Jan.-Mar. 2009

Feature
from the hexane fraction of the plant,
identified as 1,8-dihydroxy-3,5-dimethoxyxanthone (swerchirin). It has a very significant
blood sugar lowering effect in fasted, fed,
glucose loaded, and tolbutamide pretreated
albino rat models. The ED50 for 40% blood
sugar lowering in CF male albino rats (body
weight 140-165 g) is 23.1 mg/kg/oral8.
O
O

OH
OH O
Swerchirin

Syzigium cumini/ Eugenia jambolana Lam.


(Family: Myrtaceae)
Administration of the extract for 6 weeks
resulted in significant reductions in plasma
lipid peroxide, ceruloplasmin and -tocopherol
and a significant elevation in plasma reduced
glutathione and vitamin C in alloxan diabetic
rats. Insulin restored all the parameters to their
normal values. The seed extract was also more
effective than glibenclamide in restoring the
values of these parameters58,59. Oral
administration of 2.5 and 5.0 g/kg body weight
of the aqueous extract of the seed for 6 weeks
resulted in a significant reduction in blood
glucose and an increase in total haemoglobin,
but in the case of 7.5 g/kg body weight the
effect was not significant. It also prevents
decrease in body weight. The aqueous extract
also resulted in decreased free radical
formation in tissues studied. Thus the study
shows that Jamun seed extract (JSEt) has
hypoglycaemic action. The decrease in
thiobarbituric acid reactive substances
(TBARS) and increase in reduced glutathione
(GSH), superoxide dismutase (SOD) and
catalase (CAT) clearly show the antioxidant
property of the JSEt. The effect of JSEt was
most prominently seen in the case of animals
given 5.0 g/kg body weight. JSEt was more
effective than glibenclamide. 58,59

Current R&D Highlights, Jan.-Mar. 2009

Terminalia
catappa
Combretaceae)

L.

(Family:

Commonly known as Badam in Hindi and


Indian Almond Tree in English. Terminalia
catappa fruit extracts have good antidiabetic
activity. Petroleum ether, methanol and
aqueous extracts of T. catappa produced a
significant antidiabetic activity at dose levels
1/5 of their lethal doses. Methanol and aqueous
extracts of Terminalia catappa exhibited
significant anti-hyperglycemic activities in
alloxaninduced hyperglycemic rats without
significant change in body weight51.
Terminalia pallida
Combretaceae)

Brandis

(Family:

Different doses of ethanolic fraction of


fruits of Terminalia pallida were evaluated for
hypoglycemic and antihyperglycemic activity
in normal and alloxan diabetic rats. The oral
administration of ethanolic extract at a dosage
of 0.5 g/kg body weight exhibited a significant
antihyperglycemic activity in alloxan diabetic
rats, whereas in normal rats no hypoglycemic
activity was observed61.
Trigonella foenum graecum L. (Family:
Fabaceae)
Commonly
known
as
fenugreek.
Galactomannan, extracted from T. foenum
reported to reduce postprandial blood glucose
response. Using this fiber, extracted from The
segments of jejunum and ileum from
genetically determined lean and obese rats
were incubated with labeled glucose (2 or 32
mmol/L) in the presence of different
concentrations of galactomannan ranging from
0.1% to 0.5% (wt/wt). The uptake of low or
high concentration of glucose was significantly
and progressively reduced by increasing
concentrations of galactomannan in both lean
and obese rats. No significant difference was
observed in the uptake of glucose between the
2 groups. The viscosity of various
concentrations of galactomannan solutions was
determined after stirring for 60 minutes at a
temperature-controlled (37C) fixed sheer rate
17

Feature
of 1.29 (1/s). The inhibitory effect of
galactomannan on glucose uptake was found to
be in parallel with the degree of viscosity of
the fiber solutions. Because of its viscous
property, galactomannan has the potential to
reduce intestinal absorption of low or high
concentrations of glucose and hence for the
benefit of blood glucose management72 .
Tinospora
cordifolia
Menispermaceae)

(Family:

Commonly known as Giloe in Hindi.


Treatment with plant extract showed
significant anti-hyperglycemic activity in mild
to moderate degree of hyperglycemia. In mild
diabetes, the maximum percent reduction in
glucose levels was 70.37%, seen in groups
receiving 400 mg/kg/day of aqueous extract of
T. cordifolia. In moderate diabetes, 4 months
of T. cordifolia treatment resulted in a
moderate reduction in plasma glucose level of
48.81%. In severe diabetes, it did not show any
reduction in plasma glucose level. Since the
percentage fall in plasma glucose levels was
different in models with varying intensity of
hyperglycemia, it implies that the antihyperglycemic effect of these plants is
dependent upon the dose of diabetogenic agent
and therefore on the degree of -cell
destruction23.

Withania coagulans (Family: Solanaceae)


Commonly known as Paneer ke phool
in Hindi and Vegetable Rennet in English. At
the dose of 1 g/kg of aqueous extract of fruits
of W. coagulans significantly lowered the
blood sugar, serum cholesterol, serum LPO
and hepatic LPO levels in streptozotocin
induced diabetic rats after 7 days of treatment
(p<0.001). It also significantly (p<0.01)
decreased blood glucose level in normal rats
(at the dose 1 g/kg; po)28. Coagulin C, 17hydroxywithanolide K, withanolide F,
coagulanolide and coagulin L, isolated from
the fruits, showed significant inhibition on
postprandial rise in hyperglycemia post
sucrose load in normoglycemic rats and in
streptozotocin-induced diabetic rats. Coagulin
L showed significant fall in peripheral blood
glucose profile and also improved the glucose
tolerance of db/db mice. It also showed
antidyslipidemic activity in db/db mice that is
comparable to median effective dose of
fenofibrate i.e., 50 mg/kg body weight. The
median effective dose of the coagulin L was
determined to be around 25 mg/kg in
streptozotocin-induced diabetic rats, which is
better than the standard drug metformin.
Beside this, coagulin L also showed
antidyslipidemic activity in db/db mice44.

OH
HO
O

H O
O

O O

H
H

OH

H O
OH

OH

OH
O

H O
OH

H
OH

OH

HO
HO

18

officinale

Roscoe

OH

O
OH
Coagulin L

Coagulanolide

Zingiber

OH
H O
OH

HO

OH

Withanolide F

17-Hydroxywithanolide K

Coagulin C

H O
OH

(Family:

Zingiberaceae)
Current R&D Highlights, Jan.-Mar. 2009

Feature
Commonly known as Adrak in Hindi and
Ginger in English. Treatment with Z. officinale
produced a significant increase in insulin
levels and a decrease in fasting glucose levels
in diabetic rats. In an oral glucose tolerance
test, treatment with Z. officinale was found to
decrease significantly the area under the curve
of glucose and to increase the area under the
curve of insulin in STZ-diabetic rats.
Treatment with Z. officinale also caused a
decrease in serum cholesterol, serum
triglyceride and blood pressure in diabetic
rats3. 6-shogaol (6S) and 6-gingerol (6G),
present in Z. officinale significantly inhibited
the tumor necrosis factor- (TNF-) mediated
downregulation of the adiponectin expression
in 3T3-L1 adipocytes. 6S functions as a
PPAR agonist with its inhibitory mechanism
due to the PPAR transactivation, and 6G is an
effective inhibitor of TNF- induced c-JunNH2-terminal kinase signaling activation and
thus, its inhibitory mechanism is due to this
inhibitory effect99.

Conclusion
Treatment of diabetes with synthetic drugs
is associated with several complications. The
most severe complication associated is
condition of hypoglycemia. Plants and natural
products are in use to prevent and cure
diabetes since past. They show comparatively
less or no side effects. As far as cost is
concerned, herbal treatment is cheaper than
synthetic drugs. A wide and diverse range of
plants is reported to prevent and treat diabetes.
A lot of work has been done on the
antidiabetic potential of various plants by
numerous workers. We have worked on
Pongamia pinnata, Pterocarpus marsupium,
Withania coagulans, Zingiber officinale and
Ficus racemosa and have isolated antidiabetic
principals from them. There is endless scope in
natural product chemistry for the identification
of active leads. Immense work is needed to
make new drugs for diabetes of natural origin.
Active leads can be derivatized to ameliorate
their antidiabetic potential
8.

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Current R&D Highlights, Jan.-Mar. 2009

21

Feature

Development of the Thiazolidinediones as PPAR


Agonists for the Treatment of Type 2 Diabetes
Saman Raza and Seturam B. Katti*
Medicinal and Process Chemistry Division,
Central Drug Research Institute, Lucknow

Introduction
Diabetes mellitus (DM) is a major and
growing public health problem throughout the
world. Diabetes has reached epidemic
proportions and affects more than 170 million
individuals worldwide. It is a disease
characterized by high levels of blood glucose
resulting from defects in: insulin production,
insulin action or both. The basic types of
diabetes mellitus are type 1 and type 2. Type 1
(insulin dependant) DM can occur at any age
and is characterized by the marked and
progressive inability of the pancreas to secrete
insulin because of autoimmune destruction of
the beta cells. Therefore, these patients are
dependent on exogenous insulin.
Type 2 (non-insulin-dependent) DM,
which affects 90% of diabetic individuals, is
more of a lifestyle related disorder, with
obesity being a major risk factor for its
development. It is characterized by insulin
resistance: the inability of insulin-sensitive
tissues to respond to normal circulating
concentrations of insulin. To offset resistance
to insulin, the beta cells of the pancreas
increase insulin secretion. However over time,
beta-cell function deteriorates, less insulin is
secreted and hyperglycemia
develops.
Treatment of type 2 diabetes is aimed at
22

lowering insulin resistance and increasing


function of beta cells. Current therapeutic
approaches for type 2 DM include: 1) insulin;
2) enhancers of insulin release eg.
Sulfonylureas, Dipeptidyl Peptidase IV (DPP4) Inhibitors and Meglitinides; 3) inhibitors of
hepatic glucose production eg. biguanides; 4)
inhibitors of glucose uptake eg. -glucosidase
inhibitors; and 5) insulin sensitizers eg.
peroxisome proliferator-activated receptor
(PPAR ) agonists [1]. As the number and types
of the therapeutic options are so vast and
varied, it is not possible to elaborate on all of
them and hence we have chosen to focus on
the one which is of particular interest to
researchers today, that is: PPAR PPAR
agonists, dual and pan agonists as well as
PPAR modulators have become exciting
therapeutic targets for type 2 diabetes as they
also address the complications related with
diabetes.

Peroxisome
Proliferator-activated
Receptor Gamma (PPAR ) Role in
Type 2 Diabetes
The peroxisome proliferator-activated
receptors belong to the superfamily of nuclear
receptors and are ligand-activated transcription
factors. There are three PPAR isoforms, which
are the products of distinct genes and are
Current R&D Highlights, Jan.-Mar. 2009

Feature
commonly designated as PPAR , PPAR and
PPAR /
. The three subtypes of PPAR bind
to fatty acids and fatty acid metabolites and
regulate the expression of genes involved in
the transport, metabolism and buffering of
these ligands within the cells. PPARs are
known to be activated by a wide array of
structurally diverse ligands, ranging from
prostaglandins and thiazolidinediones(TZDs)
to fibrates, eicosanoids, nonsteroidal NSAIDs,
glucocorticoids, PUFAs, and aromatic fatty
acids[2].
While PPAR regulates fatty acid
oxidation and PPAR is involved in
cholesterol homeostasis, PPAR agonists
regulate adipogenesis and are effective insulin
sensitizers. Thus, the PPARs possess the
ability to address many features of the diabetic
phenotype. PPAR agonists and PPAR /
dual agonists are interesting compounds for the
development of anti-diabetic agents. PPAR
agonists reduce plasma glucose, lipids and
insulin levels in type 2 diabetic patients while
PPAR / dual agonists improve both lipid
metabolism and glucose tolerance- two key
factors in the treatment of type 2 diabetes.

Synthetic Agonists of PPAR -G


eneral
Structure
As the role of PPAR in adipogenesis,
energy storage and insulin sensitization came
into light, it quickly evolved over the last
decade from a new orphan receptor to one of
the best characterized nuclear receptors.
Structures of the ligand binding domain (LBD)
of the PPARs in the absence and presence of
ligands have been solved by x-ray
crystallography. The solved structures for
ligand-bound PPARs reveal that its agonists,
such as TZDs, fibrates and fatty acids, share a
common binding mode in which their acidic
head groups participate in a hydrogen bonding
network within a Y-shaped ligand binding
pocket in the ligand binding domain of the
receptor [3].
Guided by the mutual pharmacophore, the
Current R&D Highlights, Jan.-Mar. 2009

general structure of PPAR as well as /


agonists can be divided into three regions:
A is the acidic head group,
B is the central spacer group, and
C is the linear lipophilic tail group (figure 1).

Figure 1: General structure of PPAR and /


agonists

The spacer connecting the lipophilic


heterocyclic tail and the central ring of the
molecule has been examined. The compounds
with three carbon spacer seem to be favorable
for agonism of PPAR over those with two
carbon atoms [4]. Variation of the length of the
spacer could alter its in vitro functional
activity profile without regularity.
For the lipophilic tail a variety of aryl and
heteroaryl groups such as, pyridyl, oxazoyl,
benzoxazoyl have been found to be tolerated.
Also, when one tries to rationalize the shape of
the heterocyclic moiety, the planar heterocycle
is preferred.
The desired linker fragment between the
head group (2,4-thiazolidinedione) and the
central spacer group has been suggested to be
the methylene moiety. Any deviation in the
linker fragment length has been reported to
reduce the PPAR activity.
Based on the chemical structure, some of
the PPAR agonists have been broadly
classified as follows:
1.The first generation thiazolidinediones
2.The second generation glitazones:
23

Feature
compounds with tail group modifications

3.Compounds with head group modifications.


O

NH
O

NH
O

Ciglitazone

S
O

NH
O

HO

Troglitazone

NH

S
O

Rosiglitazone

S
O

Pioglitazone

Figure 2: Structures of the first generation glitazones

1. The Thiazolidinediones or Glitazones


The TZDs (figure 2) were developed over
a period of 15 years through empirical
compound screening in rodent models of
insulin
resistance.
Ever
since
a
thiazolidinedione-based
compound,
ciglitazone, was developed from a class of
fibrate lipid-lowering agents and was reported
as a novel anti-diabetic agent that enhanced
insulin sensitivity in patients with type-2
diabetes, many studies on new analogues have
been carried out.
The molecular mechanism of action of the
TZDs remained unknown until several reports
in the mid-1990s suggested a possible
connection between these agents and the
PPARs. In 1995,
Lehmann et al [5] made the important
discovery that the TZDs were potent and
selective activators of PPAR .
Troglitazone was derived from ciglitazone
by replacing the lipophilic tail (which is a
methylcyclohexylmethyl ether moiety), with a
vitamin E residue [6]. Troglitazone (Rezulin),
was the first TZD to reach the market as an
anti-diabetic agent, but was withdrawn from
clinical use in 2000 due to reports of severe,
idiosyncratic hepatotoxicity [7].
Two TZDs approved for clinical use today
are rosiglitazone (Avandia) and pioglitazone
(Actos); both have a pyridyl tail group.

24

In general, pioglitazone and rosiglitazone


have similar clinical efficacy with both
demonstrating improvements in insulin
sensitivity and the ability to lower fasting
plasma glucose levels [8]. However one
potential area of distinction between these two
TZDs is the greater impact of pioglitazone on
diabetic dyslipidemia. Although pioglitazone
was initially found to be a PPAR agonist,
additional preclinical data show that this
compound has some, although minimal,
activity on PPAR as well in standard
cotransfection (CTF) assays [9]. Consistent
with these data are clinical findings showing
that pioglitazone has beneficial effects on
lipids not seen with rosiglitazone, which is a
pure PPAR agonist.
In addition to the improvement in
glycemic control, the glitazones have a
beneficial effect on many of the traditional as
well as the new risk factors and can help
inpreventing or lessening the impact of the
cardiovascular consequences of type 2
diabetes. They have been shown to lower the
levels of atherogenic dyslipidemia, lower
blood pressure [10] as well as visceral obesity,
lessen the levels of the pro-inflammatory and
pro-thrombotic cytokines and adipokines as
well as increase the levels of the antiatherogenic adinopectin. Unfortunately, these
compounds are also associated with the side
effects of obesity, hemodilution and edema [8].
Thus, there is significant interest in the design
Current R&D Highlights, Jan.-Mar. 2009

Feature
of novel PPAR modulating drugs that retain
efficacious insulin sensitizing properties while

minimizing potential adverse side effects.

O
O

NH

BRL-48482

N
H

NH
S

F3 C

Englitazone

NH

PAT5A

DRF-2189

NH

NH
S

KRP-297
OCH 3

O
R

NH
O

COOCH3

Netoglitazone (X=C, R=F)


NC-2100
(X=N, R=H)

H3 CO

NH
O

S
O

CLX-0921

Figure 3: Structure of the Second Generation Glitazones

2. The Second Generation Glitazones:


Compounds With Tail Group Modifications
In an effort to reduce the side effects
associated with the glitazones, the second
generation glitazones were developed. Some of
these compounds have been profiled here.
They include netoglitazone (MCC-555),
rivoglitazone (CS-011), CLX-0921, DRF2189, ciglitazone, englitazone, NIP-221 and
NIP-223 among others (figure 3).
The glitazones MCC-555 and NC-2100,
which contain a naphthalene moiety as the
central linker group, represent a second class
of PPAR modulators[11].These structurally
related glitazones (MCC-555: X=C, R=F; NC2100: X=N, R=H; figure 3) profile as weakbinding full agonists in cell-based reporter
assays. Both MCC-555 and NC-2100 promote
adipocyte differentiation in cell culture. MCC555 and NC-2100 each possess in vivo activity
in obese insulin-resistant mice comparable to
Current R&D Highlights, Jan.-Mar. 2009

rosiglitazone despite their weak agonist


profiles. In mice, NC-2100 produced less
weight gain compared to other glitazones when
similar mice maintained comparable levels of
glycemic control.
CS-011(rivoglitazone) which has a
benzimidazolyl tail group, was reported to be
approximately three times more active than
rosiglitazone in a cell based PPAR
transfection assay. In vivo, it was found to be
more potent than rosiglitazone, which can be
explained not only by the enhanced in vitro
activity but also by its longer half life [12]. CS011 is in Phase I trials in US.
The TZD analog KRP- 297(MK767) is a
PPAR agonist with similar affinity for PPAR
. In vivo, KRP-297 has been reported to
improve abnormal lipid metabolism in liver
and elicit hypoglycemic, hypoinsulinemic and
hypolipidemic conditions in obese rats [13].
However, further development of KRP297 was
25

Feature
recently terminated, owing to findings of a rare
malignant tumor in mice.

3.
Compounds
Modifications

CLX-0921, that is derived from a natural


product and has a polyphenol based structure
is another second generation glitazone which
has shown encouraging findings in early
clinical testing. This TZD has a spectrum of
activity that differs from commercially
available TZDs. It is a weak activator of PPAR
compared to rosiglitazone. Despite this
difference, the drug maintains potent glucose
uptake activity in vitro and glucose-lowering
activity in vivo that is equipotent to that of
Rosiglitazone [14].

Since the structure of the thiazolidine-2, 4dione ring was considered to be optimum and
the acidic functionality of the ring was
considered to be essential for its insulinsensitizing activity, replacement of this ring
has been tried using closely related acidic
heterocyclic rings as well as acyclic acidic
moieties.

DRF-2189 has an indole based tail group


and was reported to be equipotent to
rosiglitazone yet distinct from it in its ability to
lower cholesterol [15].
Benzoxazole derivatives such as BRL
48482 have been reported to have potent
agonism to PPAR , comparable to
rosiglitazone.
Balaglitazone (DRF2593) is a PPAR
partial agonist that recently completed Phase II
clinical trials and results from these studies
show that treatment with balaglitazone led to
significant improvement in glycemic control
and HDL-C level, with minimum side effects
[16]
.
Another interesting compound in this
category is PAT5A which has a pyridinyl
pyrolidide tail group and a chemically distinct
unsaturated linker fragment. PAT5A is a
PPAR partial agonist with a minimal amount
of PPAR activity. In contrast to
rosiglitazone, PAT5A inhibits cholesterol and
fatty acid biosynthesis suggesting that PAT5A
possesses a unique receptor independent nonPPAR related property. As expected,
administration of PAT5A to a rodent model of
type 2 diabetes (db/db mice) resulted in a dosedependent reduction in plasma glucose that
was similar to that seen with rosiglitazone but
with less drug-induced weight gain[17].
26

with

Head

Group

3.1. Compounds with Isoxazolidinedione


Based Head Group
Replacement of the thiazolidine-2, 4-dione
ring with an oxazolidine-2, 4-dione ring or a 1oxa-2,4-diazolidine-3,5-dione ring led to
decreased activity. JTT-501(Figure 4), an
isoxazolidine-3, 5-dione, was designed as a
more acidic heterocyclic compound than
thiazolidine-2,4-dione. Although JTT-501 was
less potent than its parent (a TZD with a
phenyl oxazolidine tail group), the side-effect
profile was improved. It was found that JTT501 is a PPAR agonist that possesses some
PPAR activity [18].
Its activity is believed to be mediated
through a malonic amide metabolite derived
from hydrolysis of the heterocyclic head
group.
O
O
N

NH
O

Figure 4: JTT-501

3.2. Compounds with Acyclic Head Groups


Replacement of the thiazolidine-2,4-dione
ring with acyclic structures, such as
carbonylated hydroxyureas, -heteroatomsubstituted
carboxylic
acids,
-carbon
substituted carboxylic acids and 1,3-dicarbonyl
compounds, was unexpectedly successful.
Current R&D Highlights, Jan.-Mar. 2009

Feature
a) A Carboxylated Hydroxyurea: The
first acyclic non-carboxylic acid compound,
was able to normalize blood glucose level in
an in vivo study [19].

CO 2H
N

O
O
N

N
O

CF3

SB-219994
CO 2H

NH2
OCH

O
O

Figure 5: Carboxylated Hydroxyurea Derivative

b)
-Carbon
Substituted
Phenylpropanoic Acid Based PPAR
Agonists: The thiazolidine-2,4-dione ring can
be replaced by -acyl-, -alkyl- and (aralkyl)-carboxylic acids. Inclusion of an
additional
lipophilic
moiety
affords
compounds which are equipotent to BRL
48482. These results were surprising since it
had previously been shown that in the
heterocyclic series, the thiazolidine-2, 4-dione
ring was preferred over the oxazolidine-2, 4dione. It was assumed that the role of the
acidic thiazolidine-2,4-dione was played by
carboxylic acid in these compounds and that
an appropriate substituent at the -position
could alter the chemical environment around
the carboxylic acid in such a way that the
whole group came to mimic the thiazolidine2,4-dione ring. Higher binding affinities and
functional activity for PPAR were observed
for the (S)-enantiomers of this series.
Several -oxy-acids showed activities an
order of magnitude more potent than BRL48482. In particular the -ethoxyacid SB
213068 is one of the most potent antihyperglycemic agents yet reported[20](figure
6).

Current R&D Highlights, Jan.-Mar. 2009

SB-213068

Figure 6: -Oxy-acid Based PPAR Agonists

The PPAR / dual agonists


muraglitazar, tesaglitazar, naveglitazar and
ragaglitazar belong to this class of compounds
(figure 7).
Muraglitazar
(N-[(4-methoxyphenoxy)
carbonyl]-N-{4-[2-(5-methyl-2-phenyl-1,3
oxazol-4-yl)ethoxy]benzyl}glycine),
demonstrated significant glucose lowering,
reduction in triglycerides and increase in HDLC in patients with type 2 diabetes, in early
clinical studies[21].
Tesaglitazar
(2S)-2-Ethoxy-3-[4-[2-(4methylsulfonyl oxyphenyl) ethoxy] phenyl]
propanoic acid), is an orally active, potent
PPAR / dual agonist under development
for the potential improvement of dyslipidemia
and glycemic control in individuals with type 2
diabetes [22]. However in 2006, its further
development was discontinued, after several
phase III clinical trials.
Naveglitazar( -methoxy-4-[3-(phenoxyphenoxy)propoxy]phenylpropanoic acid) is
another interesting PPAR / dual agonist in
clinical development. Data from a recent Phase
II clinical

27

Feature
O
S
O
O

H 3C
CO 2H

O
N

CO2 H

Ragaglitazar

Tesaglitazar
CO2 H

N
O

O
O

OCH 3

CO2 H

Muraglitazar

Aleglitazar

Figure 7: Structures of a Few PPAR / Dual Agonists

trial in patients with type 2 diabetes showed


that naveglitazar administration resulted in
significant reductions in mean fasting serum
glucose levels from baseline compared with
placebo at all doses and triglyceride levels
were also significantly reduced[23].
Aleglitazar ((2S)-2-methoxy-3-[4-[2-(5methyl-2-phenyl-4-oxazolyl)
ethoxy]7benzothiophenyl]propanoic acid ) is another
PPAR / dual agonist. It is currently in
phase II clinical trials.
The PPAR / dual agonist TAK559 was
placed on clinical hold owing to findings of
abnormalities in liver enzymes in a small
number of patients during the course of the
Phase III studies. Further development of this
compound was discontinued in 2005.

advantages in preclinical models, ragaglitazar


(DRF2725, NN622), which has a phenoxazinyl
tail group, was suspended from clinical
development, owing to the development of
urine bladder tumors in rodents.
c) Tyrosine Based PPAR Agonists: A
series of tyrosine-based PPAR agonists have
also been developed [24] and represent some of
the most potent agonists reported to date
(figure 8). The (S)-enantiomers have been
shown to possess greater binding affinity and
functional activity at PPAR than the
corresponding (R)-enantiomers [25].
In cell based transactivation assays, these
analogs exhibit up to 1000-fold selectivity for
PPAR over the PPAR and PPAR
subtypes

Despite demonstrating glucose and lipid

CO2 H

CO2 H

O
O

HN

HN

CO2H

HN
H3CO 2C

Farglitazar

GW-1929

GW-7845

Figure 8: Tyrosine Based PPAR Agonists


28

Current R&D Highlights, Jan.-Mar. 2009

Feature
GW1929 possesses potent and efficacious anti-hyperglycemic activity in ZDF rats.
undesirable action of these agents, research is
Farglitazar has shown potent reduction of
glucose activity, reduction of triglycerides and now being done to develop partial PPAR /
agonists, which combine the beneficial
elevation of HDL cholesterol in diabetic
patients in Phase II studies. The positive lipid metabolic effects of PPAR and PPAR
effects of farglitazar may be due to residual activation with fewer side effects. Along with
PPAR activity in the compound [26]. the dual agonists, PPAR pan agonists are also
However, owing to side effects, its further being explored which would combine the
development has been discontinued
agonist activities of PPAR , PPAR and
PPAR in a single ligand and may prove to be
Conclusion
the ultimate combination of PPAR activities
The demonstration that PPAR was the
for the treatment of type 2 diabetes and its
receptor through which the glitazone drugs
further complications. Also, recent findings
mediate their biological activity has led to from genetic and pharmacologic studies
resurgence in nuclear receptor research to suggest that activating PPAR in moderation
develop drugs for diabetes and cardiovascular can lead to better therapeutic outcomes
disease. Knowledge of the molecular targets compared with modifying the receptor with a
for the glitazones has enabled medicinal high affinity, full agonist. These results have
chemists to synthesize a new generation of
been translated into the identification and
drugs that have been optimized for activity exploration of PPAR partial agonists and
against the human PPARs. Several of these
selective PPAR modulators (SPPARMs) which
drugs are currently in clinical development. would retain efficacious insulin sensitizing
Compounds with dual PPAR and PPAR
properties while minimizing the adverse side
activity, which may combine the benefits of
effects. With recent advances in our
insulin sensitization and lipid lowering into a
understanding of the molecular mechanism of
single drug, are also being investigated. The
PPAR action, the future holds great promise
safety liabilities of the dual agonists may be
towards
developing
anti-diabetic
the result of the imbalanced activities on PPARcompounds with greater efficacy as well
PPAR and PPAR . To overcome the
as reduced side effect profile.

References
1. Vats,R.K,Kumar,V,et al.,Current Science,
2005, 88, 241.
2. Kliewer SA, Lenhard JM, Lehmann JM.
Proc Natl Acad Sci USA, 1997, 94, 431823.
3. Nolte, R.T. et al., Nature, 1998, 395, 137143.
4. Y. Lu et al., Bioorg. Med. Chem. Lett.,
2006, 16 915919
5. Lehmann, J.M. et al., J. Biol. Chem., 1995,
270, 1295312956.
6. Yoshioka, T. et al., J. Med. Chem., 1989,
32, 421428
7. Press
Release:
21March,
2000,
lambert.com/press/release.asp?release=109
Current R&D Highlights, Jan.-Mar. 2009

8. Diamant, M. and Heine, R.J., Drugs, 2003,


63, 13731405.
9. Sakamoto, J. et al., Biochem. Biophys.Res.
Commun., 2000, 278, 704711.
10. Ryan, M.J. et al., Hypertension, 2004, 43,
661666.
11. Fukui, Y. et al., Diabetes, 2000, 49, 759767.
12. Araki K,Yachi M,Hagisawa Y et al.,
Diabetes, 2000, 49(Suppl.1):A-105.
13. Murakami, K. et al., Diabetes, 1998, 47,
1841-1847.
14. Medicheria S,Dey D,Neogi P et al.,
Diabetes,2000, 49(Suppl.1):475-P.
15. Lohray BB, Bhushan V, Rao BP et al.,
J.Med. Chem., 1998, 41 (10):1619-1630.
16. D. Koev, C. Ionescu-Trgoviste, A.
Rosenthal, et al., Diabetes, 2003, 52,
supplement 1, 530-P.
17. Vikramadithyan, et al., Metabolism, 2000,
29

Feature
49, 14171424.
18. Shinkai, H. et al., J. Med. Chem., 1998, 41,
1927-1933.
19. Goldstein, S.W. et al. J. Med. Chem., 1993,
36, 22382240.
20. Buckle, D. R., Cantello, B. C. C., Smith,
S.A. et al., Bioorg. Med. Chem. Lett.,
1996, 6, 2127-2130.
21. Buse J, Rubin C, Frederich R, et al. Clin
Ther., 2005, 27,11811195.
22. Wilding J.P, Gause-Nilsson I, Persson A.,

Diab Vasc Dis Res, 2007, 4 (3), 194203.


23. Prince, M. et al., Diabetes, 2004, 52
(Suppl. 2), A33.
24. Henke, B.R. et al., J. Med. Chem., 1998,
41, 5020-5036.
25. Collins, J.L. et al., J. Med. Chem., 1998,
41, 5037-5054.
26. Wilson, G.G. et al., Diabetes, 2000, 49, 39

Drugs and Pharmaceuticals

Current R & D Highlights


Title

30

Volume

No.

Biotherapeutics
Marine Based Bioactives
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Drug Targets

23
23
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1
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4

Month
Jan.,-March 2000
Apr.,-June 2000
July- Sept., 2000
Oct.,-Dec., 2000

Immunotherapeutics
Gene Therapy
Neurologicals
Bioinformatics

24
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24
24

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3
4

Jan.,-March 2001
Apr.,-June 2001
July- Sept.,2001
Oct.,-Dec., 2001

Protein Structure & Drug Discovery


Stem cell Research & Health Care
Chemoinformatics
Pharmacogenomics

25
25
25
25

1
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4

Jan.,-March 2002
Apr.,-June 2002
July- Sept., 2002
Oct.,-Dec., 2002

Emerging & Re-emerging Diseases


Recombinant Pharmaceutical Proteins
Opthalmic Disorders
Proteomics

26
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Jan.,-March 2003
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Musculosketel Disorders
Proteomics
Pharmacogenomics
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27
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27
27

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Jan.,-March 2004
Apr.,-June 2004
July- Sept., 2004
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Heart Failure
Osteoporosis
Asthma
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28
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Jan.,-March 2005
Apr.,-June 2005
July- Sept., 2005
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Ageing
Cancer
Tuberculosis
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29
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Jan.,-March 2006
Apr.,-June 2006
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30
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Psoriasis
Metabolic Syndrome
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31
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Jan.,-March 2008
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Current R&D Highlights, Jan.-Mar. 2009

Feature

Exploring Role of 5-Hydroxytryptamine in Diabetes


Mellitus and Cardiovascular Complications
Dr. Ramesh K. Goyal* & Hitesh B. Vaidya+
*The M. S. University of Baroda,Vadodara; +L.M.College of Pharmacy, Ahmedabad

The prevalence of type 2 diabetes has


surged in recent decades. A growing body of
work suggests not only that central neural
pathways may play an important role in
dysregulation of glucose homeostasis but also
that these pathways are potentially amenable to
therapeutic manipulation. Diabetes mellitus is
associated with regionally specific changes in
brain monoamines1 and the turnover rate of
monoamines is reportedly decreased in
diabetic rats2. Pharmacological compounds
augmenting the tone of the neurotransmitter
serotonin (5-hydroxytryptamine, 5-HT) were
investigated for the treatment of obesity, a
major risk factor for type 2 diabetes. However,
the possibility of a direct role for serotonin in
the pathophysiology and treatment of type 2
diabetes received little attention. Mental illness
can be a manifestation of a diabetic brain state
or a sort of cerebral diabetes3. Mania and
positive schizophrenia have been reported to
be
associated
with
hyperglycemia,
hyperdopaminergia,
hyperserotonergia,
whereas,
depression
and
negative
schizophrenia have been associated with
hypoglycemia,
hypodopaminergia
and
hyposerotonergia. This indicates link between
diabetes mellitus and neurotransmitters like 5HT and dopamine. In the present article we
have made an attempt to explore the role of 5HT in diabetes mellitus and cardiovascular
complication base on some of our own data.

5-HT Receptor Subtype and Diabetic


Mellitus
The association between 5-HT and its role
in glucose control has been a subject of
Current R&D Highlights, Jan.-Mar. 2009

controversy for last couple of decades. 5-HT is


shown to have differential effects on blood
glucose levels, that is, hyperglycemia and
hypoglycemia. Earlier studies reported that 5HT does produce hypoglycemia. In mice, it
has been reported that 5-HT precursor 5hydroxytryptophan
(5-HTP)
produces
hypoglycemia, and the effects of 5-HT are due
to formation of 5-HT4. It was shown that 5HTP causes accumulation of 5-HT in liver and
5-HT then causes increase in serum insulin
levels resulting into hypoglycemia. 5-HT when
injected in rats or dogs is reported to produce
hypoglycemia36. The studies involving
incubation of isolated pancreatic islets with 5HT revealed that 5-HT stimulates increase in
insulin release from pancreatic islets37. This
action of 5-HT was later shown to be mediated
through 5-HT1 and 5-HT2 receptors using
specific antagonists like methysergide and
ketanserin5.
Although the earlier 5-HT was reported to
cause hyperglycemia and many other
activities, both centrally and peripherally
acting 5-HT receptor agonists cause
hyperglycemia. Centrally, 5-HT1A receptor
agonist
8-hydroxy-2-di-n-(propylamine)
tetralin (8-OH-DPAT) and 5-HT1A receptor
partial agonists including buspirone and
ipsapirone
are
reported
to
induce
hyperglycemia in rats6. Similarly, 5-HT2
receptor agonists like 1-(2, 5-dimethoxy-4iodophenyl)-2-aminopropane (DOI) and 1-(3chloro-phenyl) piperazine (mCPPP) are
reported elicit hyperglycemia7. Peripheral 5HT receptors have shown to be involved in
glycemic control. Peripheral administration of
31

Feature
5-HT or a peripheral 5-HT receptor agonist
can elevate plasma glucose levels in rats37,7.
Peripherally acting 5-HT1A/1D receptor agonist
N, N-di-propyl-5-carboxamidotryptamine (DP5-CT) also elicits hyperglycemia in rats38,8.
Peripheral 5-HT3 receptor agonist 2-methyl-5HT does not produce any effect on blood
glucose, insulin or glucagons levels which rule
out the involvement of 5-HT3 receptor in blood
glucose, insulin or glucagons levels. These
conclude involvement of 5-HT1 and 5-HT2 in
glucose Homeostasis. However, involvement
of subtype 5-HT1 and 5-HT2 receptor namely,
5-HT1A, 5-HT2A and 5-HT2C receptors in 5-HT
induced hyperglycemia were studied38,7 and
reported that 5-HT2A antagonist sarpogrelate
and 5-HT2A/2C antagonist mianserin inhibited
5-HT induced hyperglycemia. However, a
fairly detailed characterization of 5-HT
receptor subtypes from our laboratory revealed
that 5-HT2A and 5HT3 receptors are involved
in 5-HT induced hyperglycemia9.

Can Sarpogrelate be used


treatment of Type 2 diabetes?

in

the

Since sarpogrelate that produced a


decrease in glucose levels is reported to be a
specific 5-HT2A receptor antagonist, it could be
hypothesized that 5-HT2A receptors are
involved in glycemic control. Murine knockout
studies also revealed that only deletion of the
gene encoding the 5-HT2C receptor (5-HT2C
receptor, formerly denoted 5-HT1C receptor)
produces insulin resistance and type-2
diabetes, with antecedent hyperphagia and
obesity. These genetic studies demonstrate that
5-HT2C receptors are critical for energy
homeostasis but do not indicate whether
serotonin generally or 5-HT2CRs specifically
have a primary effect on glucose homeostasis
that is dissociable from effects on body weight.
By targeting 5-HT2C receptors agonist which
enhance glucose tolerance independently of
alterations in body weight an effective and

32

mechanistically novel strategy in the treatment


for type 2 diabetes may be developed.
Several studies have indicated that 5-HT2
receptors play an important role in
cardiovascular
functions
(Table-1)10.
Sarpogrelate has shown to produce
cardioprotective11 and anti-platelet activity in
both, experimental12 and clinical settings13.
Treatment with sarpogrelate was reported to
significantly lower fasting glucose levels with
corresponding increase in insulin levels
(Table-2). It also significantly prevented STZinduced
polydypsia,
hyperphagia,
hypertension, and bradycardia but not the loss
of body weight. 5-HT produced dosedependent positive inotropic effect that was
found to be decreased significantly in STZdiabetic
rats.
Hearts
obtained
from
sarpogrelate treated diabetic rats did not show
any decrease in responsiveness to 5-HT.
Relative platelet aggregation per se was found
to be higher in STZ-diabetic rats as compared
to control and this was significantly prevented
by sarpogrelate treatment14. 5-HT produced a
dose dependent increase in platelet aggregation
in non-diabetic and sarpogrelate treated
diabetic rats. However, 5-HT failed to produce
any increase in platelet aggregation in
untreated diabetic rats. From our laboratory, it
was reported that STZ-induced diabetes may
produce down regulation of cardiac 5-HT2A
receptors and increased platelet aggregation.
Further suggested that treatment with
sarpogrelate prevented STZ-induced decrease
in responsiveness to 5-HT suggests that there
may be a down-regulation of 5-HT2A receptors
and that sarpogrelate produces beneficial
effects in diabetic heart possibly by preventing
diabetes induced down-regulation of 5-HT
receptors. Treatment with sarpogrelate seems
to prevent STZ-induced down-regulation of 5HT receptors and increase in platelet activity
in diabetic rats.14

Current R&D Highlights, Jan.-Mar. 2009

Feature
Table-1 summary of beneficial effect of sarpogrelate and its mechanism

Sarpogrelate (Beneficial effects on CVS)

Mechanism

Anti platelets

Inhibits collagen induced platelets aggregation


or ADP-epinephrine induced aggregation.

Antithrombotic

It blocked induction of tissue factor and


plasminogen activator inhibitor-1 and reduced
thrombus formation.

Antiatherosclerotic

It inhibits Matrix Metalloprotease I and II, it


also enhance production of Nitric Oxide.

Antianginal

It
inhibits
vasoconstriction
of
non
atherosclerotic human coronary. It has
protective effect with the patients with stable
angina.

VSMCs Proliferation/Neointimal hyperplasia

It inhibit 5-HT stimulated DNA synthesis, also


inhibit 5-HT mediated [Ca2+]i in VSMCs. It
also inhibits 5-HT mediated mitogen activated
protein kinase (MAPK) phosphorylation.

Heart failure and MI

It also inhibit thrombotic and vasoconstrictor


effect of 5-HT. It causes marked reduction in
infract size and left ventricular diastolic
pressure helps to improve MI.
Sarpogrelate inhibits angiotensin-II and
endotheline-1 induced cardiac hypertrophy and
it also inhibits 5-HT mediated increase in
[Ca2+]i concentration in extra cellular and
intracellular myocytes which helps to improve
in heart failure.

Pulmonary Hypertension

Reduced thickness of medial wall of small


pulmonary artery and right ventricle/left
ventricle and septum ratio. It also prevents
platelets aggregation in lungs.

Restenosis after coronary stenting

Mechanism of action is not known exactly but


probably it inhibits intimal hyperplasia.

Current R&D Highlights, Jan.-Mar. 2009

33

Feature
Table-2 Effect of 6 week treatment with sarpogrelate on various parameters in STZ diabetic rats

Parameter

Non-diabetic
control

Non-diabetic
Diabetic
treated
with control
sarpogrelate

Diabetic treated
with sarpogrelate

Body weight (g)

290.26 18.12

291.25 8.26

160.0 6.5*

181.66 9.29*

Food intake

41.29 5.63

44.5 2.20

115 2.88*

82.5 4.33**

53.75 5.05

40.0 1.15

118.75 0.72*

87.5 7.21**

105.62 10.12

98.23 8.23

146.23 3.75*

82.5 3.22**

405.23 22.68

385.56 23.73

321.25
12.31*

4.34 0.7

4.58 0.41

14.89 0.6*

6.69 0.9**

514.02 25.08

474.72 81.36

342 29.58*

595.98 62.88**

(g/day/rat)
Water intake
(ml/day/rat)
Blood pressure
(mmHg)
Heart rate
(beats/min)
Serum glucose

378.75 10.48**

(mmol/L)
Serum insulin
(pmol/L)
Data is shown as mean S.E.M. (n = 6). *Significantly different than non-diabetic control (p < 0.05), **significantly different than
diabetic control (p <0.05)

As mention earlier, 5-HT levels are high


in diabetes and 5-HT is one of the stimuli for
the translocation of glucose transporters. Both
GLUT 1 and GLUT 4 levels were reported to
be decreased in cardiomyocytes from STZdiabetic rats15,9.. Insulin was found to prevent
only GLUT 4 in STZ-diabetic rats. However,
sarpogrelate, a specific 5-HT2A receptor
antagonist was found to increase both GLUT 1
and GLUT 4 levels in diabetic rats. These
results indicate that not only 5-HT2A receptors
are involved in glucose transport mechanisms
but also that increase in glucose transporters in
cardiomyocytes by sarpogrelate may be
34

independent of insulin. Hajduch et al (1999)35


have reported that rat and human skeletal
muscles both express 5-HT2A receptors and
that specific 5-HT2A receptor agonists can
stimulate glucose uptake in skeletal muscles by
a mechanism which does not depend upon
components that participate in the insulin
signaling pathway. Figure-1 illustrates
proposed mechanism of sarpogrelate. tudies
with extracts and fractions of Z. officinale
(ginger) and active isolated compound 6Gingerol had shown insulin release activity in
STZ-induced diabetic rats. To correlate in-vivo
and in-vitro actions of these drugs on insulin
Current R&D Highlights, Jan.-Mar. 2009

Feature
release activity and to show the evidence of
involvement of 5-HT receptors in insulin
release activity of extracts and fractions of
drug, insulin release studies using cultured
pancreatic islet cells were carried out. In our
laboratory these experiments involved
incubation of 5-HT alone with diabetic
pancreatic islets and co-incubation of 5-HT
with sarpogrelate (Sanjay, 2004). Thus
involvement of 5-HT in insulin releasing effect
of these agents, was evident from our data.
Pancreas
5-HT2A Receptors
Insulin

Sarpogrelate

(-)

(-)
5-HT in blood
(Higher in Diabetes)

(-)
Glucose

Insulin Receptor

(-)
(-)

GLUT

Sarpogrelate

Target Cell
(Cardiomyocyte, Skeletal muscle, Adipocyte)

Fig.1 Proposed mechanism for glucose lowering


effect of Sarpogrelate in diabetic rats

with sarpogrelate and insulin. Diabetic control


islets produced significantly lower levels of
insulin secretion in response to glucose as
compared to normal control. Diabetic islets
when treated with glibenclamide produced a
significant increase in insulin release in
response to glucose as compared to diabetic
control. Diabetic pancreatic islets when treated
with 5-HT alone did not show any significant
change in insulin release in response to
glucose as compared to diabetic control islets
but it produced significant increase in insulin
secretion in response to glucose when coincubated 5-HT in diabetic pancreatic islets

Current R&D Highlights, Jan.-Mar. 2009

Role of 5-HT
complications

in

Cardiovascular

Historically involvement of 5-HT in


cardiovascular system was observed first time
between in 1869 an 1896. It was reported that
a substance active on blood vessels and the
heart appears in serum when blood is allowed
to clot. For instance, Weiss et al., (1896)39
reported that if serum was continuously but
slowly injected into a rabbit, cat or dog until it
caused death, the heart rate was increased and
at first the beat was stronger but gradually
failed, although it persisted until the
respiration had ceased; in addition, an increase
in the peristalsis of the small intestines and
death due to paralysis of the respiratory and
vasomotor centres was noticed. At the same
time, cardiovascular 5-HT research was
advanced by the development of two drugs,
ketanserin (a 5-HT2-receptor antagonist) and
8-hydroxy-2-(di-n-propylamino) tetralin (8OH-DPAT; a 5-HT1A-receptor agonist); both
drugs lower blood pressure. During the same
period, triptans, selective 5-HT1B/1D -receptor
agonists (selective cranial vasoconstrictors),
were also being developed for the treatment of
migraine16. The observation that ketanserin
lowers blood pressure generated a huge
interest in the potential role of 5-HT in
cardiovascular regulation, but this action of
ketanserin was shown to be primarily due to
blockade of 1-adrenoceptors17. Even now, 25
years later, the involvement of 5-HT in
hypertension is poorly understood and the
peripheral physiological role, that is the
importance of 5-HT in control of vascular tone
and, thus, blood pressure, is poorly understood
(even though 5-HT is found in large amounts
in platelets). Current views on the peripheral
mechanisms by which 5-HT affects the
cardiovascular system are summarized in
Table-3 and Figure-2.

35

Feature

Figure.2 Actions of peripheral 5HT receptors on the cardiovascular system

Table-3 List of the main peripheral cardiovascular responses caused by 5-HT receptors and their
selective ligands
Receptor
5-HT1B/1D

Agonist
Sumatriptan

Antagonist
GR127935

5-HT1B

CP-93129 In Rats

GR 55562

Cardiovascular effect
Reduce sympathetic drive (i.e. reduction in
noradrenaline release to the heart and
vasculature)
Vasoconstriction

5-HT1D

BRL15572

-----

5-HT2A

PNU-109291
PNU-142633
DOI
Also has affinity for
5-HT2C

MDL 100907

Vasoconstriction, platelet aggregation and


direct tachycardia in rats.
Adrenaline release from the adrenal
medulla?

5-HT2B

BW723C86

RS 127445

Release of NO, thus, vasodilation

36

Current R&D Highlights, Jan.-Mar. 2009

Feature
5-HT3

PBG

Granisetron
Ondansetron

Reflex bradycardia and hypotension


Rabbit heart where it causes the release of
noradrenaline from sympathetic terminals

5-HT4

BMIU4

GR113808
SB-204070

5-ht5A/5B

None

None. SB-269970
does have good
affinity, but is also a
5-HT7 antagonist

Tachycardia (positive chronotropy) and


increase in atrial force (positive iontrophy)
dilation.
Reduce sympathetic drive (i.e reduction in
noradrenaline release, to the heart and
vasculature)

5-HT7

None. 5-CT is often


used, but it shows
poor
selectivity.
Newer agonists are
AS19 and LP44, but
their selectivity is
not clear

SB-269970 (also has


affinity
for
5ht5a/5b)
SB-258719

Chronic diabetes mellitus is associated


with depressed heart functions and diabetic
cardiomyopathy. It is characterized by
decreased left ventricular developed pressure
(LVDP), decreased rate of ventricular pressure
development (+dP/dt), decreased rate of
ventricular pressure decline (-dP/dt) and
decreased heart rate. From our study, we have
reported that type 1 diabetes produces decrease
in LVDP, +dP/dt, -dP/dt and heart rate.
Treatment with sarpogrelate has been reported
to produce significant increase in LVDP,
+dP/dt, -dP/dt and heart rate. In addition, the
diabetic rats showed increase in heart weight
to body weight and left ventricle weight to
body weight ratios indicating hypertrophy of
the heart. Sarpogrelate significantly decreased
heart weight to body weight ratio indicating
reduction in hypertrophy18. Circulating levels
of 5-HT are increased in diabetics as well as
patients with coronary artery disease as
compared to the normal subjects. This increase
in 5-HT levels may be due to release of 5-HT
from platelets as well as mast cells19.
Sarpogrelate treatment restores the 5-HT2A
receptor sensitivity and reverses the inotropic
effects of 5-HT, thus improves the heart
function. However, chronic hyperglycemia
may alter the hemodynamic responses in
Current R&D Highlights, Jan.-Mar. 2009

Vasodilation

Tachycardia in cats

experimental animals due to more than one


factor. The attenuation in the ability to
generate contractile force has been suggested
to be due to the depression in the ATPase
activity of contractile proteins21,22 and
alteration in the sarcolemmal membrane20,21.
The defects in cardiac relaxation have been
attributed to the depression in the sarcoplasmic
reticular calcium uptake22 and the sarcolemmal
calcium exchange activities 23. It has also been
reported that cardiac mitochondria isolated
from diabetic animals have reduced capacity to
accumulate calcium 20,21. All this evidence lead
to the conclusion that condition of calcium
overload may present be present in
mitochondrial cells in chronic diabetes 20,21. 5HT causes very strong smooth muscle cell
contraction that is considered to be associated
with cardiovascular diseases like hypertension
(Frishman, et al, 1995)24. 5-HT causes an
increase in [Ca2+]i of smooth muscle cells via
5-HT2 receptor through the release of calcium
from intracellular stores as well as the influx of
extracellular calcium 25,26. 5-HT induced influx
may occur through both, voltage dependent
and independent channels26. Chronic treatment
with 5-HT2A antagonist sarpogrelate may have
led to the suppression of this resultant calcium
overload leading to improvement in cardiac
37

Feature
function.

Role of 5HT in Obesity


It is well established that enhancing 5-HT
neurotransmission in the brain regulates
feeding habits by inducing hypophagia.
Fenfluramine and D-fenfluramine, compounds
that stimulate 5-HT release from the synapse
and block its reuptake, reduce the volume of
food intake in both rats and humans13,
potentially through the promotion of satiety23.
Similarly, administration of the SSRI
antidepressant, fluoxetine, presumably also
potentiating central 5-HT function, also results
in lower food intake in both rats and humans27.
It is believed that distinct 5-HT receptor
subtypes are responsible for mediating the
hypophagic response of this neurotransmitter,
with the primary candidates being the 5-HT1B
and 5-HT2C receptors. Evidence for the
involvement of the 5-HT1B receptor is based
largely on the ability of pharmacological
agents, including the selective 5-HT1B receptor
agonist, CP94, 253 and the nonselective 5HT1A/1B receptor agonist, RU24969, to reduce
food intake in rodents28,29. Similarly, evidence
implicating the 5-HT2C receptor in the
regulation of feeding is supported by
pharmacological studies. For instance, the
mixed 5-HT1B/2C receptor agonist, mchlorophenylpiperazine (mCPP),
induces
hypophagia in mice, which is blocked

following pre-treatment with the selective 5HT2C receptor antagonist, SB24208430;


although some reports do suggest the actions
of mCPP are not solely 5-HT2C receptormediated but also 5-HT1B receptor-mediated31.
Another 5-HT2C receptor agonist, Ro60-0175,
also induces hypophagia32, although this
compound also interacts with 5-HT2A/2B
receptors, the hypophagic response appears to
at least necessitate 5-HT2C receptor activation
due to prevention of the response by
pretreatment with the selective 5-HT2C
receptor antagonist, SB242084. It is reported
that serotonergic mechanism is involved in
secretion of leptin and that both leptin and 5HT may interact for the regulation of food
intake. From our laboratory we have reported
glucose and lipid lowering effect of fresh juice
of ginger is mediated through 5-HT
receptors33. Further evaluation of active
fractions of ginger in goldthioglucose induced
obese mice suggests that ethyl acetate and
methanolic fraction of Z. Officinale (ginger)
has beneficial effect in condition of obesity. In
addition to decrease serum glucose, insulin and
lipid levels it can also significantly retard gain
in body weight. Based on our data (Table-4),
these beneficial effects, Z.Officinale can be
considered as supplementary herbal therapy in
obese patients for prevention or treatment of
obesity.

Table: 4 Effects of ginger methanolic and ethyl acetate extracts on body weight, serum glucose and
insulin levels on goldthioglucose-induced obesity in mice34.
Groups

Body weight (g/mice)

Glucose (mg/dl)

Insulin (U/ml)

Normal control (vehicle)

22.5 1.1

78.5 1.1

31.0 0.8

Obesity control (OB) (vehicle)

41.6 1.6a

156.7 1.7a

91.3 2.1a

OB+
methanolic
(250mg/kg)

extract

32.5 1.1

124.4 2.5

75.0 1.5b

OB+
ethyl
(250mg/kg)

extract

35.8 0.8b

128.7 2.1b

88.3 1.8b

acetate

N=6, values represent mean S.E.M. a Significantly different from normal control P<0.05. b Significantly different from obesity
control P<0.05.

38

Current R&D Highlights, Jan.-Mar. 2009

Feature
Conclusions
From the forgoing discussion, it is evident
that sarpogrelate is a specific 5HT2A receptor
antagonist. Many experimental studies suggest
that
sarpogrelate
has
number
of
pharmacological effect namely, anti-platelet,

antiatherosclerotic, antithrombotic and anti


anginal effect. It seems that sarpogrelate is an
excellent drug for the treatment of peripheral
vascular disease and can be an effective drug
for the treatment of diabetes and associate
cardiovascular complications.
Cell Cardiol 1981, 13: 303-309.

References

23. Rowland, N.E. et al., J.. Progr. Neurobiol. 1986, 27, 13

1.

24. Frishman WH, et al.,. J Clin Pharmacol 1995, 35: 541-

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Chen CC, et al., Res 1991, 552: 175-179.

3.

Holden RJ. Schizophrenia, Med Hypotheses 1995, 44:


379-391.

72.
25. Doyle VM,

et al., Naunyn Schmiedebergs Arch

Pharmacol 1986, 333: 98-103.

4.

Furman BL, et al., Diabetologia 1980, 19: 386-390.

5.

Yamada J, et al.,. Life Sci 1995, 57:819-825.

6.

Chaouloff F, et al., Eur J Pharmacol 1990a, 177: 107-

27. McGuirk, J. et al.,.. Int. J. Obesity 1990, 14, 361372.

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28. Lee, M.D. et al.. Eur. J. Neurosci. 2004, 19, 30173025.

7.

Baudrie V, et al., DOI. Eur J Pharmacol 1992, 213:41-

29. Lucas, J.J. et al. J. Neurosci. 1989,18, 55375544.

46.

30. Kennett, G.A. et al. Neuropharmacology 1997, 36, 609

8.

Laude D,

et al., Naunyn-Schmiedebergs Arch

Pharmacol 1990, 342: 378-381.


9.

Umrani DN, et al., J. Mol Cell Cardio. 2001; 33:A124.

10. McCall RB, et al., Pharm Rev 1994, 46: 231243.


11. Sharma SK, et al., J Pharmacol Exp Ther 1999, 290:
14751481.

26. Hirafuji M, et al., Res Commun Mol Pathol Pharmacol


1998, 99: 305-319.

620.
31. Schreiber, R. et al., J.. Progr. Neuro-Psychopharmacol.
Biol. Psychiatry 2002, 26, 441449.
32. Clifton, P.G. et al. Psychopharmacology 2000, 152, 256
267.
33. Akhani SP, et al., J Pharm pharmacol 2004; 56 101.

12. Hara H, et al., Thromb Haemost 1991, 65: 415


420.
13. Blundell, J.E.. Appetite 1988, 7, 3956.

36. Yamada J, et al.,.. Life Sci 1989, 45:1931-1936.

14. Umrani DN, et al., Mol Cell Biochem 2003, 249: 5357.

37. Lechin F, et al.,. Acta Physiol Lat Am 1975, 25: 339-46.

34. Goyal RK, et al.,. Fitotherapia 2006, 77, 160-163.


35. Hajduch E, et al., J Biol Chem 1999, 274: 13563-13568.

15. Garvey W, et al., Am J Physiol 1993, 264: H837-H844.

38. Sugimoto Y, et al.,. Eur J Pharmacol 1996a, 307: 75-80.

16. Humphrey, P.P. et al.,. Trends Pharmacol. Sci. 1991, 12,

39. Weiss, O. Ueber die Wirkungen von Blutserum-

444446.

Injectionen ins Blut. Archiv fu r die Gesamte

17. Fozard, J.R. J. Cardiovasc. Pharmacol. 1982, 4, 829838.

Physiologie des Menschen und der Thiere LXV, 1896,

18. Temsah RM, et al.,. Can. J. physiol. pharmacol. 2001;

215230.

79:761-733.
19. Van Den Berg EK, et al., Circulation 1989, 79:116-124.
20. Pierce GN, et al., Am J Physiol 1985a, 248: E170-E175
21. Pierce GN, et al., Can J Cardiol 1985b, 1: 48-54.
22. Penpparkgul S, et al., Sonnenblick EH, Scheuer J. J Mol

Current R&D Highlights, Jan.-Mar. 2009

39

Feature

System Biology Enables Novel Strategies for the


Management of Type 2 Diabetes
Alok Kumar Verma, Ram Raghubir and Ram Pratap*
Division of Medicinal and Process Chemistry,
Central Drug Research Institute, Lucknow

System biology is a new concept in


biological sciences to understand complex
molecular networking of the system. A proper
understanding of the failure of the inbuilt
robustness mechanisms inviting the disease
state, may offer system-based approach for the
future drug design for the effective and safe
management of systemic diseases.
In perspective of the system biology,
diseases are viewed as breakdown of
robustness and disease evolves when damage
to the mechanisms that maintain robustness
can not be repaired. In general, robustness is
manifested as adaptation to the dynamic
environment and as stability against external
and internal disturbances. Living systems are
generally robust against various perturbations,
such as mutation, toxin and environmental
changes, but can be extremely fragile to the
perturbations of high amplitude for which the
system has not been optimized. The
mechanism that provide robustness and protect
normal functions in a dynamic environment
may also be used to maintain abnormal states.
When fundamental robustes mechanisms are
co-opted by the disease process as in cancer,
then it becomes difficult to treat the disease.
Drugs can be ineffective when the inherent
robustness of the system in patients, that is
being targeted, is compensated by redundant
pathways. Also the side effects of drugs can be
the result of its interference at an unexpected
points of fragility (divergent point) of these
40

systems.
Robustness consists of four basic
mechanisms, which ensure the robustness of
the system: system control, alternative means
of redundancy (or fail safe) and diversity,
modularity and decoupling in which physicallevel perturbation is isolated from functional
level activities of the system. Robustness is
enhanced in biological systems as there are
multiple means to achieve a specific function.
This encompasses redundancy, overlapping
function and diversity. Redundancy generally
refers to a situation, in which several identical,
or similar, components (or modules) can
replace with each other, when another
component fails. This implies that drugs
targeting such pathways are likely to have
limited efficacy. Diversity, or heterogeneity,
represents the other extreme, whereby a
specific function can be attained by different
means available in a population of
heterogeneous components. The biological
system has evolved decoupling mechanism for
its robustness like capacitors in electrical lines
decouple the voltage fluctuations. The
biological systems have also evolved
decoupling mechanisms for its robustness by
assigning different functions to different cell
constituents, which is known as physical
separation of various functions inside the cell
so that functional fluctuations in one part is not
transferred to another and also repairing
mechanism e.g. heat shock proteins fix misCurrent R&D Highlights, Jan.-Mar. 2009

Feature
folded proteins as a result of environmental
stress, which also decouples genetic variations
from the phenotype variations. System control
introduces positive and negative feed back,
feed forward and other regularity loops to
maintain homeostasis of the system as well as
bi-stable behaviors, which enables the system
to move between two stable states.
Positive
feedback
contributes
to
robustness by amplifying the stimuli, often
producing bi-stability, so that the activation
level of a downstream pathway can be clearly
distinguished from non-stimulated states, and
so that these states can be maintained. Positive
feedback is also used in signal transduction
and the cell cycle to form switchlike behavior
of the system by amplification of stimuli, so
that it initiates transition and a new state of the
system is made that is more robust against
noise and fluctuations of stimuli.
Negative feedback is the principal mode
of control that enables robust response to
perturbations. For example in relation to
obesity and diabetes, food intake and its
disposition is controlled by anabolic and stress
hormones. Leptin secreted by adipocytes and
ghrelin by the stomach, are centrally regulated
by hypothalamus, a brain loci, controlling
appetite. Hypothalmus also activate release of
stress hormone noradrenaline from adrenal
glands to initiate thermogenesis to protect
animals from cold. These negative feed back
mechanisms respond with perturbations for
adaptation to the dynamic environment and
hence can be utilized for drug interference in
diabetes and obesity.
Type-2 diabetes is a major manifestation
of metabolic syndrome, which is a highly
complex disease comprising obesity, insulin
resistance, hyperlipidemia and hypertension.
Metabolic syndrome is a systemic disease
affecting multiple organ systems through the
narrowing of macro- and micro-vascular
systems under the influence of the oxidative
stress provided in the system and thereby
Current R&D Highlights, Jan.-Mar. 2009

affecting the supply of nutrients to the organs.


Oxidative stress in human biology comes from
variety of sources e.g. in aerobic cells,
incomplete reduction of oxygen in the
mitochondrial electron transport chain releases
superoxide anion, which on reaction with iron
or copper produce the highly reactive and
damaging hydroxyl radicals into cytosol. Our
biological system utilizes oxidative stress to
defend itself e.g. inflammatory cells, such as
macrophages
and neutrophils
produce
hydrogen peroxide and hypochlorous acid as a
means of bactericidal activity. Diabetes results
owing to an imbalance between oxidative
stress and its defense mechanism for its
proliferation and hence convert excess plasma
glucose to keto-aldehyde, a highly reactive
intermediate called Amadori adduct, which
ultimately reacts indiscriminately with proteins
under non-enzymatic conditions to produce
advanced glycation endproducts (AGEs). The
oxidative stress therefore could be one of the
important target for interference. The system
biology based analysis of diabetes led Kitano
et al (2004)1 to suggest that the TNF- and
adiponectin loop may be the target for new
antidiabetic drugs, which the nature has
evolved for emergency supply of glucose to
the brain. In ancient environment during
evolution, the TNF- and adiponectin loop was
evolved to impart insulin resistance so as to
maintain glucose supply to the neuronal and
innate immune related cells and thus providing
robustness against near-starvation levels of
food supply by maintaining a higher bloodsugar level. So, the system has adapted the
mechanism to provide robustness against low
level of glucose supply by a negative feed back
loop where TNF- makes insulin resistant so
that glucose is not completely converted to
glycogen and is always available for brain and
immune cells to function. The phenomenon
has been taken over by the disease metabolic
syndrome, where adipocytes releases cytokines
TNF- and IL6 to keep off glucose uptake.
Besides TNF-, some other hormonal and
cytokines factors affect insulin sensitivity such
41

Feature
as resistin and glucocorticoids and that these
may serve newer targets for diabetes.
In the light of the robustness and fragility
of the biological systems, Kitano et al (1994)
has analyzed diabetes in detail and categorized
it into energy supply, its utilization and
maintenance of homeostatic status and their
failure leads to diabetes. This opens new vistas
to understand the therapeutic measures and to
future designing strategies for developing
novel drugs. We will attempt a brief
description of these categories and treatment
available and the targets currently being
pursued in-view of the recent advancements in
molecular biology of the disease.

A. Food Intake, Absorption and Control


Mechanism
The process of food intake can be
categorized under positive feed back in process
of energy intake, whereas negative feed back
loops regulate appetite by hormonal
messengers. The hormonal messengers
controlling the food intake (appetite) are
leptin, secreted by adipocytes and ghrelin by
the stomach are controlled at the level of
hypothalamus.
After the ingestion of food, the
carbohydrate constituents are absorbed into the
system through their conversion to mono
saccharides. Pancreatic amylase in the intestine
degrades complex carbohydrates to oligo and
disaccharides. Within the brush border of the
intestinal villi of small intestine, -glucosidase
enzymes break down the oligo- and
disaccharides to monosaccharides, which are
absorbed through the mucosal border.
Competitive inhibition of these enzymes
reduces the rate of absorption and hence
postprandial
hyperglycemia.
-1,
4glucosidase inhibitors such as acarbose,
voglibose and miglitol are therefore used for
the treatment of patients with diabetes
mellitus.
In diabetic patients, the short-term effect
of these drugs is to decrease current blood
42

OH

OH
OH
HO

OH
HO

NH

OH

HO

HO

OH

Miglitol

OH

OH

HO

HO

OH

HO
O

OH

HO

OH

O
O

HO
OH

OH
HO

N
H

OH
OH

Acarbose

Voglibose

glucose levels and the long term effect of these


drugs is only a small reduction in blood. Since
alpha-glucosidase inhibitors prevent the
degradation of complex carbohydrates into
glucose, the undigested complex carbohydrates
move to the colon, where bacteria digests them
causing gastrointestinal side effects such as
flatulence and diarrhoea.
The
appetite
control
mechanisms
however, may be exploited for the
management of obesity. To control
hyperglycemic
condition,
the
peptide
hormones called incretins have been targeted.
The arrival of food in the duodenum stimulates
the release of polypeptides called glucagonlike peptide-1 (incretin) and glucose-dependent
insulinotropic polypeptide (GLP). They
enhance the ability of glucose to stimulate
insulin secretion by the pancreas and stimulate
the ability of the tissues to take up glucose
from the blood. GLP-1 is rapidly degraded in
vivo through the action of dipeptidyl peptidase
IV (DPP-IV), which cleaves the N-terminal
two amino acids to give the inactive GLP-1
amide.
A cell surface serine protease, DPP-IV is
ubiquitously expressed, with highest levels
found in the kidney and the lower levels in
liver and pancreas, where it rapidly terminates
the activity of GLP-1 by cleaving the Nterminal dipeptide (His-Ala) of GLP-1. DPPIV inhibitors, therefore stabilize endogenous
GLP-1 at the physiological concentrations, and
Current R&D Highlights, Jan.-Mar. 2009

Feature
induce insulin secretion in a glucosedependent manner. They also stabilize other
F

H
O

CN

N
H

NH2

OH

N
NH2
F

BMS-477118 (Saxagliptin)

GSK 832093C (Denagliptin)

NH

CN

H
N

H2N
N

N
HO

NC

SYR-322 (Alogliptin)

LAF 237 (Vildagliptin)


F
F

B. Control Mechanisms For Energy


Storage:
The energy transport and storage
mechanism is primarily governed by the
hormone insulin forming a negative feed back
loop in glucose homeostasis. A primary
metabolic action of insulin is to facilitate the
postprandial disposition of glucose via its
actions on three key target tissues: suppression
of glucose output from the liver and
stimulation of glucose uptake and metabolism
in skeletal muscle and adipose tissue. Defects
in insulin secretion and action on its target
tissues manifest diabetes. Reduced insulin
action and its resistance for glucose transport
in skeletal muscle and adipose tissue have
therefore been targets of drug design for type 2
diabetes.

F
F

N
N
N

NH2

F
F

MK0431(Sitagliptin)

incretins, including gastric inhibitory peptide


and pituitary adenylate cyclase activating
peptide. Further they reduce the antagonistic
and desensitizing effects of the fragments
formed by the truncation of the incretins.
Several
DPP-IV
inhibitors
have
progressed in clinical development, and their
characteristics have recently been reviewed.
These agents have consistently reduced blood
glucose, predominantly post-prandially, and
this appears to be associated with increases in
active circulating GLP-1 (and possibly other
incretins) as well as reductions in glucagon.
Acutely, DPP-IV inhibitors seem to increase
the insulin response to glucose. LAF237(Novartis) is a second generation DPP-IV
inhibitor that lowers the blood sugar levels
towards normal and prevented large
fluctuation after meals in type II diabetes. It is
presently in phase III human clinical trials.

Current R&D Highlights, Jan.-Mar. 2009

Insulin-stimulated glucose transport in


skeletal muscle in type 2 diabetes is impaired
resulting in enhanced insulin secretion from
pancreatic -cells, the phenomenon is termed
as hyper-insulinemia. Peripheral insulin
resistance combined with impairment of
insulin secretion results into hyperglycemia. At
the end stage, changes in insulin signaling,
such as its inability to inhibit hepatic
gluconeogenesis
is
accompanied
by
deterioration of pancreatic beta cell function
resulting in failure of hyper secretion of insulin
to compensate insulin resistance. Such a
situation results in long term micro-vascular,
neurological,
and
macro-vascular
complications
including
retinopathy,
nephropathy, neuropathy and increased risk of
cardiovascular diseases.
a). Stimulation of insulin secretion:
Glucose induced insulin secretion from
pancreatic -cells is the end result of a
complex cascade of actions initiated by ligand
sensitive potassium sensitive ATP channels.
Binding of glucose on the receptor brings
closure of the ATP-sensitive potassium
channels. As a result the decrease in potassium
ion efflux leads to depolarization of the cell
43

Feature
membrane, opening of voltage-gated Ca2+
channels, elevation of the cytoplasmic Ca2+
concentration and stimulation of Ca 2+ ion
dependent exocytosis of the insulin. The KATP
channel is a heteroctameric complex composed
of four inwardly rectifying K+ channel subunits
(Kir6.2) and four sulfonylurea receptors
(SUR1). Two isoforms of the receptor have
been indentified, SUR1 on pancreatic cells
and SUR2 on vascular smooth muscle and
cardiac termed as SUR2B and SUR2A
respectively. This KATP channel has been
utilized to enhance insulin secretion from
pancreatic cells in diabetic patients.
i) KATP closing by sulfonylurea stimulated
secretion:
The first-generation agents include
acetohexamide, chlorpropamide, tolazamide,
and tolbutamide.
H 3C

O
O
H
H
S N C N
O

O
H
H
S N C N
O

CH 3
Cl

Tolbutamide
O
H3C

Chloropropamide

H
H
S N C N N
O
Tolazamide

CH3

O
H 3C

O
H
H
S N C N
O
Acetohexamide

First generation sulfonylureas as insulin secretogogs.

The
second-generation
agents
include
glimepiride, glipizide, and glyburide. The
second-generation agents are more potent and
in general have better pharmacokinetic and
safety profiles. This mechanism only works if
insulin is present in the -cells. Sulfonylureas
display more pronounced action in the
presence of glucose. The increased insulin
flows into the portal veins to suppress the
elevated basal rate of hepatic glucose
production. One concern with these agents is
the loss of efficacy over time, which may be
related to the potential to exhaust -cell
function. Because these agents increase plasma
levels of insulin, they may cause

44

hypoglycemia. Glimepiride has also been


shown to increase insulin sensitivity of
peripheral tissues to insulin. Sulfonylureas do
not have a clinically significant effect on the
lipid profile.
H 3C
H3C

C
H2

O
N C HN

O
O
S NH C NH

H 2 C H2 C

CH 3

O
O
Glimepiride

Cl
O
C
O
CH3

H
N

H2
H 2C C

S NH C NH
O

Glibenclamide

Second generation sulfonylureas as insulin


secretogogs

ii) KATP closing non-sulfonylurea stimulated


secretion:
The
non-SU
secretagogs
include
meglitinide, repaglinide and nateglinide. Like
the sulfonylureas, the non-SU secretagogs
made available since 1998 lower plasma
glucose by increasing the release of insulin
from functional pancreatic -cells.
The
mechanism is exactly the same as that of
sulfonylureas, except the non-SU secretagogs
are more selective as they lack affinity towards
SUR2A and SUR2B channels. Unlike
sulfonylureas, non-SU secretagogs have a very
short half-life and duration of action, so they
stimulate insulin secretion for brief episodes.
Therefore, they are dosed with meals and are
most helpful in decreasing postprandial
hyperglycemia. Unlike sulfonylureas, non-SU
secretagogs have decreased incidence of
hypoglycemia. Compound BTS 67582 binds to
the KATP channel at the site different from
sulfonylureas and is therefore effective in
sulfonylurea resistant animal models.

Current R&D Highlights, Jan.-Mar. 2009

Feature
H3 C
H2 H H O H 2
CH C C N C C
H3 C
N

COOH
O

CH 3

H3 C
CH
H3 C

channel

opener

stimulated

MCC 134 opens potassium channels,


activates KATP channel on smooth muscle cells
and inhibits SUR1 resulting in reduced insulin
secretion. Therefore it is effective in
hypertensive diabetic patients. NN 414 opens
KATP channels on pancreatic -cells, thereby
reduces insulin secretion. It also prevents
glucose induced apoptosis of human islets.
O
O

O
N
H

N
MCC 134

CH 3

O
S
N
N
H

O H
2 H H2
N C C C C
COOH

KAD-1229 (Meglitinide)

Nateglinide

Repaglinide

iii) KATP
secretion:

O
H H H2
C N C C
COOH

NH 2

effect on the exocytotic machinery of -cells.


These compounds are at different phases of
development as novel oral insulinotropic
agents.
The imidazoline compounds such as KU
14R act via another putative imidazoline
receptors on pancreatic islet. The classical
imidazoline receptors (I1 and I2) occur on
smooth muscle cells. The imidazoline
compound KU 14R causing insulin secretion
from pancreatic islet acts through another
unknown imidazoline receptor on -cells,
termed as I3.

N
N
H

CH 3

NN 414

N CH
3
CH 3

NH2

BTS 67582

MeO

iv) 2A - Adrenoceptor/ imidazoline receptor


antagonists as insulin secreting agents:
The studies on the mechanism of action of
prazosin, revealed that -2A adrenoceptors
cause stimulation of pancreatic sympathetic
nerve to inhibit the insulin release. This target
therefore led designing of drugs through its
interference. The scientists at Central Drug
Research Institute, prepared prazosin analog
centpiperalone which exhibited significant
sugar lowering activity but was abandoned due
to its minor nausea sensation in clinical
studies. However its mechanism of action
could not be established.
Further studies towards the search of -2A
adrenoceptors antagonist led discovery of
compounds such as RX 801080, KU 14R,
Efaroxan and RX 871024. The mechanism of
RX 801080 revealed that its insulinotropic
effect is mainly due to dual mechanisms: by
closing KATP channel and activating voltagegated Ca2+ channels secondly by its direct
Current R&D Highlights, Jan.-Mar. 2009

MeO

NH
N

NH
O

Prazosin

Centpiperalone

H 3C

O
N
HN

RX 801080

O
N

N
H

H3 C
O
N

HN
Efaroxan

HN
RX 871024

KU 14R

v) Sodium dependent glucose transport pump


inhibition:
In normal individuals, more than 99% of
the plasma glucose that is filtered through
glomerulus of kidney is reabsorbed, resulting
in only less than 1% of the total filtered
glucose being excreted in urine. This reabsorption process is mediated by two sodium
dependent glucose co-transporters (SGLTs):
SGLT1, a low capacity, high-affinity
transporter expressed in the gut, heart, and
kidney and SGLT2, a high-capacity, lowaffinity transporter that is expressed mainly in
45

Feature
the kidney. 90% of renal glucose re-absorption
is facilitated by SGLT2 residing on the surface
of the epithelial cells lining the S1 segment of
the proximal tubule, while the remaining 10%
is likely to be mediated by SGLT1 localized on
the more distal S3 segment of the proximal
tubule. Humans with SGLT1 gene mutations
experience glucose-galactose mal-absorption,
resulting in frequent, watery diarrhoea and
dehydration, when on a glucose diet,
confirming that SGLT1 is the major glucose
transporter in the small intestine. These
individuals present with little or no glucosuria,
suggesting that SGLT1 is not the major
glucose transporter in the kidney. However,
since persistent renal glucosuria is the sole
reported phenotype of humans with SGLT2
gene mutations, selective inhibition of SGLT2
has been proposed to aid in the normalization
of plasma glucose levels in patients with
diabetes by preventing the renal glucose reabsorption process and promoting glucose
excretion in urine. Selective SGLT2 inhibitors
would be desirable, since gastrointestinal side
effects associated with SGLT1 inhibition
would be minimized. This mechanism is
expected to be associated with a low risk of
hypoglycemia, because there is no interference
with the
normal counter regulatory
mechanisms for glucose.
Cl
HO

OEt

HO

OH
OH
Dapagliflozin

Bristol-Mayers have recently developed


the C-aryl glucoside (dapagliflozin) getting
lead from natural product as a potent and
selective hSGLT2 inhibitor which reduced
blood glucose levels in a dose-dependent
manner by as much as 55% in hyperglycemic
46

streptozotocin (STZ) rats. These findings,


combined with a favorable ADME profile,
have prompted clinical evaluation of
dapagliflozin for the treatment of type 2
diabetes.
b). Desensitization of insulin resistance:
Glucose transport is thought to be ratelimiting for glucose uptake and metabolism by
skeletal muscle and adipose tissue. Insulin
mediated glucose transport could occur by
either stimulating the activity of existing cell
surface glucose transport proteins or by
translocation of an intracellular transporter
(glucose transporter iso-type 4, Glut 4) to the
cell surface in response to insulin. In type 2
diabetes the insulinstimulated translocation of
Glut 4 to the cell surface of muscle and fat
tissue is defective and therefore requires
intervention. In order to find points of
therapeutic intervention the understanding of
insulin signaling pathway is essential.
In the event of diabetic signaling cascade,
the insulin first bind to an enzyme receptor
referred as insulin receptor (IR) on the target
tissue. The protein has a ligand-binding
domain on the extracellular surface of the
plasma membrane and an enzyme active site
on the cytosolic side. The enzyme is a protein
kinase that phosphorylates Tyr residues in
specific target protein, known as insulin
receptor substance (IRS-1). Once the protein is
phosphorylated on Tyr residues of IRS-1, it
carries the message to targets in the cytosol
and nucleus through the phosphorylation of
intermediate proteins involving Grb2, Sos and
Ras. Ras then activates protein kinase, Raf-1
which in turn activates MEK followed by
activation of MAPK. Activated MAPK moves
into nucleus and modulates the transcription of
insulin regulated genes. When Grb2 associates
with PI3K, PI3K gets activated to convert PIP2
to PIP3. PIP3 indirectly activates PKB, which
phosphorylates serine/threonine residues on
its target proteins e.g. GSK3. Activated PKB
triggers the movement of GLUT-4 from
Current R&D Highlights, Jan.-Mar. 2009

Feature
internal membrane vesicles to the plasma
membrane.
Insulin resistance is a central feature of the
metabolic syndrome, leading to hyperinsulinaemia and involves multiple defects of
insulin receptor and post-receptor signaling.
Pathways that control non-genomic effects of
insulin appear to be more vulnerable to the
disruption. In the insulin resistance state,
insulin fails to induce normal GLUT-4 protein
translocation in skeletal muscles, resulting in
the hyperglycemic stage in the plasma.
Adipocytes play a regulatory role in the
development of insulin resistance as they can
produce adipokines (hormones and cytokines)
and also as they become saturated with their
excess lipid storage capacity leading to the
abnormal distribution of lipids to other organs
and tissues. Adipocytokines such as TNF-
and IL-6 are pro-inflammatory factors
contributing to the development of insulin
resistance. TNF- induces the serine
phosphorylation of IRS-1 causing serine
phosphorylation of the insulin receptor
resulting in blockade of normal tyrosine
phosphorylation of the insulin receptor causing
interference with insulin signal transduction.
Further IL-6 and TNF- induce suppression of
cytokines signaling-3 (SOC-3) resulting in
inhibition of tyrosine phosphorylation of IRS-1
and thus reduce the activation of Akt (PKB),
which finally results in reduction in the release
of GLUT-4 from secretory vesicles. Leptin is
an adipocyte hormone which decreases TG
synthesis, stimulates -oxidation and enhance
insulin secretion through modulation of
various insulin targets including IRS-1,
MAPK, ERK, p38 MAP kinase, PKB, P kinase
and PI-3 kinase. Adiponectin increases insulin
sensitivity by activation of AMPK and by
increase in tyrosine phosphorylation of insulin
receptor. In liver it inhibits both the hepatic
gluconeogenesis enzyme and the rate of
endogenous glucose synthesis while in
muscles it increases glucose transport and
increases fatty acid oxidation. It suppresses
Current R&D Highlights, Jan.-Mar. 2009

TNF- induced inflammatory changes in the


endothelial cells by blocking inhibitory NF-B
phosphorylation and NF-B activation. The
newly identified adipokine omentin increases
insulin stimulated storage of glucose in
adipocytes and increases PKB phosphorrylation.
Besides the above revelation in the
forward direction, the molecular level studies
have also identified pathways which modulate
signaling pathways at insulin receptor
substrate-1. Protein tyrosine phosphatase-1B
(PTP-1B) dephosphorylates tyrosine residues
on the insulin receptor, which negatively
regulates insulin signaling and therefore
requires intervention. Serine phosphorylation
of IRS-1 catalyzed by protein kinase C (PKC),
which itself get activated by inositol 1, 4, 5triphosphate, attenuates IRS-1 signaling
activity
via
prevention
of
tyrosine
phosphorylation is another modifier of tyrosine
kinase activity. Recent studies on c-Jun NH2
kinase iso-type 1 (JNK-1) suggest that this
kinase is also a mediator of insulin resistance
as it phosphorylates Ser on IRS-1.
i) Metformin, a biguanidinide as insulin
sensitizer:
Metformin presents several mechanisms
of action, but its primary mechanism for
lowering plasma glucose is to decrease hepatic
gluconeogenesis. To some extent, it also
improves insulin sensitivity of peripheral
tissues. It does this by increasing insulinstimulated uptake and use of glucose. This is
shown by a reduction in fasting plasma
glucose and insulin concentrations. It is not
effective in the absence of insulin. Metformin
also decreases intestinal absorption of glucose.
Metformin has been shown to decrease the
low-density lipoprotein (LDL) levels and
triglycerides (TGL) by about 10% to 15% and
may slightly increase the high-density
lipoprotein (HDL) levels. The improvement in
insulin sensitivity is a by product of these
alterations. Metformin has anorexigenic
47

Feature
properties. It acutely and selectively stimulates
p44/ p42 MAP kinase. Adverse effects of
metformin therapy include gastrointestinal
distress, such as abdominal pain, nausea, and
diarrhoea in up to half of patients.
CH3
H
N

NH2

H3C
NH

NH

Metformin

ii) Stimulation of Peroxisome-proliferatoractivated-receptor- (PPAR) led insulin


sensitization:
Adipocyte is a central player in the control
of energy balance and whole body lipid
homeostasis. Storage and release of fatty acids
and glycerol from the adipocyte impact overall
lipid homeostasis as well as hepatic and
peripheral glucose metabolism. Adipocytes
also perform an important endocrine function
by secreting numerous cytokines, bioactive
peptides, and complement factors. Upon
secretion into the bloodstream, adipocyte
derived signaling molecules act at distant sites
to regulate energy homeostasis. The
peroxisome is a sub-cellular organelle, whose
functions extend well beyond the removal of
molecular oxygen and later breakdown of
hydrogen peroxide, to include glycerolipid
synthesis, cholesterol biosynthesis and
breakdown,
and
fatty-acid
oxidation.
Peroxisome proliferator-activated receptors
(PPARs) are members of the nuclear receptor
family of ligand-activated transcription factors
that bind to fatty acids and their metabolites.
The three PPARs (alpha, beta/delta, and
gamma) are distributed differently in the
various organs. PPAR is expressed mainly in
tissues, where active fatty acid catabolism
occurs (e.g. liver, brown fat, kidney, heart, and
skeletal muscle) and PPAR m
ainly in white
and brown adipose tissue. PPAR is expressed
48

in most tissues. PPAR regulates genes


involved in fatty acid uptake and oxidation,
inflammation, and vascular function, whereas
PPAR regulates genes involved in fatty acid
uptake and storage, inflammation and glucose
homeostasis. Insulin resistance starts with
obesity, which resists anti-lipolytic effects of
insulin leading to increased plasma free fatty
acid levels and altered partitioning of FFA
between the adipose tissue, skeletal muscle,
and liver. This imbalance results in
intracellular accumulation of triglycerides and
fatty acid metabolites in muscle and liver.
Dysfunctional fat cells also produce excessive
amounts of cytokines e.g. tumor necrosis
factors-, interlukin-6 and resistin. The insulin
sensitivity thus can be improved by selective
stimulation by PPAR ligands. This property
has been attributed to the direct effect of
agonists on lipid metabolism in adipose tissue
and secondary effects on lipid and glucose
metabolism in liver and skeletal muscle.
PPAR
a gonists
promote
adipocyte
differentiation and promote FFA uptake and
storage in subcutaneous adipose tissue. This
reduces FFA levels, with associated reductions
in insulin resistance. PPAR is also believed to
increase the expression and translocation to the
cell surface of the glucose transporters thus
increasing glucose uptake into liver and
skeletal muscle cells and reducing plasma
glucose levels. PPAR agonists also restore
insulin sensitivity by decreasing TNF- and
increasing adiponectin expression.
O
N

NH
N

Pioglitazone

BRL-49653
O

NH

NH

CO2 H
O

Englitazone

Murglitazar

CH 3

NH
O

NH
O

HO
Ciglitazone

Troglitazone

Current R&D Highlights, Jan.-Mar. 2009

Feature
The thiazolidinediones more specifically
enhance insulin sensitivity, but they also
potently promote adipocyte differentiation and
often increase total fat mass. For example
rosiglitazone and pioglitazone are effective
glucose-lowering drugs but have moderate
effects on lipids resulting in increase of
adipocytes in patients with type 2 diabetes.
However, the L-tyrosine analogue farglitazar
has robust effects on glucose, high-density
lipoprotein as well as on triglycerides in
diabetic patients.
COOH

O
N

HN H

Farglitazar

C. Utilization of Stored Energy and Its


Control Mechanisms:
As we have seen above that the diabetes is
a consequence of obesity which results from a
chronic imbalance between energy intake and
energy expenditure. Energy expenditure
includes basal metabolism, physical activity
and adaptive (non-shivering) thermogenesis.
Adaptive thermogenesis is regulated at least
two hormonal effectors: -adrenergic agents
and thyroid hormone. On stimulation by adrenergic hormone norepinephrine in
adipocytes it starts lipolysis of stored
triglycerides to release fatty acid (FA) and
glycerol into the blood, which are taken up by
skeletal muscle cells for FA based -oxidation.
The fatty acid oxidation releases energy as
heat. These back up feed forward reactions
ensure energy supplies in case of emergency
and their stimulation have therefore been the
target for glucose homeostasis in present day
life style utilizing high energy food.
i) 3- Adrenergic receptor stimulation led
Current R&D Highlights, Jan.-Mar. 2009

thermogenesis:
Adipose tissue serves not only as a depot
for triglyceride storage but also as a dynamic
endocrine organ involved in the control of
energy balance. Adipocytes are responsible for
the storage of fat and its breakdown (lipolysis)
is primarily controlled by the sympathetic
nervous system. Activation of -adrenergic
receptors decreases lipolysis and activation of
-adrenergic receptors increases lipolysis.
They are members of the large family of Gprotein-coupled receptors that regulate an
assortment of intracellular second messenger
systems, including cAMP, phospholipid
hydrolysis, ion fluxes, and mitogen-activated
protein (MAP) kinase cascades. 3-adrenergic
receptor is expressed in white, brown as well
in skeletal tissue and its stimulation elevates
the levels of cAMP and thereby stimulation of
lipolysis and adipose specific genes. The
increased expression of uncoupling protein-1
in skeletal muscle and UCP-2, and - 3 in
adipose tissues uncouples the fatty acid
oxidation from oxidative phosphorylation. The
process increases heat production with a boost
in energy consumption rendering 3-adrenergic
receptor agonist as potential anti-obesity
agents and through stimulation of lipolysis
sensitization of insulin action. Some of the 3OH
NH
OH

HN
O

NH
O S O

H
N

NH2
O

O
HN

HN

LY 377604

L-757, 793
OH

HO
NH

OH

O
CH 3

Cl

N
H

NH

OH

N
NH2

AJ-9677

CP-331, 684
OH
O

NH
CH3
Cl

COONa
COONa

CL-316,243

agonists under development are mentioned


here. Encouraging data has emerged from
clinical studies of CL-316,243 a highly
selective albeit rodent specific 3-adrenergic
49

Feature
receptor agonist. It has been observed that it
increases lipolysis, fat oxidation and insulin
action in human. However due to its poor
bioavailability it has been abandoned. At
present the compound LY 377604 up in phase
III trial. With regard to thyroid hormone
stimulation, tyrosine analogs have also been
prepared and one of these compounds
farglitazar, dual activators of PPAR- and
PPAR- lowers lipids and improves insulin
action and is in phase III clinical settings.
Thus the several mechanistic aspect of
energy homeostasis including energy intake,
storage and its supply has been considered for
drug design. However, the area of adipocyte
cytokines e.g. tumor necrosis factor-,
interlukin-6, IKK-, JNK-1 etc. which are

major contributor for insulin resistance, has


not yet been exploited. Adiponectin modulates
in a way to neutralize the effect of TNF- and
sensitizes insulin action which has not received
attention so far. The stimulation of
thermogenesis by thyroid hormone and 3adrenergic system need further exploration to
obtain clinically useful molecules. The -cell
apoptosis decreases the -cell mass and hence
leads to defective insulin secretion which is
mediated by interleukin-1 secreted from
macrophage.
Anti-apoptotic
molecules
directed to -cell may prevent the damage and
should therefore enhance insulin level to
control type 2 diabetes. The subject therefore
requires attention.
Subunits. J. Gen. Physiol. 114, 203-213

Further Readings:
1.

6.

Metabolic syndrome and robustness tradeoffs. Diabetes,

(2008). J. R. White.
7.

Muramatsu.
2.

Novel strategies for the pharmacological management of

4.

5.

Insulin and Oral Antidiabetic Agents. Am. J. Pharm.


Educ. 69 (5), Article 89, 1-11 (2005); M. S. Ahmed.

8.

Therapeutic roles of peroxisome proliferator- activated

type 2 diabetes. Trends in Pharmacological Sciences

receptor agonists. Diabetes 51, 2460-2470 (2005). B.

25(2), 86-91 (2004). A. Nourparvar, A. Bulatta, U. D.

Staels and C. J. Fruchart.

Mario and R. Perfetti.


3.

Dipeptidyl Peptidase-IV Inhibitors: Pharmacological


Profile and Clinical Use. Clinical diabetes 26 (2), 53-57

53 (Supplement 3) S6-S15 (2004). H. Kitano, K.. Oda, T.


Kimura, Y. Matsudoka, M. Csete, J. Doyle and M.

(1999). J.C.

Koster, Q. Sha, and C.G. Nichols.

9.

A cold inducible Co-activator of nuclear receptors linked

Lehninger Principles of Biochemistry, D.L. Nelson and

to adaptive thermogenesis. Cell 92, 829-839 (1998). P.

M.M. Cox; Macmillan Worth Publishers Third Edition

Puigserver, Z. Wu, W. C. Park, R. Graves, M. Wright and

2003.

S. M. Bruce.

Dipeptidyl peptidase IV (DPP IV) inhibitors a newly

10. Discovery of Dapagliflozin: A potent, selective renal

emerging drug class for the treatment of type 2 diabetes.

sodium-dependent

Diabetes Vasc. Dis. Res. 3(3), 159165 (2006). Brian D.

Inhibitor for the Treatment of Type 2 Diabetes. J. Med.

Green, Peter R. Flatt, Clifford J. Bailey.

Chem, 51, 11451149 (2008). Meng et al.

glucose

co-transporter

2(SGLT2)

Sulfonylurea and K1-Channel Opener Sensitivity of KATP


Channels Functional Coupling of Kir6.2 and SUR1

50

Current R&D Highlights, Jan.-Mar. 2009

Feature

Overview of Diabetes Mellitus Management


Dr Ashim Ghatak
Division of Clinical & Experimental Medicine
Central Drug Research Institute, Lucknow
The major goal in treating diabetes is to weight loss, exercise, and oral medications.
minimize any elevation of blood sugar
Ideally, insulin should be administered in
(glucose) without causing abnormally low a manner that mimics the natural pattern of
levels of blood sugar. Type 1 diabetes is insulin secretion by a healthy pancreas;
treated with insulin, exercise, and a diabetic
however, the complex pattern of insulin
diet. Type 2 diabetes is treated first with secretion by the pancreas is difficult to
weight reduction, a diabetic diet, and exercise. duplicate. Still, adequate blood glucose control
When these measures fail to control the
can be achieved with careful attention to diet,
elevated blood sugars, oral medications are
regular exercise, home blood glucose
used. If oral medications are still insufficient, monitoring, and multiple insulin injections
treatment with insulin is considered.
throughout the day.
Adherence to a diabetic diet is an
important aspect of controlling elevated blood
sugar in patients with diabetes. The American
Diabetes Association (ADA) has provided
guidelines for a diabetic diet. The ADA diet is
a balanced, nutritious diet that is low in fat,
cholesterol, and simple sugars. The total daily
calories are evenly divided into three meals. In
the past two years, the ADA has lifted the
absolute ban on simple sugars. Small amounts
of simple sugars are allowed when consumed
with a complex meal.
Weight reduction and exercise are
important treatments for diabetes. Weight
reduction and exercise increase the body's
sensitivity to insulin, thus helping to control
blood sugar elevations.

Management of Type-I Diabetes Mellitus


Insulin is the mainstay of treatment for
patients with type 1 diabetes. Insulin is also
important in type 2 diabetes when blood
glucose levels cannot be controlled by diet,
Current R&D Highlights, Jan.-Mar. 2009

In the past, the insulin was being derived


from animal sources, particularly cows and
pigs. Not only was there a problem with
enough supply of insulin to meet the demand,
but beef and pork insulin also had specific
problems. Originating from animals, these
types of insulin caused immune reactions in
some people. Patients would become intolerant
or resistant to animal insulin. With the
acceleration of scientific research in the latter
half of the twentieth century, beef and pork
insulin were replaced by human insulin. In
1977, the gene for human insulin was cloned,
and through modern Recombinant technology,
human insulin is being manufactured in huge
amounts and is freely available Human insulin
is now widely used.
Insulin now comes in a variety of
preparations that differ in the amount of time
following injection until they begin to work
and the duration of their action. Because of
these differences, combinations of insulin are
51

Feature
often used to allow for a more tailored regimen
the most common types of insulin currently in
of blood sugar control. The table below lists use in the U.S. and their specific properties.
Table 1: Insulin Formulations Available[4,5]
Insulin

Onset of action

Peak

Duration

Rapid acting (analog)


As part lisproglulisine

10-20
minutes15-30 1-3 hours.5-2.5 hours1-1.5 3-5 hours3-6.5 hours3minutes10-15 minutes hours
5 hours

Short-acting (human)
Regular

30-60 minutes

1-5 hours

6-10 hours

1-2 hours

6-14 hours

16-24+ hours

0.8-2 hours1.1 hours

No significant
significant peak

Intermediate (human)
NPH
Long-acting (analog)
detemirglargine

peakNo Up to 24 hoursUp to 24
hours

Premixed (analog)
70%
APS/30%
aspart 10-20
minutes10-30 1-4 (2.4) hours1-6.5(2.6) Up to 24 hoursUp to 24
75%
NPL/25%
lispro minutes10-30 minutes hours0.8-4.8 (2.3) hours hoursUp to 24 hour
50% NPL/50% lispro
Premixed (human)
70% NPH/30% regular50% 30-60
NPH/50% regular
minutes

minutes30-60 1.5-16 (4.4) hours2-5.5 Up to 18-24 hoursUp


(3.3) hours
to 18-24 hours

Range (mean)NPH = neutral protamine Hagedorn; APS = aspart protamine suspension; NPL = neutral protamine
lispro

Table 2: Currently Available Methods for Insulin Delivery


Device

Advantages

Disadvantages

Prefilled pen, eg, FlexPen


(Novo Nordisk, Bagsvaerd,
Denmark), Humalog Pen (Eli
Lilly and Co, Indianapolis,
Indiana), SoloSTAR (Aventis
Pharma Holding GmbH,
Frankfurt, Germany)

Less wastage of pen contents vs Initially can be more expensive than


vial/syringe Discreet Appears less vial/ syringe Cannot mix insulins
''medical''Injection may be more Possibility of air bubbles
comfortable than vial and syringe
Less time consuming Refrigeration
not required Easy to use Accurate
dosing Disposable

Reusable pen, eg, NovoPen Discreet Sturdier than prefilled pens As above Need to change cartridges

52

Current R&D Highlights, Jan.-Mar. 2009

Feature
(Novo Nordisk), HumaPen Injection may be more comfortable (time consuming and less convenient
MEMOIR (Eli Lilly and Co), than vial and syringeAccurate dosing than prefilled pens)
OptiClik (Aventis Pharma
Holding GmbH)
Dosers, eg, InnoLet (Novo Easy to use Accurate dosing Suitable As above Not currently available with
for patients with visual/ dexterity insulin analogs
Nordisk)
problems Disposable
Insulin pump

Uses only rapid-acting insulin (most


consistent profile) Most accurate
dosing Allows very flexible lifestyle
Closest to replacing body's own
insulin

Jet injectors

Needle-free Single component May May cause bruising Potential for


benefit patients with severe insulin- decreased amount of absorbed insulin
induced lipoatrophy
Requires weekly cleaningRisk of
infection May be less comfortable
than needle-based devices Not suited
to intermediate- or long-acting
insulins

Pump and supplies expensive


Undetected interruptions in insulin
delivery may occur, with possible
increased risk of ketoacidosisMay
cause
discomfort
as
worn
continuously Needs high patient
motivation,
involvement,
and
commitment to use

Table 3: Insulin Analog Formulations Available in Pen and Doser Devices


Device

Insulin

Manufacturer

Disposable (prefilled) pens


Levemir, NovoLog, NovoLog Mix 70/30

FlexPen
Lilly
Pen

Novo Nordisk

Prefilled Humalog, Humalog Mix 70/30, Humalog Mix 75/25, Humalog Mix Eli Lilly
50/50, Humulin N

SoloSTAR

Lantus, Apidra

Sanofi-Aventis

Durable (cartridge) pens


NovoPen 3

Levemir, NovoLog, NovoLog Mix 70/30

Novo Nordisk

NovoPen Junior

Levemir, NovoLog, NovoLog Mix 70/30

Novo Nordisk

HumaPen
LUXURA

Humalog, Humulin

Eli Lilly

Current R&D Highlights, Jan.-Mar. 2009

53

Feature
HumaPen
MEMOIR

Humalog

Eli Lilly

OptiClik

Lantus, Apidra

Sanofi-Aventis

Novolin N, Novolin R, Novolin 70/30

Novo Nordisk

Dosers
InnoLet

For example, a patient may take an


injection of Lantus in the morning and evening
to provide a baseline of insulin throughout a
24-hour period. In addition, the same patient
may take an injection of Humalog just before
meals to cover the increase in carbohydrate
load after eating.

Different Methods of Delivering Insulin


There are now a variety of insulin
preparations and also there are various
methods for administering insulin.
Pre-filled insulin pens: In the past, insulin
was available only in an injectable form that
involved carrying syringes (which a few
decades ago were made of glass and required
sterilization), needles, vials of insulin, and
alcohol swabs. Needless to say, patients often
found it difficult to take multiple shots each
day, and, as a result, good blood sugar control
was often compromised. Many pharmaceutical
companies are now offering discreet and
convenient methods of delivering insulin.
Both Novo Nordisk and Lilly have an
insulin pen delivery system. This system is
similar to an ink cartridge in a fountain pen. A
small pen-sized device holds an insulin
cartridge (usually containing 300 units).
Cartridges are available in the most widely
used insulin formulations, such as those listed
in the table above. The amount of insulin to be
injected is dialed in by turning the bottom of
the pen until the required number of units is
seen in the dose-viewing window. The tip of
the pen consists of a needle that is replaced
with each injection. A release mechanism
allows the needle to penetrate just under the
skin and deliver the required amount of
54

insulin. The cartridges and needles are


disposed of when finished and new ones
simply are inserted. In many cases, the entire
pen is disposed of. These insulin delivery
devices are less cumbersome than traditional
methods.
Insulin pump: The most recently
available advance in insulin delivery is the
insulin pump. In the U. S., MiniMed, Deltec
and Disetronic market the insulin pump. An
insulin pump is composed of a pump reservoir
similar to that of an insulin cartridge, a batteryoperated pump, and a computer chip that
allows the user to control the exact amount of
insulin being delivered. Currently, pumps on
the market are about the size of a pager or
beeper. The pump is attached to a thin plastic
tube (an infusion set) that has a cannula (like a
needle but soft) at the end through which
insulin passes. This cannula is inserted under
the skin, usually on the abdomen. The cannula
is changed every two days. The tubing can be
disconnected from the pump while showering
or swimming. The pump is used for continuous
insulin delivery, 24 hours a day. The amount
of insulin is programmed and is administered
at a constant rate (basal rate). Often, the
amount of insulin needed over the course of 24
hours varies depending on factors like
exercise, activity level, and sleep. The insulin
pump allows for the user to program many
different basal rates to allow for this variation
in lifestyle. In addition, the user can program
the pump to deliver additional insulin during
meals to cover the excess demands for insulin
caused by the ingestion of carbohydrates with
the meal.
Over 50,000 people worldwide are using
Current R&D Highlights, Jan.-Mar. 2009

Feature
an insulin pump. This number is growing
dramatically as these devices become smaller
and more user-friendly. Insulin pumps allow
for tight blood sugar control and lifestyle
flexibility while minimizing the effects of low
blood sugar (hypoglycemia). At present, the
pump is the closest device on the market to an
artificial pancreas. More recently, newer
models of the pump have been developed that
do not require a tubing, in fact - the insulin
delivery device is placed directly on the skin
and any adjustments needed for insulin
delivery are made through a PDA like device
that must be kept within a 6 foot range of the
insulin delivery device, and can be worn in a
pocket, kept in a purse, or on a tabletop when
working.
Probably the most exciting innovation in
pump technology is the ability to use the pump
in tandem with newer glucose sensing
technology. Glucose sensors have improved
dramatically in the last few years, and are an
option for patients to gain further insight into
their patterns of glucose response to tailor a
more individual treatment regimen. The
newest generation of sensors allows for a real
time glucose value to be given to the patient.
The implantable sensor communicates
wirelessly with a pager-sized device that has a
screen. The device is kept in proximity to the
sensor to allow for transfer of data, however, it
can be a few feet away and still receive
transmitted information. Depending on the
model, the screen displays the blood glucose
reading, a thread of readings over time, and a
potential rate of change in the glucose values.
The sensors can be programmed to produce a
"beep" if blood sugars are in a range that is
selected as too high or too low. Some can
provide a warning beep if the drop in blood
sugar is occurring too quickly.
To take things one step further, there is
one particular sensor that is new to the market
that is designed to communicate directly with
the insulin pump. While the pump does not yet
respond directly to information from the
Current R&D Highlights, Jan.-Mar. 2009

sensor, it does "request" a response from the


patient if there is a need for adjustments
according to the patterns it is programmed to
detect. The ultimate goal of this technology is
to "close the loop" by continuously sensing
what the body needs, and then responding by
providing the appropriate dose of insulin.
While this technology is a few more years in
the making, the strides in this direction
continue to grow.
Inhaled Insulin Inhaled insulin, marketed
by Pfizer in 2006, was approved by the FDA.
This inhaled form of insulin is called Exubera.
The insulin is packaged in dry blister packs
that are inserted into an inhalation device. This
device lances the powder packs allowing the
insulin to enter a chamber that has a mouth
piece through which the user can inhale the
insulin. Exubera has a peak of action similar to
Humalog (rapid acting), and a duration of
action similar to regular insulin (short acting).
It can be combined with oral medication in
patients with type 2 diabetes or used alone. In
patients with type 1 diabetes the insulin should
be combined with a longer acting basal insulin
such as glargine.
The side effect profile of inhaled insulin is
similar to other insulins, and the user must be
aware of hypoglycemia. In addition, since the
insulin is absorbed through the lungs, there
was initial concern regarding lung function.
While there is a slight decrease in lung
function with the initial use of Exubera, this
stabilizes quickly and returns to baseline of
aged matched controls when the Exubera is
discontinued. Since this is still a new product,
it is recommended that any patient starting on
inhaled insulin have lung function tests done
prior to starting treatment. If baseline values of
FEV1 (a measure of lung function) are < 70%,
Exubera is not given. After six months of use
lung function tests are performed again; if
deterioration is noted, Exubera is discontinued.
Exubera is not to be used in regular or
intermittent smokers and patients requiring
55

Feature
very small doses of insulin. Nevertheless, in
the right population, this is a great option.
Intranasal, Transdermal: Other routes for
the delivery of insulin have also been tried.
Intranasal insulin delivery was thought to be
promising. However, this method was
associated with poor absorption and nasal
irritation. Transdermal insulin (skin patch
delivery) has also yielded disappointing results
to date. Insulin in pill form is also not yet
effective since the digestive enzymes in the gut
break it down.
Pancreas transplantation: Ultimately, the
goal in the management of type 1 diabetes is to
provide insulin therapy in a manner that
mimics the natural pancreas. Perhaps the
closest therapy available at this time is a
transplant of the pancreas. Several approaches
to pancreatic transplantation are currently
being studied, including the whole pancreas
and isolated islet cells (these groups of cells
contain beta cells that are responsible for
insulin production). Data available from 1995
indicates that almost 8,000 patients underwent
pancreatic transplantation. Most patients
undergo pancreatic transplantation at the time
of kidney transplantation for diabetic kidney
disease.
Transplantation is not without risk. Both
the surgery itself and the immnosuppression
that must occur afterward pose significant risks
to the patient. For these reasons, the kidney
and pancreas are usually transplanted at the
same time. At present, there is disagreement
about whole pancreas transplantation in
patients not currently requiring kidney
transplantation. The issue of whether the
benefits outweigh the risks in these patients is
under debate. There is also a chance that
diabetes will occur in the transplanted
pancreas. Selectively transplanting islet cells is
an interesting alternative to whole pancreas
transplantation. However, the concern over
rejection remains. Attempts to disguise the
islet cells in tissues that the body won't reject
56

(for example, by surrounding the islet cells by


the patient's own cells and then implanting
them) are underway. In addition, researchers
are exploring artificial barriers that can
surround the islet cells, provide protection
against rejection, and still allow insulin to
enter the bloodstream.

Management of Type II Diabetes


Based on what is known, medications for
type 2 diabetes are designed to:
o
o
o
o
o

o
o
o
o
o
o

Increase the insulin output by the pancreas.


Decrease the amount of glucose released from the
liver.
Increase the sensitivity (response) of cells to
insulin.
Decrease the absorption of carbohydrates from the
intestine.
Slow emptying of the stomach to delay the
presentation of carbohydrates for digestion and
absorption in the small intestine.
When selecting therapy for type 2 diabetes,
consideration should be given to:
The magnitude of change in blood sugar control
that each medication will provide.
Other coexisting medical conditions (high blood
pressure, high cholesterol, etc.)
Adverse effects of the therapy
Contraindications to therapy
Issues that may affect compliance (timing of
medication, frequency of dosing)
Cost to the patient and the healthcare system

It's important to remember that if a drug


can provide more than one benefit (lower
blood sugar and have a beneficial effect on
cholesterol, for example), it should be
preferred. It's also important to bear in mind
that the cost of drug therapy is relatively small
compared to the cost of managing the longterm complications associated with poorly
controlled diabetes.
Varying combinations of medications also
are used to correct abnormally elevated levels
of blood glucose in diabetes. As the list of
medications continues to expand, treatment
options for type 2 diabetes can be better
tailored to meet an individuals needs. Not
every patient with type 2 diabetes will benefit
from every drug, and not every drug is suitable
for each patient. Patients with type 2 diabetes
Current R&D Highlights, Jan.-Mar. 2009

Feature
should work closely with their physicians to
achieve an approach that provides the greatest
benefits while minimizing risks.
Patients with diabetes should never forget
the importance of diet and exercise. The
control of diabetes starts with a healthy
lifestyle regardless of what medications are
being used.
Medications that increase the insulin
output by the pancreas - sulfonylureas and
meglitinides :
Sulfonylureas - Historically, increasing
insulin output by the pancreas has been the
major area targeted by medications used to
treat type 2 diabetes. Medications that increase
the output of insulin belong to a class of drugs
called sulfonylureas. Sulfonylureas primarily
lower blood glucose levels by increasing the
release of insulin from the pancreas. Older
generations
of
these
drugs
include
chlorpropamide and tolbutamide, while newer
drugs include glyburide (DiaBeta), glipizide
(Glucotrol), and glimepiride (Amaryl). These
drugs are effective in rapidly lowering blood
sugar but run the risk of causing hypoglycemia
(abnormally low and dangerous levels of blood
sugar). In addition, they are sulfa-containing
drugs and should be avoided by patients who
are allergic to sulfa.
Meglitinides - Repaglinide and Nateglinide:
The class of drugs known as meglitinides is
relatively new. Meglitinides also work on the
pancreas to promote insulin secretion. Unlike
sulfonylureas that bind to receptors on the
insulin producing cells, meglitinides work
through a separate potassium based channel on
the cell surface. Unlike the sulfonylureas
which last longer in the body, repaglinide and
nateglinide are very short acting, with peak
effects within one hour. For this reason, they
are given up to three times a day just before
meals. Since these drugs also increase
circulating insulin levels, they may cause
hypoglycemia, but the literature suggests this
is less frequent than the hypoglycemia seen
Current R&D Highlights, Jan.-Mar. 2009

with sulfonylureas.
In a three month study, repaglinide
dropped fasting blood glucose values by 61
mg/dL and post meal blood glucose values by
100 mg/dL. Because repaglinide is short acting
and given before meals, it is particularly
beneficial in lowering blood glucose after
meals and does not tend to lower fasting
glucose levels to the same degree. Repaglinide
has been used in combination with other
medications, such as metformin (Glyciphage),
with impressive results. In 83 patients with
type 2 diabetes, blood sugar control improved
significantly with the addition of repaglinide to
Glyciphage.
Repaglinide
interacts
with
other
medications. Therefore, the doctor must be
aware of all other medications a patient is
taking before prescribing repaglinide. The
usual starting dose is 0.5mg before each meal
and can be increased to 4mg. The maximum
daily dose is 16mg. Repaglinide is used with
caution in people with kidney or liver
abnormalities. Since repaglinide increases
insulin levels, it has the risk of causing
abnormally low blood sugars. Blood sugars
that remain severely low can result in
sweating, tremors, confusion, and may lead to
coma and seizure. In addition, the use of
repaglinide has been associated with
headaches, muscle and joint aches, along with
sinus infections in some individuals. This drug
should not be used in pregnancy or by nursing
mothers. The dose may need to be adjusted in
older people, since the elderly may metabolize
(eliminate) medications at a slower rate. For
more, please read the drug information on
repaglinide.
Nateglinide has essentially the same
profile of side effects and interactions as
repaglinide. The major benefit of Nateglinide
is that the starting dose of 120mg does not
need to be adjusted upward, but rather remains
constant. These medications are also relatively
safe to use in people with impaired kidney
57

Feature
function..
Biguanides: Medications that decrease the
amount of glucose produced by the liver : A
class of drugs called biguanides has been used
for many years in Europe and Canada. In 1994,
the FDA approved the use of the biguanide
metformin (Glyciphage) for the treatment of
type 2 diabetes in the U.S. Glyciphage is
unique in its ability to decrease glucose
production by the liver. Briefly, because
metformin does not increase insulin levels,
when used alone, it does not usually cause
hypoglycemia. In addition, metformin has an
effect whereby it tends to suppress appetite,
which may be beneficial in diabetics who tend
to be overweight. Metformin may be used by
itself or together with other oral drugs or
insulin. It should not be used in patients with
kidney impairment and should be used with
caution in those with liver impairment. The
older biguanides that preceded metformin were
associated with a serious condition called
lactic acidosis, a dangerous acid build up in the
blood resulting from accumulation of the drug
and its breakdown products. While metformin
is safer in this regard, it is recommended that
the drug be discontinued for 24 hours before
any procedure involving the intravenous
injection of dyes (such as for some x-ray
studies of the kidney) or surgery is performed.
The dyes may impair kidney function and
cause a build up of the drug in the blood.
Metformin can be restarted after these
procedures once the patient is urinating
normally.
Medications that increase the sensitivity of
cells to insulin: The class of drugs known as
thiazolidinediones lowers blood glucose by
improving target cell response to insulin (that
is, increasing the sensitivity of the cells to
insulin). Troglitazone (Rezulin) was the first of
this class in the U.S. Because of severe toxic
liver effects, troglitazone has been taken off
the market. Sister compounds are now
available with a better safety profile. These
drugs include pioglitazone and rosiglitazone.
58

and
rosiglitazone
are
thiazolidinediones approved for use in the
India. While they are sister compounds to
Rezulin, extensive studies have failed to show
that they are associated with any liver
problems. Both Pioglitazone and rosiglitazone
act
by
increasing
the
sensitivity
(responsiveness) of cells to insulin. They
improve the sensitivity of muscle and fat cells
to insulin. These drugs have been effective in
lowering blood sugars in patients with type 2
diabetes, Pioglitazone and rosiglitazone act
within one hour of administration and are
taken once daily. It is important to note that it
takes up to six weeks to see a drop in blood
glucose levels with these drugs and up to 12
weeks to see a maximum benefit. Pioglitazone
and rosiglitazone have been approved as first
line therapy in diabetes and for use in
combination with other drugs. Both drugs may
be used in patients taking other oral drugs as
well as those using insulin.
Pioglitazone

While reported liver problems with these


agents are mild (and reversible with
discontinuation of the drug), most physicians
choose to follow an earlier recommendation to
do blood tests to detect liver injury every two
months or so during the first year of therapy.
Recently this recommendation has been
removed. If at any point the liver tests increase
to three times the normal upper limit, the drug
should be stopped.
The most important contraindications to
these medications include any type of liver
disease, and heart failure. Fluid retention can
be of particular concern in patients with signs
or symptoms of heart failure and in those with
ejection fractions of less than 40% which
indicates poor function of the heart. While the
reports are three to eight pounds, clinical
experience shows up to 12-15 pounds of
weight gain can occur. Usually the majority of
this is fluid, but an absolute body weight gain
can also occur. This is likely to be dosedependent and, therefore, the increases in
weight may be greater with higher doses of
Current R&D Highlights, Jan.-Mar. 2009

Feature
drug. Weight gain is more pronounced in
patients who are also taking insulin. In general,
the ankle swelling and puffiness due to the
accumulation of fluid can be controlled with
the addition of a diuretic such as
spironolactone (Aldactone) furosemide
(Lasix) does not work as well) or by
reducing the dose. On occasion, patients may
be symptomatic enough from fluid retention to
warrant withdrawal of the drug. Some recent
studies have suggested an association between
pioglitazone and rosiglitazone and untoward
cardiac events, for example, heart attacks,
though this association is controversial.
Regardless of the controversy, it is well
established that pioglitazone and rosiglitazone
should be avoided in patients with
symptomatic heart failure or heart failure.
Another newer concern is an association
of treatment with a small increase in the
frequency of fractures of the distal long bones
of the arms and legs. At present, this does not
translate into fractures of the hip and spine,
which would be clinically more worrisome.
More data is needed to make a definitive
statement about cause and effect at this time.
As
an
aside,
Pioglitazone
and
rosiglitazone have an added benefit of
changing cholesterol patterns in diabetes. HDL
(or good cholesterol) increases with these
medications, and triglycerides often decrease.
While there is some controversy regarding
what happens to bad cholesterol (LDL) levels,
there is a suggestion that Pioglitazone may be
superior in changing lipid profiles than
rosiglitazone. In this population of diabetics
that is already at an increased risk for heart
disease, an improvement in cholesterol profile
is beneficial. As more and more data becomes
available, there is mounting evidence that this
class of drugs may provide direct benefits to
the heart and large blood vessels and may
actually be valuable in preventing the
progression of diabetes in high-risk individuals
by reducing inflammation and by decreasing
clotting factors. As time goes on, there is no
Current R&D Highlights, Jan.-Mar. 2009

doubt that the uses for this class of medications


will expand.
Pioglitazone is used for the treatment of
type II diabetes along with a healthy diabetic
diet, regular exercise, weight control, smoking
reduction, and careful monitoring of blood
glucose. Pioglitazone may be used alone or in
combination with metformin, a drug in a
different class of anti-diabetic drugs, that also
lowers blood glucose. Since it requires
naturally-secreted insulin to be effective,
pioglitazone is not recommended in type I
diabetes where the amount of insulin is very
low or absent. Nevertheless, pioglitazone is
approved for treating type II diabetes in
combination with insulin as well as another
class of anti-diabetic drugs, the sulfonylureas.
Dosing- Pioglitazone is prescribed once daily
in doses ranging from 15 to 45 mg.
Pioglitazone may be taken any time of the day,
with or without meals. If a dose is missed on
one day, two doses should not be taken the
next day to make up for the missed dose.
Drug Interactions: To date, no formal
studies to evaluate drug interactions of
pioglitazone with other drugs have been
conducted.
However,
since
another
thiazolidinedione that is similar to pioglitazone
may reduce the effectiveness of oral
contraceptives
(potentially
leading
to
pregnancy), caution should be used when
using pioglitazone with an oral contraceptive.
Clinical studies using pioglitazone 1545mg did not reveal changes in blood levels
for the following drugs: glipizide, digoxin,
warfarin or metformin. In addition, the clotting
of blood did not appear to be changed enough
by pioglitazone to require alterations in the
doses of the blood thinner, warfarin.
Pregnancy- There are no adequate studies of
pioglitazone in pregnant women. Pioglitazone
may be used in pregnancy if the physician
feels the potential risks are justified. Nursing
Mothers: It is unknown if pioglitazone is
secreted in breast milk. Therefore, the safety to
59

Feature
a nursing infant when the mother is taking
pioglitazone is unknown.
Side Effects and Precautions-The most
common side effects seen in clinical trials with
pioglitazone alone or in combination with
sulfonylureas, metformin, or insulin were
upper respiratory tract infection, headache,
sinusitis, muscle aches, tooth disorders,
hypoglycemia, and sore throat. In addition,
fluid accumulation (edema) occurred in less
than 5% of patients taking pioglitazone alone
but 15% of patients taking pioglitazone and
insulin (as compared with 2% and 7% of
patients receiving placebo, respectively). Fluid
accumulation can lead to heart failure.
To date, no formal studies to evaluate
drug interactions of pioglitazone with other
drugs have been conducted. Nevertheless,
because it interacts with the liver enzymes that
eliminate some other drugs, there is the
potential for pioglitazone to increase the
elimination of such drugs as erythromycin,
calcium channel blockers (e.g., Cardizem),
cisapride
(Propulsid),
corticosteroids,
cyclosporine, tracrolimus, trizolam (e.g.,
Halcion), trimetrexate, and HMG-CoA
reductase inhibitors (e.g., Lipitor). This would
reduce their effectiveness.
Since
another
thiazolidinedione
antidiabetic drug has been associated with liver
injury, it is recommended that periodic
monitoring of liver-related side effects and
liver function be done in patients taking
pioglitazone. Side effects while taking
pioglitazone which may be due to liver injury
include nausea, vomiting, abdominal pain,
fatigue, anorexia (loss of appetite), or dark
urine. Blood liver tests also are recommended
during pioglitazone therapy.
Rosiglitazone, combined with diet,
exercise, weight control and cessation of
smoking is used for treating type II diabetes.
Rosiglitazone may be used alone or in
combination with other types of anti-diabetic
drugs such as metformin or sulfonylureas as
60

well as insulin. Since it requires naturallysecreted insulin to be effective, rosiglitazone is


not recommended for use in type I diabetes
where the amount of insulin is very low or
absent.
Dosing- Rosiglitazone may be taken once or
twice daily, with or without meals. Daily doses
range from 4 to 8 mg either with or without
other antidiabetic medications. Studies do not
demonstrate additional effects when more than
8mg per day are taken.
Drug Interactions- Rifampin decreases the
blood concentration of rosiglitazone by
increasing its breakdown in the liver.
Therefore, use of rifampin may decrease the
effect of rosiglitazone.
Gemfibrozil increases the concentration of
rosiglitazone in the blood by reducing its
breakdown. Therefore, rosiglitazone may
increase the side effects of rosiglitazone.
Pregnancy- There are no adequate studies of
rosiglitazone in pregnant women. Nursing
Mothers: It is unknown if rosiglitazone is
secreted in breast milk. Therefore, the safety of
rosiglitazone to nursing infants also is
unknown.
Side Effects and Precautions- The most
common side effects seen with rosiglitazone
alone or in combination with metformin are
upper respiratory tract infection, haedache,
back pain, hyperglycemia, fatigue, sinusitis,
diarrhea and hypoglycemia. Rosiglitazone has
been shown to cause mild to moderate
accumulation of fluid (edema) and can lead to
heart failure. Patients who already have heart
failure. may develop worsening symptoms
with rosiglitazone. In addition, anemiamay
occur with rosiglitazone alone or combined
with metformin. Rosiglitazone also causes
increasing amounts of weight gain with
increasing doses.
A review of the studies of rosiglitazone
led the FDA to conclude that the medication
might increase the risk of heart attacks and
Current R&D Highlights, Jan.-Mar. 2009

Feature
angina, but left the association as inconclusive.
Additionally, there isn't enough evidence that
the risk of heart attack and angina is any
greater with rosiglitazone than with other oral
medicines used in the treatment of diabetes.
Uses: Rosiglitazone is an anti-diabetic
drug (thiazolidinedione-type, also called
"glitazones") used with a proper diet and
exercise program to control high blood sugar
in patients with type 2 diabetes (non-insulindependent diabetes). Rosiglitazone works by
helping to restore your body's proper response
to insulin, thereby lowering your blood sugar.
Effectively controlling high blood sugar helps
prevent heart disease, strokes, kidney disease,
blindness, and circulation problems, as well as
sexual function problems (impotence).
Rosiglitazone is used either alone or in
combination
with
other
anti-diabetic
medications (e.g., metformin, sulfonylureas,
insulin).

Medications
that
Decrease
the
Absorption of Carbohydrates from the
Intestine
Before being absorbed into the
bloodstream, carbohydrates must be broken
down into smaller sugar particles, such as
glucose, by enzymes in the small intestine.
One of the enzymes involved in breaking
down carbohydrates is called alpha
glucosidase. By inhibiting this enzyme,
carbohydrates are not broken down as
efficiently and glucose absorption is delayed.
Acarbose: The alpha glucosidase inhibitor
available in the India. is arcabose (Multibay).
In clinical trials with over 700 patients, the use
of arcabose was associated with a reduction in
hemoglobin Alc values (a well known
measurement of average blood sugars over the
preceding three months) that was significantly
greater than the use of placebo (no treatment).
However, as a single agent, arcabose is not as
effective as the other medications for diabetes.
Since arcabose works in the intestine, its
effects are additive to diabetic medications that
Current R&D Highlights, Jan.-Mar. 2009

work at other sites, such as sulfonylureas.


Clinical studies have shown statistically better
control of blood glucose in patients treated
with Precose and a sulfonylurea compared to
the sulfonylurea alone. arcabose is currently
used alone or in combination with a
sulfonylurea.
Arcabose is taken three times a day at the
beginning of meals. The dosage varies from 25
to 100mg with each meal. The maximum
recommended dose is 100mg three times a
day. At doses greater than this, reversible
abnormalities in liver tests may be seen.
Because of its mechanism of action, arcabose
has significant gastrointestinal side effects.
Abdominal pain, diarrhea, and gas are
common and are seen in up to 75% of patients
taking Arcabose. For this reason, arcabose is
administered using a low initial dose that is
increased over weeks depending on the
patient's tolerance. Most of the gastrointestinal
symptoms tend to subside over the course of a
few weeks although some patients report
persistent problems.

New Medications that Affect Glycemic


Control
Symlin (pramlintide): Symlin is the first in
a new class of injectable, anti-hyperglycemic
medications for use in patients with type 2 or
type 1 diabetes treated with insulin.
Pramlintide, the active ingredient in Symlin, is
a synthetic analog of human amylin, a
naturally occurring neuroendocrine hormone
synthesized by pancreatic beta cells that helps
control glucose control after meals. Amylin,
similar to insulin, is absent or deficient in
patients with diabetes. When used with insulin,
this compound can improve glycemic control
and has additional benefits that cannot be
realized with insulin alone.
According to published data, Symlin
reduces post meal blood sugar peaks, reduces
glucose fluctuations throughout the day,
enhances satiety (the sensation of fullness)
leading to potential weight loss, and lowers
61

Feature
mealtime insulin requirements. Studies have
shown it improves A1C beyond the effect of
insulin alone.
Symlin is taken just prior to meals, three
times a day. It is given in injection form and is
used for: Type 2 diabetes, as an additional
treatment in patients who use mealtime insulin
therapy and have failed to achieve desired
glucose control despite optimal insulin
therapy, with or without a concurrent
sulfonylurea agent and/or metformin. Type 1
diabetes, as an additional treatment in patients
who use mealtime insulin therapy and who
have failed to achieve desired glucose control
despite optimal insulin therapy.
Symlin is considered a therapy option in
patients with insulin-using type 2 or type 1
diabetes, that are unable to achieve adequate
glycemic control despite individualized insulin
management. Insulin-using patients with type
2 diabetes may also be taking a concurrent
sulfonylurea agent and/or metformin.
The major side effect of Symlin is nausea,
and this can be reduced with a slow, steady,
increase in dose. The other major side effect is
hypoglycemia (dangerously low levels of
blood sugar). To avoid this, the dose of
mealtime insulin should be cut in half when
starting Symlin. Of note is the degree of
weight loss seen with Symlin therapy. Studies
for up to six months show weight loss of
greater than six pounds more than placebo
(inactive pills). For more, please read the drug
information on pramlintide (Symlin).
Byetta (exenatide)- Byetta (exenatide) is a
new medication on the market that has it's
origins in an interesting place--the Gila
monster's saliva. Scientists studying this small
lizard noted it could go a long time without
eating. They found a substance in it's saliva
that slowed stomach emptying, thus making
the lizard feel fuller longer. This substance was
similar in nature to a gut hormone found in
humans known as GLP-1. GLP-1 is broken
down in the body by an enzyme called DPP62

IV. So, if you could make a substance like


GLP-1 that was not so easy to breakdown, this
would have potential benefit; thus, the studies
began. Ultimately, after modifying this
hormone, exenatide (with the trade name
Byetta) was developed. Byetta is the first in a
new class of drugs for the treatment of type 2
diabetes called incretin mimetics. Byetta has
been shown to have many of the same effects
on sugar regulation as GLP-1, so it mimics the
body's natural physiology for self-regulating
blood sugar. Namely, it slows the release of
glucose from the liver, slows stomach
emptying thereby regulating delivery of
nutrients to the intestine for absorption, and
works centrally in the brain to regulate hunger.
Byetta is indicated as additional therapy to
improve control of blood sugars in patients
with type 2 diabetes who are taking metformin,
a sulfonylurea, or a combination of metformin
and a sulfonylurea but who have not achieved
adequate sugar control. It enhances the way the
insulin producing beta cells in the pancreas
work. Insulin secretion increases only when
blood sugars are high and decreases as blood
sugars approach normal. In addition to
enhancing the normal physiology of the beta
cell, Byetta suppresses glucose release from
the liver, slows stomach emptying and the
absorption of nutrients including carbohydrate,
and reduces intake of food.
Just like Symlin, Byetta is given by
injection, but it is given twice a day (usually
before breakfast and dinner meals). It comes in
a disposable pen form and is available in two
doses. The goal is to start with the lower dose
for a month or so and then move up to the
higher dose if needed and if tolerated. Similar
to Symlin, the main side effect is nausea, most
likely due to its effects on stomach emptying.
This medication is temperature sensitive and it
was recommended that the pens be stored at
36-46 degrees F. Recently, this has changed,
with a recommendation that unopened pens be
refrigerated, and once opened, the pens can be
left at room temperature. The risk of
Current R&D Highlights, Jan.-Mar. 2009

Feature
hypoglycemia is still a possibility with Byetta,
especially when used in combination with
sulfonylureas. Your physician may choose to
decrease the dose of some of your other
medications when initially evaluating how you
respond to Byetta.
Similar to Symlin, weight reduction is
seen with Byetta in the majority of patients.
This makes it particularly suitable for the
typical patient with type 2 diabetes who is also
overweight. For more, please read the drug
information pamphlet on exenatide (Byetta).
A longer acting from of Byetta is currently
being considered for approval by the FDA.
This would allow for the same benefits (and
side effects) without need for such frequent
injections. DPP-IV inhibitors. GLP-1 in the
body is broken down by an enzyme called DPP
IV. Logically, you can either make a synthetic
GLP-1 that is not broken down by this enzyme
(for example, Byetta) or you could try to stop
the enzyme that breaks down the GLP-1 your
body already makes. Hence, the new class of
drugs called DPP IV inhibitors. They do just
that, that is, they inhibit this enzyme from
breaking down GLP-1. This allows GLP-1
already in the blood to circulate longer. There
are a number of companies working on this
class of drug and the FDA just approved the
first drug in this class made by Merck and
called Januvia. Januvia can be used in
combination with certain other medications
and must be dose adjusted in patients with
poor kidney function. For more, please read
the Januvia pamplet.
These drugs have essentially the same side
effect profile as Byetta; however, they are in

Current R&D Highlights, Jan.-Mar. 2009

pill form. While Byetta has a significant


weight loss profile, DPP-IV inhibitors so far
have had no effect on weight.

Combination Medications
Glyburide/ metformin, rosiglitazone/
metformin,
glipizide/
metformin,
and
pioglitazone/metformin are four relatively new
combination pills in varying strengths are in
the market to treat diabetes.
The benefit to these combination drugs is
that there are fewer pills to take, hopefully
leading to better compliance. While they work
well, it is preferable to give patients individual
medications until we know what doses are
working, and then switch to a combination pill
once the patient has been stable on the doses of
individual medications for a period of time.

A Final Word
These last few years have been an exciting
time in diabetes care. Many agents for the
treatment of type 2 diabetes are under
development and the options for insulin
therapy continue to grow and methods for
insulin delivery continue to become more
refined. While research continues to expand in
these areas, one thing remains constant.
Achieving the best blood sugar control
possible remains the ultimate goal in both type
1 and type 2 diabetes. We now know, beyond a
doubt, that good blood sugar control
minimizes the long-term complications of
diabetes, including blindness, nerve damage,
and kidney damage. Finally, a healthy lifestyle
can do nothing bad...it should remain the
cornerstone of management for diabetes.
.

63

News & Views


mmol/l. In the United States normal fasting
blood glucose is considered to be below 5.6
mmol/l and normal concentrations after an oral
two hour glucose tolerance test to be below 7.8
mmol/l.

57 Million Americans Should be Treated


for Prediabetes
Some 57 million US residents have
prediabetes, and almost 24 million, 8% of the
population, already have diabetes, says the
American
Association
of
Clinical
Endocrinologists.
Speaking at a meeting in Washington, DC,
the endocrinologists said that doctors need to
identify people with prediabetes and treat them
by recommending changes to lifestyle, and
exercise such as diet, and prescribing drugs if
necessary. Otherwise the human and financial
cost would be huge, they warned. In a
consensus statement they said that prediabetes"
raises short term absolute risk of type 2
diabetes five to six fold. Complications of
diabetes begin early in the progression from
normal glucose tolerance to diabetes, and some
people with prediabetes already have
microvascular changes and end organ damage.
Most of these people have not had diabetes
diagnosed, and primary care doctors will need
to identify and treat most of them, the panel
said.
People with prediabetes have blood
glucose levels that "are not normal but not
diabetic. This should not be an area of benign
neglect," said Alan Garber, chairman of the
organisation's task force on prediabetes and a
professor at Baylor College of Medicine in
Houston, Texas. Such people have more risk
of cardiovascular disease, blindness, kidney
problems, and amputations and are likely to go
on to develop diabetes, he said.
Dr Garber informed that people with
prediabetes had fasting blood glucose
concentrations of 5.6-6.9 mmol/l and two hour
glucose tolerance test concentrations of 7.8-11
64

(BMJ, 337 , p. 255 (August 2,2008))

Raised Blood Glucose Concentration


and Diagnosis of Diabetes
Diagnosis of diabetes is usually based on
the clinical symptoms and fasting blood
glucose results. A further fasting plasma
glucose (FPG) or oral glucose tolerance test
(OGTT) should be arranged to confirm the
diagnosis; this is usually advisable unless the
symptoms are convincing. If the patient is of
south Asian origin, OGTT is appropriate, as
using FPG alone in this group can miss
diabetes. If it was a random sample, arrange a
fasting test. In the context of cardiovascular
risk assessment, all concentrations 6.1
mmol/l from a random sample should be
followed up in this way. If the fasting sample
result is <6.1 mmol/l then the asymptomatic
patient could simply be given lifestyle advice,
particularly if the risk of diabetes is low. If the
sample suggests impaired fasting glycaemia
then follow up with a further fasting sample or
OGTT. OGTT is better if there are risk factors
or a raised clinical . suspicion of diabetes.
In either case withhold advice on dietary
modification until the follow-up fasting test or
OGTT, to avoid masking the diagnosis:
Clearly agree the follow-up arrangements to
discuss the results and give advice, as
boroerline glucose test results can easily go
unnoticed.
"Impaired glucose regulation" covers
impaired glucose tolerance (IGT) and impaired
fasting glycaemia (IFG). IGT can be identified
only under standardised conditions of
carbohydrate challenge and not from random
samples. Both IGT and IFG are risk factors for
diabetes,
but
IGT
carries
greater
cardiovascular risk. The implications for care
under current UK policy are the same for
Current R&D Highlights, Jan.-Mar. 2009

News & Views


either condition: assessment and reduction of
overall cardiovascular risk (recognising the 1.5
times greater risk in those with IGT) and
annual blood glucose testing (FPG or OGTT)
to identify the development of diabetes. A
range of interventions may reduce progression
to diabetes.
Lifestyle interventions seem at least as
effective as drugs, whose exact role is still
unclear. Targeting of such patients for risk
factor control has great potential for prevention
of cardiovascular disease.
The continuous glucose monitor used by
Murphy and colleagues can be thought of as
diabetology's answer to cardiology's:2.1, hour
electrocardiography monitor. It is used as an
investigative tool, is attached to the patient
(usually for 7:2 hours), and requires the user to
return to hospital for its removal. The data are
downloaded and examined for abnormal
glucose levels and trends.
The sensor is inserted through the
abdominal wall, so that its glucose oxidase tip
lies within subcutaneous tissue, where it
measures the giucose level of interstitial fluid,
not of bloud. The sensor is wired to a palm
sized monitor, which can be clipped to
clothing. The sensor cannot be disconnected,
even
temporarily-for
example,
when
showering. The monitor captures and stores
the average glucose measurement every five
minutes, yielding 288 readings in 2.1, hours. I
The patient is taught .to key in the times
of food, exercise, insulin, and symptoms of
hypo glycaemia. The device also requires at
least four self monitored blood glucose
readings to be entered each day for calibration,
obtained by finger prick.
The device used by Murphy and
colleagues does not give "real time" readings;
both patient and professional are unaware of
the measurements until the end of the 3-7 day
period of recording, determined by the life of
the sensor. The data are then downloaded.
Software ensures adequate correlation between
Current R&D Highlights, Jan.-Mar. 2009

the sensor's interstitial fluid readings and the


more reliable" self monitored glucose readings.
A lag exists between changes in blood
glucose levels and those of interstitial fluid,
and readings from interstitial fluid are slightly
lower than those from blood. This is of
particular concern at times of rapidly changing
blood glucose levels and in hypoglycaemia.
The National Institute for Health and Clinical
Excellence has yet to appraise the technology.
Real time continuous glucose monitoring
displays the most recent glucose reading and
alerts the user when a preset glucose range is
breached. The advantages of rapid response,
particularly to hypo glycaemia, are evident but
in practice there are problems with false
alarms; the temptation to give extra insulin so
often
that
it
accumulates,
causing
hypoglycaemia; the temptation not to validate
with self monitored blood glucose readings;
and the psychological morbidity of being
attached to a device for a defined period.
(BMJ, 337 , p. 873 (October11, 2008))

Novo Nordisk to Give Free Insulin to


Kids
Novo Nordisk plans to start distributing
free insulin to all diabetic children below
poverty line in India.
The $6.9-billion Danish pharma major is
also conducting human trials of six new drugs
in its 55 centres in India and plans to launch
GLP-1 - Liraglutide insulin drug globally by
2009. The company has, however, dropped its
inhaler insulin, Aerx, due to high costs and less
efficiency compared to an injected drug.
With over 40 million diabetic patients,
India has the single largest share among
countries in the world diabetic population of
over 200 million. About 11% urban population
and 4.5% rural population is diabetic. But only
a fraction of the patients get diagnosed and
among those which get diagnosed, even a
smaller fraction is able to afford treatment.
Novo Nordisk has around 60% market
65

News & Views


share by volume in India. Eli Lilly, Aventis,
Pfizer, Wockhardt, Biocon, and Zenotech Labs
are some other major players in this market.
Novo Nordisk has also announced the launch
of its mobile clinic here for free diagnosis of
diabetics. The van is equipped with blood
glucose monitoring systems for diabetes
screening and detection, weight check, body
mass index platforms and patient education
audio-visuals.
(The Economic Times, 8.2.2008)

Eli Lilly Drops


Programme

Inhaled

Insulin

Eli Lilly & Co has announced it will


terminate development of an inhaled insulin
treatment for diabetes, which it was
conducting in partnership with Alkermes Inc,
after deciding that product's commercial
potential was not strong.
Lilly's decision marks the third setback in
recent months for inhaled insulin formulations,
once deemed potential I blockbuster products
because of their greater convenience than
standard injectable insulin. Cambridge,
Massachusetts-based Alkermes, which makes
the alcohol addiction drug Vivitrol, said Lilly
has the right to terminate its license to the
inhaled treatment, Air Insulin, at its discretion.
(The Economics Times, 9.3.2008)

US FDA Asks Caraco Pharma to Recall


Diabetes Drug
The US Food and Drug Administration
(USFDA) has asked Caraco Pharmaceutical
Laboratories, the US subsidiary of Sun
Pharmaceuticals Industries, to withdraw many
batches
of
its
generic
Metformin
Hydrochloride tablets used for treating
diabetes, citing efficacy and quality issues.
According to a USFDA Class II withdrawl
announced on March 19, Caraco will have to
withdraw
seven
lots
of
Metformin
Hydrochloride in bottles of 100, 500 and 1000
tablets each. The withdrawal was necessitated
by undersized and oversized tablets; which
66

could result in patients not receiving the


expected dose, said the regulator. Caraco has
initiated the recall. The FDA said the recall
was valid nationwide and 22,156 bottles of the
drug were in circulation in the US.
In November 2007, the FDA had asked
Ranbaxy Laboratories to withdraw its
Gabapentine tablets 600 mg from the US
market for excessive impurity specification.
Metformin Hydrochloride, a bio-equivalent of
Bristol Myers Squibb's Glucophage, was
launched by Caraco in the US in February
2002.
(Business Standard, 25.3.2008)

Avesthhgen Launches
Control Blood Sugar

Bioactive

to

Avesthagen has launched its first


clinically-validated bioactive - 'Teestar' aimed
at controlling blood sugar. The company has
brought out its product as a dietary supplement
and in crackers (biscuit) form.
Dr. Morawala-Patell said, "The company
has used two of its patented technologies to
develop Teestar - 'ADEPT', a database that
brings together traditional medicine and
modem systems biology, created under World
Bank-funded SPREAD project; and 'MetaGrid
- an algorithm that enables comprehensive
constituent profiling of plant extracts and
thereby helps to maintain batch-to-batch
reproducibility of the bioactive. Teestar is the
first of the seven bioactives and will be
followed by more' which are in the pipeline.
Our goal is to incorporate, tasty, life-enhancing
natural ingredients into our lifestyle."
The research and development (R&D) for
'Teestar' was carried out on the lines of
pharmaceutical actives, wherein the bioactivity
and safety are proven at different levels. This
was prepared' from a single Indian plant
mentioned in Ayurveda using the firm's
technologies.
(Chemical Weekly, 13.5.2008, p. 138)

Current R&D Highlights, Jan.-Mar. 2009

News & Views


Aventis Pharma Launches Disposable
Insulin Pen

(NPPA) has increased the prices of 19


imported insulin-based medicines.

Aventis Pharma has launched a new prefilled disposable insulin pen for diabetic
patients as it expects to increase its market
share to 9 per cent with the launch.

The decision is in response to requests


made by importers Eli Lilly and Pfizer, who
wanted an increase in the prices of specific
brands on the grounds that the rupee had
depreciated against the dollar, leading to an
increase in the import cost. The price revision
covers 13 brands of Eli Lilly and six of Pfizer.

"SoloSTAR, a disposable insulin pen is to


be used for the treatment of hyperglycemia in
people with type 1 or type 2 diabetes and is
now available in Chandigarh, Punjab, Haryana
and Himachal Pradesh," Aventis Pharma
Senior Director Susheel Umesh said.
"This pen is designed in a very convenient
manner to enable patients carry it easily,
especially while travelling," he added.
Currently, the market for insulin stood at
Rs 460 crore and it is growing at a rate of 80
per cent.
(Financial Express 16.5.2008)

Lifestyle
Diabetes

Modification

Can

Delay

Lifestyle changes can make a big


difference. Drinking less alcohol, eating more
vegetables and exercising can prevent or delay
the onset of diabetes. Diet and exercise
reduced the incidence of diabetes by about
43% over 20 years among 577 high-risk
Chinese adults, the researchers reported in the
journal Lancet. At the end of the 20 years,
80% of those who changed what they ate and
exercised more had diabetes, compared with
93% who, made no changes, said Guangwei Li
of the China-Japan Friendship Hospital in
Beijing and Ping Zhang at the US Centers for
Disease Control and Prevention. The findings
came as part of a series of studies addressing
new research about diabetes, which affects 246
million adults worldwide, and accounts for 6%
of all global deaths.
(The Times of India, 24.5.2008)

NPPA Increases Price of 19 Imported


Insulin Drugs
National Pharmaceutical Pricing Authority
Current R&D Highlights, Jan.-Mar. 2009

The NPPA has also approved minor price


reduction for two insulin-based medicines
imported by Sanofi Aventis. The price revision
is in the range of 2-5 per cent. Thus, a 3 ml
catridge of Eli Lilly's human insulin injection
may now cost just over Rs 211, instead of
around Rs 205. The Indian anti-diabetic
medicine market is estimated at over Rs 1,000
crore.
(Business Standard, 9.7.2008)

Diabetes Drugs Need Long-Term


Cardiovascular Safety Data
All drugs in development for type 2
diabetes should undergo long-term safety trials
to rule out an excessive cardiovascular risk, the
US FDAs advisors recommended.
The recommendations, if adopted, would
mark a paradigm shift in diabetes drug
development likely to result in longer, larger
and costlier clinical studies. Diabetes drugs
would join nonsteroidal anti-inflammatories as
one of the few categories of medicines for
which long-term CV safety data are required.
The FDAs endocrinologic and metabolic
drugs advisory committee voted 14 to two in
favour of requiring sponsors to conduct a longterm trial, or provide other equivalent
evidence, to rule out an unacceptable CV risk
even in those drugs for which no adverse
signal has been detected during traditional
Phase II/III development. Most panellists
agreed such studies, at least in part, should be
conducted before approval.
Several endorsed the idea of conducting a
multi-year "screening" study to rule out an
67

News & Views


unacceptably
high,
albeitundefined,
cardiovascular risk, with completion of a
three- to five-year outcomes study after
approval. It was also suggested that Phase III
trials could be extended to collect the several
tears' worth of necessary CV safety data, or
that a Phase III programme could be
prospectively designed to allow for
aggregation of long-term safety data sufficient
for approval, with a confirmatory study after
licensing. Still others raised the spectre of
beginning a long-term CV study before
approval, but using interim safety results as the
basis for licensing. Such long-term studies
should enrol patients at high risk of CV events,
and there should be independent adjudication
of CV events in all diabetes drug studies, the
panel said. Some currently marketed diabetes
agents also should undergo long term CV
safety testing, particularly newer, on patent
agents and those for which there are little CV
data.
The panellists recommended against
requiring that diabetes drugs demonstrate a
cardiovascular benefit for approval. Instead,
they affirmed continued use of reduction in
HbAlc as a well-established surrogate for
approval based upon the microvascular
benefits that result from controlling glucose.
10 classes of therapies are available for
treating diabetes, all of which were approved
on the basis of efficacy in lowering HbAlc.
However, there is no conclusive evidence that
any of the marketed individual drugs or
treatment regimens confers a macrovascular
benefit, the FDA said. Rather than focusing on
cardiovascular benefit, the committee said it
was more important not to increase CV harm.
Patients with type 2 diabetes have a two-to
fourfold increased risk of cardiovascular
mortality compared to those without the
disease.
"The current pre-approval process is
insufficient to rule out CV risk in a disease
where CV morbidity and mortality are so
prevalent;' said panellist Dr Eric Holmboe,
68

vice-president for evaluation research at the


American Board of Internal Medicine.
(Scrip, 9.7.2008, p. 6)

India Seeks 17% Rise in Sale of Diabetic


Medicines
India, which is home to the largest
diabetic population in the world, has recorded
a 17% rise in the anti-diabetic drug segment.
The segment recorded sales of Rs 1,695 crore
in the 12 months to August 2008 compared to
Rs 1,402 crore in the corresponding period last
year, according to ORG IMS data.
The segment's contribution to the Indian
pharmaceutical market as of June 2008 was
also higher at 5.1 % compared to 4.6% in the
corresponding period up to June 2007. With
changing consumption patterns and more
sedentary lifestyles in India; industry sources
expect this to at least double in the coming
year. A study by Decision Resources, a
research based consulting organisation, shows
that the prevalence of type 2 diabetes in India
is among the highest in the world with more
than 28-million cases in 2007. The prevalence
of type 2 diabetes is expected to grow more
rapidly in India than in any other nation,
climbing to more than 60 million cases by
2017. Type 2 diabetes is the most common
form of diabetes. In type 2 diabetes, either the
body does not produce enough insulin- or the
cells ignore the insulin.
"WHO's Burden of Disease report states
that diabetes is going to grow by 40% in
developed countries, but by 70% in developing
countries. Apart from this rise, there are so
many undiagnosed people,'" said International
Diabetes Federation vice-president SM
Sadikot. A study by Mr Sadikot has shown that
by 2030, the number of rural people suffering
from diabetes will equal those in urban areas.
Oral diabetic medication generated revenues of
Rs 1,183 crore in the last year while insulin
posted sales of Rs 51-1 crore, according to an
ORG-IMS report. The top players in this
Current R&D Highlights, Jan.-Mar. 2009

News & Views


segment include Abbott, USV, Sanofi Aventis,
Sun Pharma, Nicholas Piramal and Wockhardt.
The number of companies looking to enter
this therapeutic area is also on the rise. "Lots
of companies are "looking at entering the
chronic illness space. With a slowing down of
acute illnesses in larger cities and towns and
the change in lifestyles, companies who have a
presence in anti-infectives are also entering the
anti-diabetic space," said Alok Dalal, analyst
with Religare. Trying to break into the chronic
illness segment is easier when compared to
CNS (central nervous system) segment, he
added. The UK is the first to have taken a step
in this direction. "There are 170 million
diabetic people in the world today and India
accounts for 27% of that. We plan on working
with different organisations and countries to
combat this, India being one of them," said
Ann Keen, UK under secretary of state for
health, at a diabetes conference in Mumbai.
Sujay
Shetty,
associate
director
at
PricewaterhouseCoopers,
said,
"Chronic
diseases like diabetes are going to be a big
market going forward. This segment's
contribution to the overall pharmaceutical
market is going to increase."
(The Economic Times, 18.10.2008)

Novo Nordisk Enters Pact for Insulin


from Stem Cells
Novo Nordisk, stem cell biotechnology
firm Cellartis and Swedens Lund University
Stem Cell Center have announced a
collaborative research agreement to develop
insulin-producing cells from human stem cells.
Novo Nordisk will have exclusive rights to
further develop and commercialise potential
products for the treatment of diabetes while
Cellartis has the rights to further develop and
commercialise certain other products resulting
from the technologies developed under the
collaboration. Research will be conducted into
Current R&D Highlights, Jan.-Mar. 2009

how the formation of insulin-producing cells


during embryonic development can be
mimicked by directing stem cells in culture, a
statement said. Besides developing cell therapy
for the treatment of insulin-dependent diabetes,
the collaboration will in the long term focus on
a cure for type 1 diabetes.
(The Economic Times, 27.10.2008)

Too Little Sleep may Raise Diabetes


Risk
A good night's sleep may help lower your
risk of developing type 2 diabetes, researchers
say.People averaging less than six hours of
shuteye during the work week over a period of
years were shown to have nearly five times the
chance of developing the disease compared to
those who averaged six to eight hours of sleep,
according to research scheduled to be
presented Wednesday at an American Heart
Association conference in Palm Harbor, Fla.
"This study supports growing evidence of the
association of inadequate sleep with adverse
health issues. Sleep should be assessed in the
clinical setting as part of well-care visits
throughout the life cycle," study lead author
Lisa Rafalson, a research assistant professor at
the University at Buffalo in New York, said in
a news release issued by the association. The
study, in which 1,455 people reported on their
sleep habits, compared fasting glucose levels
on people over a six-year period. The results
were based on adjustments made for age, body
mass
index,
glucose
and
insulin
concentrations, heart rate, high blood pressure,
family history of diabetes and symptoms of
depression. The study found no significant
difference in fasting glucose levels or risk of
developing type 2 diabetes between those who
averaged six to eight hours of sleep during
weeknights and those who averaged more than
eight hours a night. "Our findings will
hopefully spur additional research into this
very complex area of sleep and illness,"
Rafalson said.
(Health Day News, March 11, 2009)
69

News & Views


Abnormal Heart Rhythm Boosts Death
Risk for Diabetics
In people with diabetes, there's a strong
association between abnormal heart rhythm, or
atrial fibrillation, and increased risk of other
heart-related problems and death, according to
a
study
that
included
11,140
people.Researchers found that participants
who had atrial fibrillation (AF) at the start of
the study were 61 percent more likely to die
from any cause, 77 percent more likely to die
from cardiovascular causes such as a heart
attack or stroke, and 68 percent more likely to
develop heart failure or other problems such as
stroke.But the study also found that the risk of
developing complications or dying was lower
if doctors gave more aggressive treatments to
diabetic patients with AF. In this study,
treatment involved a combination of the blood
pressure lowering drugs perindopril and
indapamide."Active
treatment
produced
similar relative benefits to patients with and
without AF. However, because of their higher
risk at the start of the study, the absolute
benefit associated with active treatment was
greater in patients with AF than without. We
estimate that five years of active treatment
would prevent one death among every 42
patients with AF and one death among 120
patients without AF," noted study leader
Professor Anushka Patel, director of the
Cardiovascular Division at The George
Institute for International Health at the
University of Sydney in Australia.The
researchers also found that the association
between AF and deaths from cardiovascular
disease was much stronger in women than in
men. Women with AF were twice as likely to
die as women without AF, while men with AF
were 50 percent more likely to die than men
without AF.The findings were published
March 12 in the European Heart Journal."This
study informs clinicians that AF is a marker of
greater risk of cardiovascular events and
mortality among diabetics, both men and
women. Such patients should have their
70

cardiovascular risk factors, such as blood


pressure and cholesterol, controlled more
aggressively," Patel advised."This is a separate
issue from rate and rhythm control [or the use
of anticoagulants to prevent thromboembolic
events], which is the usual therapeutic focus in
patients with AF. These issues are important,
but we believe our data suggest that
heightened awareness and management of
overall cardiovascular risk is also important."
(Health Day News, March 12, 2009)

Plasma Fetuin-A Levels and the Risk of


Type 2 Diabetes
Type-2 diabetes represents a major global
public health threat and, together with obesity,
constitutes an important contributor to the
predicted decline in life expectancy. The
pathophysiology of Type 2 diabetes is
complex: In addition to impaired insulin
secretion from -cells, reduced insulin
sensitivity was found to play a predominant
role in the pathogenesis of the disease. Several
circulating proteins have been shown to be
involved in the regulation of insulin sensitivity
such as adiponectin retinol binding protein 4
and fetuin-A (former name for the human
protein 2-Heremans-Schmid glycoprotein,
AHSG). Fetuin-A is an endogenous inhibitor
of the insulin-stimulated insulin receptor
tyrosine kinase. Administration of fetuin-A to
rodents inhibited insulin-stimulated styrosine
phosphorylation of the insulin receptor and
insulin receptor substrate-1 in rat liver and
skeletal muscle. In addition, fetuin-A knockout
mice exhibited increased insulin sensitivity
and were resistant to the adipogenic effect of a
high-fat diet, supporting the hypothesis that
fetuin-A is involved in the pathophysiology of
insulin resistance in rodents.
In agreement with these data, we and
others have recently shown that high levels of
circulating fetuin-A are associated with insulin
resistance in humans, suggesting that fetuin-A
may represent a novel mechanism involved in
the pathophysiology of type 2 diabetes. In the
Current R&D Highlights, Jan.-Mar. 2009

News & Views


present study, we investigated whether
circulating fetuin-A predicted the incidence of
type 2 diabetes, independently of established
risk factors, in the large European Prospective
Investigation into Cancer and Nutrition
(EPIC)-Potsdam Study.

20 min 3 days a week. Another important


dimension is the time spent in sedentary
occupations; in the Nurses Health Study, the
number of hours spent sedentary was related
with incident diabetes even after adjusting for
total physical activity.

(Diabetes, 57, October 2008, p.2762)

Physical activity may decrease the risk of


diabetes by increasing insulin sensitivity.
Insulin sensitivity has been shown to increase
with physical activity, as assessed by
questionnaire. Objective assessment of
physical activity is now possible with
unobtrusive
accelerometer-based
motion
sensors. The aim of this study was to describe
the relationship between insulin sensitivity, as
measured
by
the
gold
standard
hyperinsulinemic-euglycemic clamp, and
habitual physical activity assessed by
accelerometer; total activity, activity intensity,
and time spent in light and sedentary activities.

Physical Activity and Insulin Sensitivity


Physical activity is now recognized as a
major component of type 2 diabetes
prevention; cohort studies have documented
the lower risk of incident diabetes even for
everyday activities such as walking. In a post
hoc analysis of the Finnish Diabetes
Prevention Study, walking for exercise for at
least 2.5 h a week in comparison with less than
1 h was associated with a 63-69% lower risk of
incident diabetes. Physical activity is a
complex behavior characterized by intensity,
duration, and frequency/ Various consensus
groups recommend physically active lifestyles
for adults, with an accumulation of at least 30
min of moderate-intensity aerobic physical
activity 5 or more days a week or vigorousintensity aerobic physical activity for at least

(Diabetes, 57, October 2008, p.2613)

Dear Readers
We are happy to receive your encouraging response to our
journal. We shall, however, appreciate receiving your critical
comments and suggestions for further improvements. We are
always looking forward to your specific contributions on
various aspects of the journal. The contributions shall be
duly acknowledged.
Editor

Current R&D Highlights, Jan.-Mar. 2009

71

R & D Highlights

Cell-based Treatments for Diabetes


Type 1 diabetes mellitus (TlDM) is a
single-cell disorder in which insulin-secreting
-cells in pancreatic islets of Langerhans are
irreversibly destroyed by an autoimmune
assault, resulting in potentially fatal metabolic
dysfunction as a consequence of insufficient
circulating levels of insulin. Since the isolation
of insulin in 1920s the main therapeutic
approach to T1DM has been insulin
replacement, but excursions in blood glucose
associated with intermittent insulin delivery
led to a high risk of long-term complications,
causing increased morbidity and mortality.
Recent clinical trials, however, have
demonstrated that transplantation of human
islets of Langerhans can offer a cure for
TlDM. There are extant problems with current
transplantation protocols, but the success of
islet transplants is proof-of-concept that cellbased treatments for T1DM can be effective.
This review will focus on one major
impediment to the widespread uptake of
transplantation therapy for TlDM, which is the
very limited availability of suitable transplant
material.
An adult human pancreas contains
approximately 106 islets (~2 x 109 -cells), but
these comprise only a minor part of total
pancreatic tissue (2-3%) so islets for
transplantation must be isolated from whole
pancreas by enzymatic digestion, which is an
inefficient process. The clinical symptoms of
diabetes do not usually become apparent until
60-80% of the -cell mass is lost, suggesting
that glycaemic control can be maintained on
20-40% of normal -cell mass. Current
evidence suggests that a significant fraction of
transplanted islets are lost in the immediate
72

post-transplantation period so, to ensure a


successful outcome, islet transplantation
protocols replace up to 106 primary human
islets per recipient. A single transplantation
may therefore require islets from up to four
donor pancreases. At present, the only suitable
source of human islets for clinical use is from
pancreases of heart-beating, brain-dead donors.
This type of organ donor is rare, so current
protocols for human islet transplantation are
unlikely to make a widespread therapeutic
impact on T1DM, with ~ 105 potential
recipients in the UK and ~ 106 in the USA.
This clinical need is therefor driving research
into alternative sources of functionally
competent, insulin-secreting -cells as
substitutes for donor islets in transplantation
therapy.
A number of different cells/tissues have
been proposed as potential starting material
from which to generate transplant material,
BOX 1
Potential Sources of -cells for Transplantation Therapy
A number of potential sources of material for cell-based therapy of
diabetes have been investigated over the past decade. This lists some
of the more promising candidates.
o
o
o
o

insulin-secreting cell lines


engineered non--cells/gene therapy
islets/l3-cells from other species
tissue stem cells
pancreas
bone marrow
liver
neural
embryonic stem cells

and some of these are shown in Box 1. The


physiological properties required of substit'!te
-cells have been considered in detail
elsewhere but it is worth considering briefly
two essential attributes of such cells. First,
they must be able to synthesise and store
Current R&D Highlights, Jan.-Mar. 2009

R & D Highlights
insulin, and to release it in sufficient amounts
to maintain plasma glucose in a narrow range
(5-8 mM) in the face of sporadic food intake.
Too much insulin is as potentially lethal as too
little insulin, so the cells must be able to
respond rapidly to changes in plasma glucose
in either direction. Pancreatic -cells have
evolved complex stimulus-response coupling
mechanisms to monitor and respond to
changes in nutrients, hormones and
neurotransmitters and substitute -cells will
require similar mechanisms to enable a tightly
regulated release of insulin in response to
environmental cues. Second, the proliferative
capacity of the replacement cells must be
tightly regulated to avoid post-transplantation
expansion of -cell mass leading to the
development
of
hyperinsulinaemic
hypoglycaemia. This is not a problem when
using authenic -cells/islets derived from
human donors because they have an
exceedingly low proliferative capacity, but it is
a potential drawback when using cells
generated in vitro from proliferative precursor
populations.
This combination of highly specialised
secretory function and controlled proliferative
capacity is a challenging target, and some
ofthe suggested starting materials (Box 1) fail
to meet one or other of these criteria and so
will not be considered in detail in this review.
For example, transformed cells derived from
human -cells offer the potential of generating
in vitro the (thousands of) billions of cells
required for transplantation therapy, and
insulin-secreting cell lines can be engineered
to produce regulated secretory responses. Such
cells show unregulated proliferation and form
insulinomas in vivo, and so are unlikely to
offer any therapeutic benefit in the foreseeable
future. Another suggested source of
replacement -cells is to engineer non--cells
to make insulin, and this has been done in a
variety of cell types including fibroblasts,
skeletal muscle, neuroendocrine, kidney and
ovarian cells. This approach has the potential
Current R&D Highlights, Jan.-Mar. 2009

advantage of using the patient's own tissue as a


starting material (e.g. fibroblasts), but these
engineered cells lack the stimulus recognition
and response elements that are expressed by
authentic -cells. Their insulin secretory
responses are therefore unregulated and are not
responsive to physiologically relevant stimuli
such as post-prandial changes in blood
glucose. There may be some therapeutic
benefit to people with diabetes in having a
low, maintained basal delivery of insulin via
genetically engineered non--cells, but this
would at best be an adjunct to, rather than' a
replacement for, conventional insulin therapy.
The remainder of this review will therefore
focus on areas that we consider most likely to
generate the quantities of cells required for
transplantation
while
maintaining
differentiated function - islets from non human
species and the de novo generation of
functional -cells from stem cell populations.

Islets/(
-Cells from other Species:
Xenografts to Treat Type 1 Diabetes
Using islets of Langerhans from other
species is an obvious way of providing the
large amounts of functional tissue required for
transplantation therapy of diabetes. Most effort
in this area has been directed towards using pig
islets because: (i) Western countries have preexisting
facilities
for
high-throughput
breeding, rearing and slaughtering of pigs
(porcine pancreas as a by-product of pork
production was a source of insulin for treating
TIDM for many years before recombinant
human insulin became widely available); (ii)
high islet yields can be obtained from porcine
pancreas using techniques similar to those for
human islet isolation; and (iii) pigs are
amenable to genetic modification to make
human insulin or to protect against immune
assault. Two important impediments have
however restricted the widespread use of pig
islets in humans. First, the hyperimmune
response to xenografts has proved difficult to
avoid. Numerous attempts to hide the
transplanted xenografts from the host immune
73

R & D Highlights
system by islet encapsulation have largely
failed to maintain islet viability and insulin
secretory responses over the prolonged periods
required of. transplanted islets. Second, the
demonstration that porcine endogenous
retroviral (PERV) sequences in the porcine
DNA
may
become
activated
on
xenotransplantation raised the possibility of
novel viral infections in humans receiving
porcine islet implants. Until recently, these
drawbacks
made
it
unlikely
that
xenotransplantation would find any major
clinical application in the treatment of TIDM.
but several recent developments have placed it
back in the spotlight.

Stem Cells as a Source of Substitute Cells


The recent explosion of interest in the
therapeutic potential of stem cells for single
cell disorders such as T1DM has generated
much research activity in this area. The article
will focus on recent advances in the generation
of functional -cells from stem cell
populations, using a broad classification of
stem cells as either tissue stem cells, which are
multi potent progenitor cells found in fetal and
adult tissues, or as embryonic stem cells,
which are pluripotent, undifferentiated cells
generated from the inner cell mass of a
developing blastocyst and which have the
potential to differentiate into any tissue in the
embryo.
Tissue stem cells
Tissue stem cells are usually considered to
be lineage-restricted, and to mature into the
differentiated cells of the host tissue/organ, but
evidence is emerging of trans-differentiation
into other types of tissue, suggesting that
disparate tissues may offer sources of
progenitor cells that have the potential to
become insulin-expressing cells.
Pancreatic stem cells
The -cell mass increases during
development, and changes with (patho)
74

physiological circumstances such as pregnancy


and obesity. The origins) of these new -cells
is important when considering how to expand
the -cell mass in or ex vivo. Recent lineage
tracing studies in mice suggest that, under
most circumstances including .acute pancreatic
regeneration, new -cells arise by a slow but
uniform self-renewal of existing -cells.
Bone marrow-derived stem cells
Bone
marrow
(BM)
contains
hematopoietic stem cells and mesenchymal
stem cells, both of which exhibit considerable
developmental plasticity. An initial report that
BM stem cells could engraft into pancreatic
islets in vivo and differentiate to an insulinexpressing phenotype could not be confirmed
by other groups. More recent reports suggest
that BM stem cells reversed experimental
diabetes in vivo by enhancing the regeneration
and survival of endogenous -cells rather than
repopulating the islets with trans-differentiated
-cells.
Liver progenitor cells
Early studies demonstrating that the
experimental overexpression of pancreatic
transcription factors in hepatic cells in vivo
produced insulin-expressing cells generated a
great deal of interest in the potential of liver
cells as a source of replacement -cells. Liver
is relatively accessible for biopsy and has the
capacity to regenerate and so is a clinically
attractive option for autologous grafting of
liver-derived cells in patients with T1DM.
Neural stem cells
The use of neural stem cells as -cell
precursors has not been much explored.
Subpopulations of neurons express functional
elements that are characteristic of -cells,
including ATP-dependent K+ channel SUR1
and Kir6.2 subunits, voltage-operated Ca2+
channels, GLUT2 glucose transporters and the
pancreatic form of glucokinase, and the
developmental pathways of -cells and
neurons show similarities with many
Current R&D Highlights, Jan.-Mar. 2009

R & D Highlights
transcription factors (e.g. PDX-l, nkx2.2,
nkx6.1, neurogenin-3, NeuroDl/Beta2, Pax4,
Pax6 and Isl1) regulating both processes.
Other tissue stem cells
There have been sporadic reports that
progenitor/stem cells from other tissues can be
induced to differentiate intoinsulin-expressing
cells, including cells localised to intestinal
epithelium, dermis, spleen, salivary gland and
blood monocytes. These studies have not
always proved to be reproducible, and have
been reviewed elsewhere
Embryonic stem cells
Embryonic stem (ES) cells have great
potential in cell/organ replacement therapies
because of two intrinsic properties. First, ES
ce\ls can produce cells of all three embryonic
germ layers (pluripotent). Second, ES cells can
proliferate indefinitely in viir.o if they are
maintained in their initial undifferentiated
state, so they are capable of produdng the large
numbers of cells required for transplantation
therapies. Initial attempts to differentiate ES
cells to insulin-expressing cells used mouse ES
(mES) cells, as did many subsequent studies,
because mES cells are much easier to obtain
and use than human ES(hES) cells, and
because they are not subject to the ethical and
legal constraints that accompany hES cells.

Concluding Remarks
Transplantation therapy offers a novel
treatment for diabetes and the potential gains,
both clinical and commercial, are enormous.
The availability of unlimited amounts of
functionally competent graft material would
allow islet transplantation to evolve from a
restricted, experimental treatment to a more
widespread applicability, much as has
happened for other organ transplantation
procedures in the past. The problems
associated with graft immunogenicity and
autoimmune destruction of engrafted material
are common to all sources of replacement cells, and beyond the scope of this review, but
Current R&D Highlights, Jan.-Mar. 2009

each of the potential sources of -cells has


specific
individual
advantages
and
disadvantages, the balance of which will
eventually determine its clinical usefulness.
Porcine islets have the great advantages of
being fully functional primary islets, and of
being available in large numbers, but these are
balanced by persistent problems with immune
rejection and fears of PERV infection in the
recipient. If these problems can be
convincingly overcome xenotransplantation
may become an effective alternative to human
islet transplantation. The concept of
autologous grafting of insulin-secreting cells
derived from the patient's own tissue stem cells
(particularly bone marrow or liver) is very
attractive, but the early promise of tissue stem
cells in experimental animals has not yet
translated into clinically useful material
because of problems with restricted
proliferative capacity, low levels of insulin
expression and poor, or non-existent, insulin
secretion. Embryonic stem cells have the
required proliferative capacity, and recent
studies have demonstrated the differentiation
of hES cells to an insulin-secreting phenotype
without using clinically unacceptable genetic
modification. It remains to be seen whether
current experimental protocols can be refined
and scaled-up to generate enough cells for
transplantation
therapy,
and
whether
purification methods of sufficient stringency
can be devised to allow the transplantation of
the differentiated -cells while ensuring the
absolute exclusion of potentially teratogenic
hES cells. For almost a century the only
available treatment for TIDM has been the
administration of exogenous insulin to
suppress hyperglycaemia. It is now a real
possibility that the next decade will see the
widespread application of cell-based therapies
to cure this disorder.
(Based on the article written by Peter M Jones;
Monica L Courtney; Christopher J Burns and Shanta
J Persaud and published in the Drug Discovery Today,
Vol. 13 (19-20), October 2008, p. 888)

75

R & D Highlights
Adipose tissue transplantation may be a
potential treatment for diabetes, atherosclerosis and nonalcoholic steatohepatitis.
Sanal, Madhusudana Girija et al.
Medical Hypotheses
Adipose tissue is critical in energy
homeostasis. Adipose tissue buffers the lipids
and energy rich compounds which are pumped
into the blood stream soon after meals. It
senses, signals other organs like liver and brain
about the energy reserves via adipokines.
Adiponectin, the most abundant adipokine has
insulin
sensitizing,
anti-inflammatory
antiatherogenic and antisteatotic effects.
Adipose tissue dysfunction is accompanied by
abnormal lipid distribution and storage which
contributes to diseases like diabetes,
nonalcoholic fatty liver disease and
atherosclerosis. Obesity and lipodystrophy are
associated with dysfunctional adipocytes. Preadipocytes are easy to isolate and culture. A
personalized depot specific liposuction to
remove the inactive adipocytes followed by
adipocyte repopulation could be useful in the
treatment of these diseases. (Scienedirect)
Attenuation of diabetic nephropathy by
tocotrienol: Involvement of NFkB signaling
pathway.
Kuhad, Anurag et al.
Life Sciences
Diabetic nephropathy is a serious
complication for patients with diabetes
mellitus. Approximately 30-40% of patients
with type I and 15% with type II diabetes
mellitus develop end stage renal disease. The
study was designed to evaluate the impact of
tocotrienol on renal function and renoinflammatory cascade in streptozotocininduced diabetes. Streptozotocin (STZ)induced diabetic rats were treated with
tocotrienol (25, 50 and 100 mg/kg), [alpha]tocopherol (100 mg/kg) or with vehicle form
5th to 8th weeks. After 8 weeks, urine albumin
excretion, urine output, serum creatinine,
blood urea nitrogen, creatinine and urea
clearance were measured. Cytoplasmic and
76

nuclear fractions of kidney was prepared for


the quantification of oxidative-nitrosative
stress
(lipid
peroxidation,
superoxide
dismutase, catalase, non protein thiols, total
nitric oxide), tumor necrosis factor-alpha
(TNF-[alpha]), tissue growth factor-1beta
(TGF-[beta]1), p65 subunit of NF[kappa][beta]
and caspase-3.Key findings
After 8 weeks of STZ injection, the rats
produced significant alteration in renal
function, increased oxidative-nitrosative stress,
TNF-[alpha], TGF-[beta]1, caspase-3 activity
in cytoplasmic lysate and active p65 subunit of
NF[kappa][beta] in nuclear lysate of kidney of
diabetic rats. Interestingly, co-administration
of tocotrienol significantly and dosedependently prevented biochemical and
molecular changes associated with diabetes.
Tocotrienol (100 mg/kg) was demonstrated to
be more effective than [alpha]-tocopherol (100
mg/kg). Moreover, diabetic rats treated with
insulin-tocotrienol combination produced more
pronounced effect on molecular parameters as
compared to their respective groups. Taken
together, the data reveal that tocotrienol
modulates the release of profibrotic cytokines,
oxidative stress, ongoing chronic inflammation
and apoptosis and thus exerts a marked
renoprotective effect.
(Scienedirect)
An update on preventive and
regenerative therapies in diabetes mellitus.
Reimann, M. et al.
Pharmacology & Therapeutics
Type 1A (immune-mediated) and type 2
diabetes mellitus are two of the most common
severe chronic illnesses, affecting over 230
million people worldwide with an estimated
global prevalence of 5.1%. Although type 1
and type 2 diabetes differ greatly in modes of
pathogenesis, these illnesses share a common
pathology and consequences characterized by
loss of functional beta-cell mass and
subsequent dysregulation of carbohydrate and
lipid metabolism. Since therapy for diabetes
and the associated complications poses
enormous public health and economic burdens,
Current R&D Highlights, Jan.-Mar. 2009

R & D Highlights
novel preventive and regenerative therapies
have emerged in the past decade with the aim
to preserve beta-cell mass and delay the onset
of diabetes. The goal of this review is to
provide a comprehensive overview of current
efforts in the fight against diabetes, and
attempt to document all strategies that have
emerged in clinical studies within the past 25
years. First, strategies to identify individuals at
risk, ranging from whole-genome scans to
autoantibody screening, will be discussed.
Second, novel approaches to prevent or delay
the onset of disease will be covered. Particular
focus is given on emerging strategies for
individuals at risk for type 1 diabetes that
target T-cell regulation and induction of
tolerance, while new pharmaceutical concepts
in combination with lifestyle interventions are
discussed within the scope of type 2 diabetes
prevention. Lastly, important efforts to halt
disease progression with emphasis on beta cell
regeneration are presented. (Scienedirect)
Suppression of NF-[
][
] signaling
pathway by tocotrienol can prevent diabetes
associated cognitive deficits.
Kuhad, Anurag et al.
Pharmacology Biochemistry and Behavior
The etiology of diabetes associated
cognitive decline is multifactorial and involves
insulin receptor down regulation, neuronal
apoptosis and glutamatergic neurotransmission. The study was designed to evaluate
the impact of tocotrienol on cognitive function
and neuroinflammatory cascade in streptozotocin-induced diabetes. Streptozotocininduced diabetic rats were treated with
tocotrienol for 10 weeks. Morris water maze
was used for behavioral assessment of
memory. Cytoplasmic and nuclear fractions of
cerebral cortex and hippocampus were
prepared
for
the
quantification
of
acetylcholinesterase
activity,
oxidativenitrosative stress, tumor necrosis factor-alpha
(TNF-[alpha]), interleukin-1beta (IL-1[beta]),
NF[kappa][beta]
and
caspase-3.
After
10 weeks of streptozotocin injection, the rats
Current R&D Highlights, Jan.-Mar. 2009

produced significant increase in transfer


latency which was coupled with enhanced
acetylcholinesterase
activity,
increased
oxidative-nitrosative stress, TNF-[alpha], IL1[beta], caspase-3 activity and active p65
subunit of NF[kappa][beta] in different regions
of diabetic rat brain. Interestingly, coadministration of tocotrienol significantly and
dose-dependently
prevented
behavioral,
biochemical and molecular changes associated
with diabetes. Moreover, diabetic rats treated
with insulin-tocotrienol combination produced
more pronounced effect on molecular
parameters as compared to their per se groups.
Collectively, the data reveal that activation of
NF[kappa][beta]
signaling
pathway
is
associated with diabetes induced cognitive
impairment and point towards the therapeutic
potential
of
tocotrienol
in
diabetic
encephalopathy.
(Scienedirect)
Can blood glucose self-monitoring
improve treatment outcomes in type 2
diabetes?
Varanauskiene, Egle et al.
Diabetes Research and Clinical Practice,
82(Suppl.2), S112 (Dec., 15, 2008)
Increased cardiovascular risk in diabetes
cannot be attributed to the higher prevalence of
classic risk factors.Importance of postprandial
hyperglycemia. Most of the cardiovascular risk
factors have shown to be directly related to the
degree of postprandial glycemia (PPG). PPG
should be recognized as a marker for the
increased
risk
of
cardiovascular
disease.Assessment of targets for glycemia
control. Two important methods available-self-monitoring of blood glucose (SMBG)
reveals immediate hour-to-hour blood glucose,
while long-term glycemia is assessed by
HbA1c. Reducing PPG and glycemia
excursions is as important as lowering fasting
plasma
glucose
and
HbA1c
levels.Effectiveness of SMBG. SMBG plays a
key role in diabetes care, and has proven to be
effective for insulin treated type 2 diabetic
patients. Debate continues on the effectiveness
77

R & D Highlights
of SMBG in non-insulin treated type 2
diabetes. Whether non-insulin treated type 2
diabetic patients benefit from SMBG, a largescale randomized controlled trial with the
follow-up period to investigate long-term
effects should be carried out. A general
recommendation is that insulin treated patients
perform SMBG at least three times per day.
SMBG frequency for non-insulin users should
be individualized to treatment regimen and
level of control.
Mutations in C2orf37, encoding a
nucleolar protein, cause hypogonadism,
alopecia,
diabetes
mellitus,
mental
retardation, and extrapyramidal syndrome.
Alazami, Anas M. et al.
The American Journal of Human
Genetics, 83(6), 684 (Dec., 12, 2008)
Hypogonadism,
alopecia,
diabetes
mellitus,
mental
retardation,
and
extrapyramidal syndrome (also referenced as
Woodhouse-Sakati syndrome) is a rare
autosomal recessive multisystemic disorder.
We have identified a founder mutation
consisting of a single base-pair deletion in
C2orf37 in eight families of Saudi origin.
Three other loss-of-function mutations were
subsequently discovered in patients of
different ethnicities. The gene encodes a
nucleolar protein of unknown function, and the
cellular phenotype observed in patient
lymphoblasts implicates a role for the
nucleolus in the pathogenesis of this disease.
Our findings expand the list of human
disorders linked to the nucleolus and further
highlight
the
developmental
and/or
maintenance functions of this organelle.
Polyelectrolyte biomaterial interactions
provide nanoparticulate carrier for oral
insulin delivery.
Catarina Pinto Reis et al.
Drug Delivery. 15: 127-139, 2008
Nanospheres are being developed for the
oral delivery of peptide-based drugs such as
insulin.
Mucoadhesive,
biodegradable,
biocompatible,
and
acid-protective
78

biomaterials are described using a combination


of natural polyelectrolytes, with particles
formulated through nanoemulsion dispersion
followed by triggered in situ gel complexation.
Biomaterials meeting these criteria include
alginate, dextran, chitosan, and albumin in
which alginate/dextran forms the core matrix
complexed with chitosan and albumin coat.
Smaller size and higher albumin-based acidprotective formulation was orally administered
to diabetic rats and glucose reduction and
physiological response analyzed. Insulin
encapsulation efficiency was 90, 82, and 66%
for uncoated, chitosan-coated, and albuminchitosan-coated
alginate
nanospheres,
respectively. The choice of coating polymer
seems to influence insulin release profile and
to be crucial to prevent peptic digestion.
Physiological response following oral delivery
showed that insulin albumin-chitosan-coated
alginate nanospheres reduced glycemia", 72%
of basal values. Albumin serves as an
important enteric coating providing acid- and
protease protection enabling uptake of active
drug following oral' dosage.
Diabetes mellitus type 1 is a generalized
disorder of glucose metabolism that is
generally attributed to an absence of insulin
secretion. The unique treatment remains
periodic insulin
Reduced serum resistin levels in
diabetic patients: Study from western India.
Mahadik, Sujata R. et al.
Diabetes and Metabolic Syndrome:
Clinical Research and Reviews
Resistin is an adipocyte-derived peptide
that might play a role in obesity and insulin
resistance (IR); however, its role in humans is
largely unknown. The aim of the study was to
elucidate the role of serum resistin and explore
its relationship with inflammatory marker Creactive protein (CRP) and adipocytokine
(leptin, adiponectin) in Indian diabetic
patients. A total of 171 subjects including 41
controls, 41 obese and 89 Type 2 diabetes
mellitus (T2DM) patients were recruited in this
Current R&D Highlights, Jan.-Mar. 2009

R & D Highlights
cross-sectional study. Fasting serum resistin,
leptin, adiponectin, insulin and CRP were
measured by enzyme immunoassay. The
relation between these variables was studied
by univariate and multiple regression analysis.
Serum resistin levels were significantly
reduced in non-obese treated T2DM patients.
In the correlation analysis after controlling for
age and BMI authors found that resistin is
significantly associated with leptin (0.687,
p < 0.002) and CRP (0.549, p < 0.018) in only
control females and with CRP (0.642,
p < 0.01) in T2DM female patients. In multiple
linear regression analysis resistin was
independently predicted by the leptin
(p < 0.01) and leukocyte (p < 0.004) in
controls, treated T2DM patients. Reduced
resistin and leptin levels in non-obese treated
T2DM and significant association between
these two in control and treated T2DM suggest
interplay between these two adipocytokines. In
addition, the weak association of resistin with
diabetes indicates that it may be playing an
indirect role in the pathogenesis of T2DM.
(Scienedirect)

Pregnancy and diabetes scenario


around the world: India.
Seshiah, Veerasamy et al.
International Journal of Gynecology &
Obstetrics, 104(Suppl. 1), S35 (Mar., 2009)
Women with gestational diabetes mellitus
(GDM) are at an increased risk of developing
diabetes in the future, as are their offspring.
GDM is not only of clinical relevance, but is
also an important public health issue. A
community-based prospective study showed
that the prevalence of GDM was 13.9%.
Authors also observed that the frequency of
GDM varied across urban, semi-urban, and
rural areas. Based on multiple logistic
regression analysis and taking the 3 areas into
consideration, family history of diabetes, age
greater than or equal to 25 years, and body
mass index greater than or equal to 25 were
found to have a significant independent
association with GDM (P < 0.001).
Current R&D Highlights, Jan.-Mar. 2009

Oxidative stress pathway genes and


chronic renal insufficiency in Asian Indians
with Type 2 diabetes.
Tiwari, Arun K. et al.
Journal
of
Diabetes
and
its
Complications, 23(2), 102 (2009)
There are significant regional variations in
prevalence of diabetes and diabetic chronic
renal insufficiency (CRI) in India. Oxidative
stress plays an important role in the
development of diabetic complications. To
determine
the
importance
of
the
polymorphisms in the genes involved in
maintenance of cellular redox balance, we
performed a case control study in subjects
from south and north India. Successive cases
presenting to the study centers with Type 2
diabetes of >2 years duration and moderate
CRI (n=194, south India 104, north India 90)
diagnosed by serum creatinine >=2 mg/dl after
exclusion of nondiabetic causes of CRI were
compared with diabetes subjects with no
evidence of renal disease (n=224, south India
149,
north
India
75).
Twenty-six
polymorphisms from 13 genes from the
oxidative stress pathway were analyzed using
polymerase chain reaction-restriction fragment
length polymorphism. Genes included were
superoxide dismutases (SOD1, 2, 3),
uncoupling proteins (UCP1, 2), endothelial
nitric oxide synthase (NOS3), glutathione-Stransferases (GST) (M1, T1, P1), vascular
endothelial
growth
factor
(VEGF),
paraoxonase (PON) 1 and 2, and nicotinamide
adenine dinucleotide phosphate reduced,
oxidase p22phox. Genes were tested for their
association with CRI using [chi]2 test. In south
Indian (SI) subjects there was significant
allelic and genotypic association of the wildtype allele in SOD2 (Ala9Val; P=.002 and
P=.013, respectively), UCP1 (-112 T>G,
P=.012 and P=.009; Ala64Thr, P=.015 and
P=.004), NOS3 (Glu298Asp, P=.002 and
P=.009) and GSTP1 (Ile105Val, P=.003 and
P=.004) genes with development of CRI. None
of these observations were replicated in the
north Indian (NI) subjects. A genotypic but not
79

R & D Highlights
allelic association was observed for two
markers, VEGF (-460 T>C) and PON1
(Arg192Gly) among NI diabetic CRI subjects.
The nonreplication of association suggests
differential genetic susceptibility of the two
populations to diabetic chronic renal
insufficiency. In the SI diabetic subjects,
oxidative stress pathway genes might be an
important predictor for the development of
diabetic complications. Further, the association
of wild-type alleles may suggest that they
confer greater survival ability to comorbid
complications and may be nephroprotective.
Poor vitamin D status may contribute
to high risk for insulin resistance, obesity,
and cardiovascular disease in Asian Indians.
McCarty, Mark F
Medical Hypotheses, 72(6), 647 (2009)
Asian Indians are highly prone to insulin
resistance syndrome, obesity, diabetes, and
coronary disease. At any given BMI, they tend
to have more body fat and more central fat
than other groups - yet their insulin resistance
is disproportionately high relative to their body
composition. They are also tend to have very
poor vitamin D status, even in UV-drenched
India, primarily owing to highly pigmented
skin and a cultural tendency to avoid direct sun
exposure. The resulting up-regulation of
parathyroid hormone (PTH) arguably may play
a role in their high risk for insulin resistance
and associated pathologies. There is suggestive
evidence that moderate elevations of PTH may
promote insulin resistance, weight gain,
hypertension, left ventricular hypertrophy, and
the acute phase response, while increasing risk
for ischemic arrhythmias and cardiovascular
mortality. Controlled studies should assess the
impact of optimal vitamin D supplementation,
with or without added calcium, on risk factors
associated with insulin resistance in Asian
Indians, as well as in other highly pigmented
urbanized ethnic groups that are at high risk
for insulin resistance and obesity.
Efficacy and safety of sitagliptin in the
treatment of patients with type 2 diabetes in
80

China, India, and Korea.


Mohan, Viswanathan et al.
Diabetes
Research
and
Clinical
Practice,83(1), 106(Jan., 2009)
The efficacy and safety of sitagliptin as
monotherapy were evaluated in Chinese,
Indian, and Korean patients with type 2
diabetes inadequately controlled by diet and
exercise. In a randomized, placebo-controlled,
double-blind, 18-week trial, 530 patients with
HbA1c >=7.5% and <=11.0% (mean baseline
8.7%) received sitagliptin 100 mg once daily
or placebo. Compared with placebo, sitagliptin
significantly (p < 0.001) reduced mean HbA1c
(-1.0%), fasting plasma glucose (-1.7 mmol/L),
and 2-h postprandial glucose (-3.1 mmol/L),
and a significantly (p < 0.001) greater
proportion of sitagliptin-treated versus
placebo-treated patients achieved HbA1c <7%
(20.6% versus 5.3%, respectively) at study
end. Efficacy of sitagliptin was demonstrated
in each country. Sitagliptin was generally welltolerated. Clinical adverse events (AEs) were
reported in 23.3% and 15.2% of sitagliptintreated
and
placebo-treated
patients,
respectively. The difference was primarily due
to increased gastrointestinal AEs in the
sitagliptin group, most of which were mild and
resolved on study drug. Serious AEs,
discontinuations due to AEs, and drug-related
AEs occurred with a low incidence in both
groups. No hypoglycemia was reported. In
conclusion, of the study, sitagliptin
monotherapy for 18 weeks significantly
improved glycemic control and was welltolerated in patients with type 2 diabetes from
China, India, and Korea.
Low bodyweight Type 2 diabetes in
India:
Clinical
characteristics
and
pathophysiology.
Das, Sidhartha et al.
Diabetes and Metabolic Syndrome:
Clinical Research and Reviews, 3(1),60 (2009)
Low body weight Type 2 DM/Type 2
DM-lean is a distinct clinical entity that is
neither related clinically or pathophysioCurrent R&D Highlights, Jan.-Mar. 2009

R & D Highlights
logically to LADA nor former fruste of Type
1DM, having absence of markers for
autoimmune destruction of [beta]-cells and
good insulin and C-peptide reserve for a
prolonged period of life. They constitute an
independent variant of Type 2 DM with
inherent peculiarities of insulin kinetics in the
liver along with altered profile and behaviour
of key enzymes related to carbohydrate
metabolism which are marked by excess
extraction of insulin in hepatic bed,
hyperactive cytochrome system and nonsupressible glucokinase activity. These
peculiarities are reflected in the peripheral
circulation as states of low circulating levels of
insulin, hyperglycemia, dyslipidemia without
low high density lipoprotein cholesterol
(HDLc), raised triglycerides (Tg), low levels
of plasma homocysteine and BMI below 19
make these diabetics less prone to develop
macrovascular disease. Peripheral neuropathy
and the consequences of poor glycemic control
such as increased succeptibility to infections
and endothelial dysfunction manifesting as
proteinuria dominate the clinical picture. In
view of more of infective complications and
coexistent severe hyperglycemia (glucose
toxicity) many of these diabetics may not
respond to OHA adequately at the initiation of
therapy. However, due presence of insulin
resistance and good []-cell reserve for insulin,
despite of lean habitus, most of them respond
well to OHA for long periods of life, as may
be comparable with any other phenotype of
Type 2 diabetes. The insulin resistance
observed in Type 2 DM-lean is not consequent
to anthropometric parameters like central
obesity and WHR as these diabetics are lean
with poor fat depot and thus it could be an
integral part of the pathogenic mechanism of
Type 2 DM per se.
Inhibition of aldose reductase from
cataracted eye lenses by finger millet
(Eleusine coracana) polyphenols.
Chethan, S. et al.
Bioorganic & Medicinal Chemistry,
Current R&D Highlights, Jan.-Mar. 2009

16(23), 10085 (Dec., 1, 2008)


Retinopathy is a major cause of blindness
in the Western world, while cataract is one of
the three major causes of blindness worldwide.
Diabetes is one of the major risk factor in
retinopathy and cataract. The prevalence of
blindness in India is 15 per 1000 while cataract
alone accounts for 80% of this blindness.
Diabetes induced cataract is characterized by
an accumulation of sorbitol which is mediated
by the action of a key enzyme aldose reductase
(AR). Non-enzymatic glycation (binding of
glucose to protein molecule) induced during
diabetes appear to be the key factor for AR
mediated sugar-induced cataract. Finger millet
polyphenols (FMP) being a major anti-diabetic
and antioxidant component, we have evaluated
them for AR inhibiting activity. Phenolic
constituents in FMP such as gallic,
protocatechuic, p-hydroxy benzoic, pcoumaric, vanillic, syringic, ferulic, transcinnamic acids and the quercetin inhibited
cataract eye lens effectively, the latter was
more potent with an IC50 of 14.8 nM.
Structure function analysis revealed that
phenolics with OH group at 4th position was
important for aldose reductase inhibitory
property. Also the presence of neighboring Omethyl group in phenolics denatured the AR
activity. Finger millet seed coat polyphenols
(SCP) has been found to inhibit AR reversibly
by non-competitive inhibition. These results
thus, provide a stronger evidence for the
potentials
of
FMP
in
inhibiting
cataractogenesis in humans.
Prevalence of diabetes mellitus and
other abnormalities of glucose tolerance in
young adults aged 20-40 years in North
India (Kashmir Valley).
Zargar, Abdul Hamid et al.
Diabetes Research and Clinical Practice,
82(2), 276 (Nov., 2008)
To assess the burden of type 2 diabetes
mellitus (T2DM) and other abnormalities of
glucose tolerance in young-adult (20-40 years)
men and non-pregnant women. prevalence of
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diagnosed T2DM, undiagnosed T2DM and
other abnormalities of glucose tolerance
studied in 3032 subjects from Kashmir Valley
of India. The study included a questionnaire,
anthropological
measurements,
blood
sampling, and a standard OGTT. Eight (0.3%)
of surveyed subjects were previously
diagnosed to have diabetes. Of 3024 subjects
screened, prevalence of diabetes, impaired
glucose tolerance (IGT), and impaired fasting
glycemia was 2.5%, 2.0%, 11.9% and 26.7%,
respectively. Overall, age-adjusted prevalence
of T2DM (known plus unknown), IGT, IFG
(WHO) and IFG (ADA) was 2.4% (95% CI:
1.9-3.0), 1.6% (95% CI: 1.3-2.2), 11.1% (95%
CI: 10.0-12.3), and 25.2% (95% CI: 23.726.8), respectively. The difference in diabetes
prevalence was significant by age, habitat,
family history of diabetes and BMI. The ratio
of known-to-unknown diabetes was 1:10. This
is the first large scale study from North India
on prevalence of type 2 diabetes in the younger
age group of 20-40 years. Abnormal glucose
tolerance including undiagnosed T2DM is
common in young adults.
Synthesis and elucidation of absolute
stereochemistry of salaprinol, another
thiosugar sulfonium sulfate from the
ayurvedic traditional medicine Salacia
prinoides.
Tanabe, Genzoh et al.
Tetrahedron, 64(43), 10080 (Oct., 20,
2008)
Synthesis and elucidation of absolute
stereochemistry of salaprinol (3) isolated from
the root and stems of Salacia prinoides, which
has been used for the treatment of diabetes in
India, Sri Lanka, and Southeast Asia countries,
is described. Compound 3 and its 2'-epimer,
epi-salaprinol (epi-3) were synthesized via the
coupling reaction of a cyclic sulfate, 2-Obenzylglycerol 1,3-cyclic sulfate (5), with a
thiosugar, 1,4-dideoxy-1,4-epithio-d-arabinitol
(6), as the key reaction, and S configuration of
the asymmetric center in the side chain of 3
was elucidated by the X-ray crystallographic
82

analysis.
High prevalence of type 2 diabetes
mellitus in affluent urban Indians.
Boddula, R et al.
Diabetes Research and Clinical Practice,
81(2), e4 (Aug., 2008)
The highest prevalence of type 2 diabetes
mellitus in developing countries occurs in the
upper socio-economic group, but this has not
been well documented in Indians. The age and
sex standardized prevalence of diabetes in
1112 affluent adult Indian subjects was 21.1%.
This is the highest prevalence of diabetes
reported from India.
Global diabetes landscape--type 2
diabetes
mellitus
in
South
Asia:
Epidemiology, risk factors, and control.
Gupta, Rajeev et al.
Insulin, 3(2), 78 (Apr., 2008)
Type 2 diabetes mellitus (DM) is a new
epidemic in South Asia and is the result of
societal influences and changing lifestyles.
Epidemiologic studies suggest that the
prevalence of DM has increased exponentially
in urban and rural populations. This study was
conducted to determine trends in the
prevalence of DM in various countries in
South Asia. We performed an extensive,
systematic MEDLINE search for primary
articles that reported on the epidemiology of
DM in South Asia. Additional articles were
obtained from personal collections and
references cited in the primary articles. No
formal meta-analysis was performed because
of differing methodologies and diagnostic
criteria. Epidemiologic studies conducted in
India during the 1960s and 1970s, using
random and postload blood glucose
estimations, reported DM in 1% to 4% of
urban populations and 1% to 2% of rural
populations. More standardized epidemiologic
studies in adults since the late 1980s reported
DM in 5% to 15% of urban populations, 4% to
6% of semiurban populations, and 2% to 5%
of rural populations. A significantly increasing
trend has been observed in urban populations
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(exponential trend R2 = 0.74), whereas the
increase is slower (R2 = 0.29) in rural
populations. The diabetes scenario is similar in
other South Asian countries. Current
prevalence rates are 5% to 16% in urban areas
and 2% to 8% in rural areas. Risk factors for
DM in this region are increasing sedentariness,
dietary excess, obesity (especially high waistto-hip ratio), low birth weight, and genetic
influences. DM is a major public health
problem in South Asia. The prevalence is
higher in urban areas than in rural areas and is
increasing. Population-based measures to
control the epidemic of DM include avoidance
of adiposity through enhanced physical
activity and regulated calorie intake. A
comprehensive national chronic care program
is needed.
Prevalence of autoantibodies and risk
estimation of development of youth onset
type 1 diabetes in northern India.
Ahmad, Jamal et al.
Diabetes and Metabolic Syndrome:
Clinical Research and Reviews,2(1), 59 (Feb.,
2008)
Autoantibodies to islet cell antigens such
as insulin (IAA), the 65-kDa isoform of
glutamate decarboxylase (GAD65) and the
protein tyrosine phosphatase (PTP) like
antigen IA-2 are markers of the autoimmune
process preceding type 1 diabetes (T1DM) and
may help to predict the rapid decrease in
residual [beta]-cell function. The present
investigation was undertaken to evaluate the
relation between GAD65 and IA-2 in children
with newly diagnosed T1DM and to compare
the frequency and levels of autoantibodies with
clinical characteristics. A total of 102 T1DM
subjects (age at onset <30 years; mean
duration of disease 6.7 2.8 years) from north
India were characterized by serological
determination of the islet cell antibodies,
GAD65 and IA-2. One hundred and two age
and sex matched non-diabetic subjects of the
non-diabetic parents served as control.
Prevalence of autoantibodies in diabetic
Current R&D Highlights, Jan.-Mar. 2009

population was 47%, GAD65 antibodies was


positive in 42 (41.2%) and IA-2 in 21 subjects
(20.6%). A total of 14.7% (n = 15) TIDM
subjects showed both GAD65 plus IA-2
autoantibody positivity. Comparison between
GAD65 positive and GAD65 negative groups
showed younger age of onset, low BMI and
decreased C-peptide. GAD65 positivity alone
was associated with 6.39 times risk, IA-2
autoantibodies positivity with 5.4 times risk of
developing TIDM. Risk increased to 7.6 times
of
control
population,
when
both
autoantibodies were positive. Prevalence of
autoantibodies in TIDM and control group is
much less than that of western population
suggesting heterogeneous nature of a young
diabetic population with substantial percentage
of patients having non-immune type 1B
diabetes. Despite low positivity, islets cell
autoimmunity plays dominant role in young
TIDM of north India.
Impact of metabolic abnormalities for
beta cell function: Clinical significance and
underlying mechanisms.
V. Grill et al.
Molecular and Cellular Endocrinology,
297, 86-92 (2009)
It is firmly established that poor metabolic
control in diabetes inhibits beta cell function.
Chronic hyperglycaemia is probably the most
important factor, exerting both primary
negative effects (by glucose per se and/or
metabolites) and secondary ones (by beta cell
exhaustion).
Dyslipidemia
in
diabetes
aggravates the glucose effects both by
inducing insulin resistance and by direct
effects on beta cells. Much experimental and
some clinical evidence indicates that therapies
that promote beta cell rest such as early and
intensive insulin treatment and K-ATP channel
blockers can be beneficial.
Proteomics in diabetes research.
Tea Sundsten et al.
Molecular and Cellular Endocrinology,
297, 93-103 (2009)
Both type 1 and type 2 diabetes mellitus
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are heterogeneous diseases with alterations in
many genes and their products. Not all
transcriptional alterations lead to protein
changes, which makes it very important to, in
conjunction with mRNA expression studies,
also address changes in cellular protein levels.
Various proteomic techniques are available for
measuring
many
protein
changes
simultaneously. Many proteomic studies have
been performed in the context of diabetes
research, with the aims of both describing the
healthy tissue and to unravel the complex
pathophysiology behind the disease. In
addition, effects on proteins induced by
different treatments have
also been
investigated using proteomic approaches. In
this paper the field of diabetes proteomics
today will be reviewed. Findings from
proteomic studies investigating pancreatic
islets and -cells as well as serum, fat, skeletal
muscle and liver are described.
The GK rat beta-cell: A prototype for
the diseased human beta-cell in type 2
diabetes?
B. Portha et al.
Molecular and Cellular Endocrinology,
297, 73-85 (2009)
Increasing evidence indicates that
decreased functional beta-cell mass is the
hallmark of type 2 diabetes (T2D) mellitus.
Nowadays, the debate focuses on the possible
mechanisms responsible for abnormal islet
microenvironment,
decreased
beta-cell
number, impaired beta-cell function, and their
multifactorial aetiologies. This review
illustrates to what extend the GotoKakizaki
rat, one of the best characterized animal
models of spontaneous T2D, has proved be a
valuable tool offering sufficient commonalities
to study these aspects. Authors have proposed
that the defective beta-cell mass and function
in the GK model reflect the complex
interactions of multiple pathogenic players: (i)
several independent loci containing genes
responsible for some diabetic traits (but not
decreased beta-cell mass); (ii) gestational
84

metabolic impairment inducing an epigenetic


programming of the pancreas (decreased betacell neogenesis and/or proliferation) which is
transmitted to the next generation; and (iii)
loss of beta-cell differentiation due to chronic
exposure to hyperglycemia/hyperlipidemia,
inflammatory mediators, oxidative stress and
to perturbed islet microarchitecture.
Oscillatory control of insulin secretion
Anders Tengholm et al.
Molecular and Cellular Endocrinology,
297, 58-72 (2009)
Pancreatic -cells possess an inherent
ability to generate oscillatory signals that
trigger insulin release. Coordination of the
secretory activity among -cells results in
pulsatile insulin secretion from the pancreas,
which is considered important for the action of
the hormone in the target tissues. This review
focuses on the mechanisms underlying
oscillatory control of insulin secretion at the
level of the individual -cell. Recent studies
have demonstrated that oscillations of the
concentration
are
cytoplasmic
Ca2+
synchronized with oscillations in -cell
metabolism, intracellular cAMP concentration,
phospholipase C activity and plasma
membrane
phosphoinositide
lipid
concentrations.
There
are
complex
interdependencies between the different
messengers and signalling pathways that
contribute to amplitude regulation and shaping
of the insulin secretory response to nutrient
stimuli and neurohormonal modulators.
Several of these pathways may be important
pharmacological targets for improving
pulsatile insulin secretion in type 2 diabetes.
Growth
hormone
signaling
in
pancreatic
-cellsCalcium
handling
regulated by growth hormone
Fan Zhang et al.
Molecular and Cellular Endocrinology,
297, 50-57 (2009)
Deficiency in insulin secretion is a
fundamental part in the pathogenesis of all
forms of diabetes, determined by impaired
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R & D Highlights
secretory function and inadequate -cell mass.
Growth hormone (GH) is a multifunctional
hormone, involved in cellular metabolism,
mitogenesis and differentiation. In pancreatic
islets, GH is involved in maintaining -cell
mass, stimulating islet hormone production
and insulin secretion, and, therefore, plays a
role in maintaining normal insulin sensitivity
and glucose homeostasis. The intracellular
events that convey the GH signal into various
cellular responses remain incompletely
understood. In this review, we discuss GH
signaling in the -cells, with emphasis on Ca2+
handling and insulin secretion regulated by
human GH (hGH). hGH-stimulated rise in
[Ca2+]i is dependent on extracellular Ca2+ and
is mediated by Ca2+-induced Ca2+ release
(CICR) in the -cell. This process is triggered
by hGH-stimulated activation of the nonreceptor tyrosine kinases JAK2 and c-Src,
which causes tyrosine phosphorylation of
RyRs, resulting in sensitization of CICR. The
rise in [Ca2+]i elicited by hGH is associated
with an enhanced insulin secretion, effects that
are mediated mainly through the prolactin
receptor. These mechanisms indicate that a rise
in [Ca2+]i elicited by activation of PRLR is
JAK2-dependent and is associated with
enhanced insulin secretion. In contrast, GH
receptor-mediated increase in [Ca2+]i is JAK2independent and is dissociated from insulin
secretion.
The AMP-regulated kinase family:
Enigmatic targets for diabetes therapy.
Guy A. Rutter et al.
Molecular and Cellular Endocrinology,
297, 41-49 (2009)
AMP-activated protein kinase (AMPK) is
a widely conserved Ser/Thr-specific protein
kinase, homologous to Saccharomyces
cerevisiae Snf1, and involved in nutrient
sensing in lower organisms. In 2003, authors
reviewed the role of this enzyme in glucose
homeostasis in mammals. In the subsequent 5
years, dramatic strides have taken place in our
understanding of the role of AMPK in the
Current R&D Highlights, Jan.-Mar. 2009

control of whole body metabolic homeostasis,


the regulation of the enzyme by upstream
kinases, and its molecular structure. These new
studies and earlier work arguably propel
AMPK, and perhaps related family members
into a super league of potential therapeutic
targets for maladies including diabetes, cancer,
heart disease, and obesity. In this article
authors have discussed some of these recent
advances, focussing on the role of this and
related enzymes in the control of pancreatic cell function and glucose homeostasis.
Mitochondrial
dysfunction
in
pancreatic -cells in Type 2 Diabetes.
Hindrik Mulder et al.
Molecular and Cellular Endocrinology,
297, 34-40 (2009)
Mitochondrial metabolism controls insulin
secretion from the pancreatic -cell. Type 2
Diabetes evolves when the -cells fail to
release appropriate amounts of insulin, causing
metabolic dysregulation and hyperglycemia. It
is attractive to assume that mitochondrial
dysfunction plays a decisive role in these
processes. Indeed, while being a rare
condition, genetically determined dysfunction
of mitochondria causes a Type 2 Diabetes-like
syndrome. Here, In this article authors have
reviewed what is known about mitochondrial
dysfunction in the -cell in Type 2 Diabetes.
The focus is on observations in humans but
relevant studies in animal models of the
disease are discussed. A particular emphasis is
placed on changes in metabolic enzymes and
function in -cell mitochondria and how
altered structure of the organelle appears to
facilitate its function. These molecular
processes are subject to tight genetic as well as
epigenetic control. Variations and implications
of these mechanisms are reviewed. The
emerging picture is that alterations in
mitochondria may be a culprit in the
pathogenetic processes culminating in Type 2
Diabetes. Such processes may prove to be
targets for therapeutic interventions in the
disease.
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The importance of RNA binding
proteins in preproinsulin mRNA stability
Rikard G. Fred et al.
Molecular and Cellular Endocrinology,
297, 28-33 (2009)
A dynamic production of insulin is
necessary for proper glucose homeostasis. In
order to generate enough insulin available for
exocytosis in response to the demands of the
organism, the level of preproinsulin mRNA in
the pancreatic -cell needs to fluctuate. In
animal models for type 2 diabetes the contents
of preproinsulin mRNA are lowered, which
might suggest that an impaired metabolism of
preproinsulin mRNA contributes to the
development of glucose intolerance and
diabetes. Thus, it is of importance to
understand the mechanisms by which
preproinsulin mRNA levels are regulated.
Although extensively studied, there are aspects
of the regulation of insulin gene expression
that still remain enigmatic. Our understanding
of insulin gene transcription has improved
considerably the last 20 years, but less effort
has been invested into the control of
preproinsulin
mRNA
stability.
The
preproinsulin mRNA has a long half-life and
changes in preproinsulin mRNA stability,
induced by glucose, are likely to be regulated
through specific mechanisms. Recent findings
indicate that the polypyrimidine tract-binding
protein (PTB), also named hnRNP I, by
binding to the 3-UTR (untranslated region) of
the preproinsulin mRNA molecule, stabilizes
the messenger, thereby participating in the
glucose-induced increase in preproinsulin
mRNA. Both recent findings pertinent to PTB
function in general, and on the specific role of
PTB on the production of insulin in -cells
have been discussed in the review. The
putative co-operativity between PTB and other
proteins in the control of preproinsulin mRNA
stability, and review -cell signaling events
that may control the mRNA stabilizing effect
of PTB.

86

Regulation of beta cell replication


Ying C. Lee et al.
Molecular and Cellular Endocrinology,
297, 18-27 (2009)
Beta cell mass, at any given time, is
governed by cell differentiation, neogenesis,
increased or decreased cell size (cell
hypertrophy or atrophy), cell death (apoptosis),
and beta cell proliferation. Nutrients,
hormones and growth factors coupled with
their signalling intermediates have been
suggested to play a role in beta cell mass
regulation. In addition, genetic mouse model
studies have indicated that cyclins and cyclindependent kinases that determine cell cycle
progression are involved in beta cell
replication, and more recently, menin in
association with cyclin-dependent kinase
inhibitors has been demonstrated to be
important in beta cell growth. In this review,
authors highlight some aspects of cell cycle
regulation in relation to beta cell replication.
The role of cell cycle regulation in beta cell
replication is mostly from studies in rodent
models, but whether these findings can be
extended to human beta cells remains to be
shown.
Genetic dissection of type 2 diabetes.
Martin Ridderstrale et al.
Molecular and Cellular Endocrinology,
297, 10-17(2009)
Compared to the successful probing of
genetic causes of monogenic disorders,
dissecting the genetics of complex polygenic
diseases has until recently been a fairly slow
and cumbersome process. With the
introduction of whole genome wide
association studies (WGAS) the situation
dramatically changed in 2007. The results
from several recent WGAS on type 2 diabetes
(T2D) and obesity have identified at least
eighteen genes consistently associated with
T2D. Many of the genes implicate pancreatic
beta-cell function in the pathogenesis of T2D
whereas only one clearly associate with insulin
resistance. The identified genes most likely
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merely represent the tip of the iceberg in the
explanation behind T2D. Refined tools will
have to provide a more complete picture of the
genetic complexity of T2D over the next few
years. In addition to common variants
increasing susceptibility for the disease, rare
variants with stronger effects, copy number
variations, and epigenetic effects like DNA
methylation and histone acetylation will
become important. Nevertheless, today we are
able for the first time to anticipate that the
genetics of a complex disease like T2D really
can be dissected.
Fetal programming of glucoseinsulin
metabolism
R. Huw Jones et al.
Molecular and Cellular Endocrinology,
297, 4-9 (2009)
Epidemiological studies have shown a link
between poor fetal growth and increased risk
of developing type 2 diabetes. These
observations are highly reproducible in many
populations
worldwide
although
the
mechanisms behind them remain elusive. The
Thrifty Phenotype Hypothesis was proposed
to explain the underlying causes of these
relationships. Animal models of poor
intrauterine nutrition have been utilised to help
to define the causal factors and identify the
molecular mechanisms. Programmed changes
in beta cell function and insulin action have
been a common feature of animal models of
poor intrauterine nutrition. Fundamental
underlying mechanisms are starting to emerge,
including changes in the epigenotype and
mitochondrial function
Insulin exhibits short-term antiinflammatory
but
long-term
proinflammatory effects in vitro.
Yasumasa Iwasaki et al.
Molecular and Cellular Endocrinology,
298, 25-32 (2009)
Although insulin is indispensable for
maintaining glucose homeostasis, it is still
controversial whether or not a high
concentration of insulin is deleterious. Authors
Current R&D Highlights, Jan.-Mar. 2009

examined the effect of insulin on the


transcriptional activity of NF-B, which
mediates the expression of a variety of
inflammation/coagulation-related genes using
hepatocyte cell lines in vitro. Authors found
that insulin (1 nM) alone caused minimal
increase in NF-B-mediated transcription. On
the
other
hand, when
cells
were
simultaneously treated with proinflammatory
cytokines such as TNF, the following dual
effect of insulin was observed: short-term (6 h)
suppressive, and long-term (36 h or later)
stimulatory effects. The former effect was
transient and appears to be mediated by the
phosphatidylinositol 3 kinase (PI3K) signaling
pathway. The latter effect, in contrast, was
more pronounced, enhancing the TNFstimulated NF-B-dependent transcription by
more than sevenfold. This positive effect was
NF-B-specific, and was eliminated by
mitogen-activated protein kinase (MAPK)
inhibitors. Altogether, our data suggest that
insulin has short-term anti-inflammatory but
long-term proinflammatory effects. From a
clinical standpoint, this implies that low basal
and periodically high plasma insulin is
beneficial, whereas a sustained rise in plasma
insulin, as often seen in patients with obesity,
may induce atherothrombotic disorders,
because
of
the
NF-B-mediated
overexpression of proinflammatory/ procoagulant/ antifibrinolytic proteins in the liver.
Inhibition of DPP-4: a new therapeutic
approach for the treatment of type 2
diabetes.
Pratley, Richard E. et al.
Current Medical Research and Opinion
(2007), 23(4), 919-931.
A review. Background: Glucagon-like
peptide-1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP) are hormones
secreted by the enteroendocrine cells of the gut
in response to the ingestion of nutrients. These
incretin hormones, so called because they
increase insulin secretion, are key modulators
of pancreatic islet hormone secretion and, thus,
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glucose homeostasis. The glucoregulatory
effects of incretins are the basis for new
therapies currently being developed for the
treatment of type 2 diabetes mellitus (T2DM).
Drugs that inhibit dipeptidyl peptidase-4
(DPP-4), a ubiquitous enzyme that rapidly
inactivates both GLP-1 and GIP, increase
active levels of these hormones and, in doing
so, improve islet function and glycemic control
in T2DM. Scope: In this review, we briefly
describe (1) the role of pancreatic islet
dysfunction in the onset and progression of
T2DM, (2) the rationale for developing drugs
that enhance incretin activity, (3) the evidence
that inhibition of DPP-4 is effective in
ameliorating islet dysfunction and improving
glycemic control in T2DM, (4) the efficacy,
safety, and tolerability of DPP-4 inhibitors as
monotherapy and in combination with other
antidiabetic agents, and (5) the potential utility
of DPP-4 inhibitors relative to existing oral
antidiabetic agents and newer antidiabetic
drugs in the pipeline. The review is based upon
MEDLINE literature searches (1966-August
2006) and abstrs and presentations from the
American Diabetes Assocn. Scientific Sessions
(2002-2006) and the European Assocn. for the
Study of Diabetes Annual Meetings (19982006).
Basic science, preclin., and clin.
studies and review articles published in the

English language were evaluated and selected


based upon consideration of their originality,
relevance, and frequency of citation. Findings:
DPP-4 inhibitors are a new class of
antidiabetogenic
drugs
that
provide
comparable efficacy to current treatments.
They are effective as monotherapy in
patients inadequately controlled with diet and
exercise and as add-on therapy in combination
with metformin, thiazolidinediones, and
insulin.
The DPP-4 inhibitors are well
tolerated, carry a low risk of producing
hypoglycemia, and are wt.-neutral. The longterm durability of effect on glycemic control
and -cell morphol. and function remain to be
established.
Conclusions: Islet cell
dysfunction is central to the pathogenesis of
T2DM. Incretin-based therapies, including
GLP-1 analogs and DPP-4 inhibitors, have
been shown to restore glucose homeostasis and
improve glycemic control.
The DPP-4
inhibitors, which can be used as monotherapy
or in combination with other antidiabetic
drugs, are a promising new treatment option,
esp. for patients with early-stage T2DM and
more severe hyperglycemia.

Views expressed in the journal are those of the authors and the
Editorial Board/Publisher takes no responsibility for the same. We are
a secondary abstracting service and the veracity of information is of
the source quoted and not our primary responsibility.
Editor

88

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R & D Technology

Risk Factors and Complications of Diabetes


Introduction
Diabetes is a complex metabolic condition
that requires meticulous management and a
global approach. Poor management and control
of diabetes often lead to poor disease
outcomes. The management of diabetes and its
complications presents an increasing challenge
to healthcare systems throughout the world.
New findings regarding complications of
diabetes, their prevalence and incidence, and
risk factors involved were discussed at the
Annual Professional Conference of Diabetes
UK, held March 5-7, 2008, in Glasgow, U.K.
Various risk factors associated with
diabetes
includediabetic
nephropathy,
cardiovascular disease, diabetic neuropathy,
diabetic retinopathy, hypoglycemia, metabolic
syndrome, musculoskeletal disease hypoglycemia, chronic liver diseases and coronary
heart disease.

Diabetic Nephropathy
Diabetes and hypertension are major risk
factors for the development of end-stage renal
disease. Increased albumin excretion is seen in
the early stage of diabetic nephropathy before
the glomerular filtration rate decreases.
Microalbuminuria, macroalbuminuria and endstage renal disease are all associated with an
increased risk of death. People with chronic
kidney disease have a greater risk of
developing cardiovascular disease and
diabetes, as seen in a multiethnic population.
Patients with type 2 diabetes are at risk of
developing chronic kidney disease. The
isotopic glomerular filtration (iGFR) rate was
measured in type 2 diabetic patients at
Current R&D Highlights, Jan.-Mar. 2009

diagnosis and then at regular intervals over the


next 10 years. It was found that there was a
marked decrease in iGFR in the first year of
diagnosis of type 2 diabetes, followed by a
subsequent more modest rate of decline in
iGFR.

Cardiovascular Disease
Cardiovascular disease is the main cause
of mortality in patients with diabetes, and risk
reduction is an important goal in the treatment
of diabetes. In individuals, little is known
about the importance of progressive change or
variability over time in risk factors for
atherosclerotic vascular disease. Data have
shown a significant increase for major
cardiovascular events and procedures in
subjects with type 2 diabetes..
Endothelial dysfunction, carotid intimamedia thickness (CIMT) and lipoprotein
abnormalities are factors contributing to
cardiovascular disease. One study found that
abnormalities in flow-mediated dilatation and
CIMT are present in young type 1 diabetic
patients and correlate well with lipoprotein
abnormalities. The PREDICT study measured
the coronary artery calcification score (CACS)
and found it to be a powerful predictor of
cardiovascular events in asymptomatic patients
with type 2 diabetes.
Both metabolic syndrome and type 2
diabetes are associated with a high
cardiovascular risk due to clustering of
atherothrombotic risk factors such as insulin
resistance,
dyslipidemia,
hypertension,
hypercoagulability and dysglycemia. Insulin
resistance in type 2 diabetic patients may be
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responsible for hypertension and dyslipidemia.
It was found that prehypertension is associated
with obesity but not specifically with insulin
resistance or metabolic syndrome. Although
the majority of type 2 diabetic patients are
obese, the body mass index was found to be a
poor discriminator of cardiovascular risk in
these patients.
Ischemic heart disease (IHD) is the most
frequent macroangiopathic complication and
the main cause of death in subjects with type 2
diabetes. Myocardial infarction often occurs in
type 2 diabetic patients with no previous
cardiac symptoms. Diabetes is an important
determinant of death after acute myocardial
infarction (AMI) and adversely affects the
outcome after AMI. Another study found
hypertension to be a risk factor for IHD in a
Scottish type 1 diabetic population and highdensity lipoprotein (HDL) was found to have a
protective effect against cardiovascular
disease.
Endothelial
dysfunction
leads
to
atherosclerosis, which is the leading cause of
macrovascular complications and death in
patients with type 2 diabetes. Investigations
within the endothelium have been limited by
access until the recent development of a new
technique to sample cells from a forearm vein
in humans.
Type 2 diabetes is associated with
increased vascular superoxide levels and
impaired endothelial function. Researchers
from Glasgow examined the effect of diabetes
on vascular superoxide production in patients
undergoing coronary artery bypass graft. They
concluded that reduced superoxide production
in patients with type 2 diabetes may be
attributable to increased use of modifiers of the
angiotensin system and oral hypoglycemic
agents. Thus, other factors such as impaired
smooth muscle function and reduced
endothelial nitric oxide generation may be
responsible
for
impaired
endothelium
dependent vasorelaxation in diabetes.

Individuals with features of metabolic


syndrome and an increased risk of
cardiovascular disease are found to have
reduced functional vasodilatory reserve and
this impaired response may contribute to
decreased insulin sensitivity and glucose
uptake by muscle. Oxidative stress markers
such as whole-blood reduced glutathione and
the ratio of reduced and oxidized glutathione
may be integrally related in the etiology of the
vasculopathy exhibited by type 2 diabetic
patients. Another interesting survey suggested
that arterial function deteriorates more rapidly
in mothers with gestational diabetes and
continues to do so postpartum, despite
resolution of glucose intolerance.
Angiogenesis
occurs
within
atherosclerotic
plaques and a
study
investigated the effects of thrombin on key
aspects of angiogenesis such as cell
proliferation, vascular tubule formation and
expression of pro- and antiangiogenic
regulators. The investigators found that
thrombin stimulates vascular smooth muscle
cell proliferation, but attenuates endothelial
cell-mediated growth of vascular tubules and
branching of new vascular structures.
Osteoprotegerin, an anti resorptive agent
in bone, is present in the systemic vasculature.
It is normally high after menopause as a
compensatory mechanism for excessive bone
turnover. The level of osteoprotegerin is also
high in type 2 diabetic patients. The earlier rise
and loss of the normal postmenopausal rise
may represent an underlying premature
vascular inflammatory process in diabetic
patients.
Adiponectin is an adipocytokine with
favorable metabolic and vascular effects. High
adiponectin levels are consistently associated
with a lower diabetes risk. However, evidence
from studies linking total adiponectin and
vascular disease indicate no clear association.

Diabetic Neuropathy
Neuropathy in diabetic patients is a major

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source of morbidity. The pathogenesis of
diabetic
neuropathy
remains
poorly
understood. Diabetic peripheral neuropathy is
a common and debilitating consequence of
diabetes. There are established risk factors for
the development of peripheral neuropathy in
patients with diabetes, such as poor glycemic
control and hypertension. Increasing subject
height was found to be associated with an
increased long-term risk of developing
neuropathy in type 1 diabetic patients who
participated in the DCCT follow-up study. In
type 1 diabetic patients, the additional
diagnosis of celiac disease appears to lead to
poorer nerve conduction even when
controlling for glycemic control.
Depression may be a major confounder of
outcomes in clinical trials in diabetic
peripheral neuropathy. Subjects with even
moderate levels of depression are more likely
to have higher baseline pain scores and to
respond favorably to any intervention, whether
placebo or active.
Although there is an increased propensity
for the development of carpal tunnel syndrome
in people with diabetes, the basis for this has
not been established. Increased upregulation of
hypoxia-inducible factor 1 (HIF-1),
vascular endothelial growth factor (VEGF) and
vascular endothelial growth factor receptor 2
(VEGFR2), suggestive of increased hypoxia
and vascular permeability, was found in
diabetic patients with established carpal tunnel
syndrome.
In an animal study, glycation adducts were
found in the extracellular matrix of the sciatic
nerve of streptozotocin-induced diabetic rats,
which may contribute
to decreased
regeneration of sensory neurons, leading to
peripheral neuropathy.
The accurate quantification of diabetic
neuropathy is important to define at-risk
patients and anticipate deterioation. Corneal
confocal microscopy is a rapid, noninvasive
technique that has been shown to be a reliable
Current R&D Highlights, Jan.-Mar. 2009

surrogate measure of somatic neuropathy and


found to be useful in diagnosing and following
the progression of diabetic neuropathy in
relation to risk factors. A study from London
revealed that Contact Heat Evoked Potential
Stimulator, which is a practical, rapid and
noninvasive clinical tool, can be used to evoke
recordable potentials for the diagnosis of
small-fiber neuropathy. Another study
suggested that mRNA for neuron-specific
enolase may be a useful marker for diabetic
neuropathy .
Autonomic
neuropathy is
another
important complication of diabetes that is
associated with increased mortality. However,
it is often not diagnosed until advanced
symptoms occur. Spectral analysis of heart rate
variability is a novel technique that detects
autonomic dysfunction in diabetes in the very
early stages. It can also be used as a measure
of peripheral neuropathy, as well as a marker
of long-term risk. Spectral analysis of heart
rate variability and baroreceptor sensitivity in
combination may detect early autonomic
dysfunction in young adults with type 1
diabetes.

Diabetic Retinopathy
Digital retinal screening was performed in
both type 1 and type 2 diabetic patients to
measure the prevalence of diabetic retinopathy.
The prevalence rate for diabetic retinopathy in
type 2 diabetic patients on oral hypoglycemic
drugs appeared to be lower than in other
population studies. Visual acuity was well
preserved and type 2 diabetic patients
receiving insulin were at high risk of diabetic
retinopathy, particularly maculopathy. A
retrospective analysis found that the
prevalence of sight-threatening maculopathy is
highest in eyes with sight-threatening diabetic
retinopathy and negligible in eyes with screennegative retinopathy.
A study from London indicated that sleepdisordered breathing, which is quite common
in type 2 diabetic patients, plays an etiological
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role in diabetic retinopathy. Another study
mentioned that sleep-disordered breathing may
play a role in metabolic syndrome via the
inflammatory pathway.

Hypoglycemia
Hypoglycemia is a common adverse event
of diabetes treatment and remains a major
barrier to achieving optimal glycemic control
in both type 1 and type 2 diabetic patients,
particularly those who are on insulin.
Hypoglycemic episodes may compromise the
patients' quality of life. Bedtime blood glucose
is a significant risk factor for nocturnal
hypoglycemia in type 1 diabetic subjects and
these subjects did not show any rebound
hyperglycemia
following
nocturnal
hypoglycemia. Gill et al. found that all the
nocturnal hypoglycemic episodes in patients
with type 1 diabetes were associated with
tachycardia and a subgroup appeared prone to
develop bradycardia, which may be
responsible for sudden death.
Researchers documented a wide range of
Q-T lengthening following inhaled salbutamol
in type 1 diabetic patients. These results can be
compared with the responses during
experimental hypoglycemia to establish it as a
screening test for those at risk of abnormal
cardiac repolarization leading to fatal cardiac
arrhythmias
during
severe
nocturnal
hypoglycemia.
Type 1 diabetic patients are likely to be
unaware of hypoglycemia because of
impairment of the protective neurohumoral
counterregulatory responses to impending
hypoglycemia due to repeated hypoglycemic
episodes. Impaired awareness of hypoglycemia
(IAH) is thought to affect approximately 25%
of subjects with type 1 diabetes. Despite
improvements in insulin therapies, intensification of insulin regimens and innovative
patient education, a survey of a large hospitalbased clinical population confirmed that 19.5%
of type 1 diabetic patients continue to have
IAH. Two different studies from the same
92

group of investigators reported that patients


with IAH had a 3-fold higher incidence of
severe hypoglycemia, a 2-fold increase in mild
biochemical hypoglycemia and a 7-fold
increase in the incidence of episodes of
asymptomatic hypoglycemia compared to type
1 diabetic patients with normal awareness. In
contrast, IAH in insulintreated type 2 diabetic
patients is less common as a clinical problem.
However, those with IAH have, an increased
risk of both mild and severe hypoglycemia .

Metabolic Syndrome
The metabolic syndrome increases
cardiovascular risk in type 2 diabetes.
Abdominal adiposity is considered a major risk
factor for type 2 diabetes, metabolic syndrome
and cardiovascular diseases. This is supported
by Yang et al., who found that visceral
adiposity remains a strong and significant
determinant of insulin resistance in WHO
grade III obesity. Neck circumference rather
than subcutaneous fat is a more reproducible
and precise measurement in this severely obese
cohort. An association between increased
central obesity and lower serum adiponectin
and an intimate relationship between
triglycerides and insulin resistance were found
in schizophrenic patients treated with
clozapine. Changes in waisthip ratio over time
may result in abnormal glucose handling and
routine measurement of this parameter is
necessary in this group of patients. Another
study suggested that plasma triglycerides and
the albumin:creatinine ratio are associated with
type 2 diabetes in morbid obese subjects.

Musculoskeletal Disease
Early detection of microvascular and
macrovascular complications in subjects with
diabetes could prevent fatal outcomes.
Locomotor disease is found in 57% of patients
with type 1 diabetes. Capsulitis invariably
coexisted with other upper limb abnormalities
and predicted the presence of retinopathy
and/or neuropathy. The mean glycosylated
hemoglobin (HbA1c) was also higher
Current R&D Highlights, Jan.-Mar. 2009

R & D Technology
inpatients with shoulder problems and these
results are very similar to those found in type 2
diabetic patients. Another study found that the
presence of diabetic peripheral neuropathy,
retinopathy and nephropathy was significantly
higher in patients with limited joint mobility.
Therefore, all diabetic patients should be
clinically examined for upper limb locomotor
disease and limited joint mobility, and if
present, they should be evaluated further for
other diabetic complications.

Other Risk Factors


Chronic liver disease is a major cause of
morbidity and mortality. Up to 75% of subjects
with type 2 diabetes have nonalcoholic fatty
liver disease at diagnosis. A secondary-care
prevalence study revealed that 20% of patients
with
diabetes
had
elevated
alanine
aminotransferase
(AL
T),
-glutamyltranspeptidase (GGT), or both. An audit found
that a significant proportion of both men and
women with poor glycemic control have
abnormal lipid profiles associated with a very
high risk of cardiovascular disease.
Coronary heart disease (CHD), diabetes
and chronic kidney disease together are
considered a 'deadly trio' and an audit by the
Deadly Trio Project found that 90% of the
patients were not receiving the optimal
standard care (47). This project identified men
at high risk of CHD mortality, including all
with known diabetes, and ensured that all will
be offered appropriate treatment (48). Another
similar study from Spain found that type 2
diabetic patients who are not well controlled
with two or more oral antidiabetic drugs have
altered metabolic profiles, with HbA 1 c levels
in the range requiring immediate intervention.
Future risk of diabetes in mother and
child after gestational diabetes mellitus.
Damm, Peter et al.
International Journal of Gynecology &
Obstetrics
Gestational diabetes mellitus (GDM) is a
Current R&D Highlights, Jan.-Mar. 2009

Cardiovascular risks in these patients were


high, with the coexistence of other risk factors.

Ethnic Variation
The incidence of diabetes and its
complications varies in different ethnic
populations. A cross-sectional survey revealed
higher plasma glucose, serum leptin, Yon
Willebrand factor, tissue
plasminogen
activator and fat mass-bioimpedence in South
Asian children compared with Europeans,
which make an important contribution to the
differences in insulin resistance observed in
these populations (50). Another similar study
found higher mean truncal skinfold thickness,
HbA 1 c, fasting insulin and triglycerides, and
lower HDL cholesterol in South Asian children
compared with age-adjusted white Europeans.
In a study it was found that the prevalence of
microvascular
complications
such
as
retinopathy, nephropathy and neuropathy and
mean HbA 1 c are significantly higher and the
use of metformin, sulfonylureas and insulin is
significantly lower in India compared to
Mauritius and the UK. Poor glycemic control
in South Asian subjects with type 2 diabetes
and chronic disease comorbidity may be
responsible for the increased risk of mortality
and morbidity. Although a higher proportion
of South Asians were found to have poor
glycemic control, the prevalence of obesity,
smoking and hypertension was lower in this
group than in non-South Asians. Therefore,
there may be important opportunities for the
early prevention of type 2 diabetes and other
microvascular and macrovascular complications in this high-risk ethnic group.
(Based on the Conference Report published in Drugs
of the Future 2008, 33(5): 463-468)

common pregnancy complication with


increased maternal and perinatal morbidity.
However, significant long-term morbidity also
exists for the mother and offspring. Women
with previous GDM have a very high risk of
developing overt diabetes, primarily type 2
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diabetes, later in life. Moreover, the risk of the
metabolic syndrome is increased 3-fold in
these women. Their offspring have an 8-fold
risk of diabetes/prediabetes at 19-27 years of
age. Thus, GDM is part of a vicious circle
which increases the development of diabetes in
the coming generations.
(ScienceDirect)
Fasting homocysteine levels in a crosssection of Saudi adults with type 1 diabetes
mellitus.
Al-Attas, Omar S. et al.
Diabetes and Metabolic Syndrome:
Clinical Research and Reviews
Studies have shown homocysteine to be
an independent risk factor for atherosclerosis
and CVD in both diabetic and non-diabetic
subjects. However, the association between the
levels of homocysteine and type 1 diabetes
mellitus remains a controversial one. A study
was conducted with the aim to test this in a
cross-section of the Saudi type 1 diabetics
against non-diabetics to establish the
relationship of homocysteine with regards to
type 1 diabetics and non-diabetics. A total of
97 subjects (41 males, 56 females) participated
in this cross-sectional study done at the
diabetic clinic of King Abdul-Aziz University
Hospital Diabetic Centre, Riyadh, KSA. They
were divided according to the presence of type
1 DM. Glycemic and lipid parameters were
measured using routing procedures. Hcys was
measured using photometric assay. Among
males, Hcys levels were significantly lower
among the diabetic subjects (p-value 0.03).
Females with type 1 diabetes however have
higher total cholesterol levels than their control
counterparts (p-value 0.003). Among the
control group, gender and HDL-cholesterol
exhibited significant inverse relationships with
hcys (p-values 0.028 and 0.032, respectively)
and a strong positive association with body
mass index (p-value 0.034). Among the
diabetic group, only age was significantly
associated with Hcys (p-value 0.009). In the
Arab population, hcys is decreased in IDDM
subjects compared to non-diabetic subjects.
94

Hcys was correlated to BMI and inversely


associated to HDL-C among the non-diabetics.
Further studies are needed to test the
hypothesis in diabetics with disease
complications.
(ScienceDirect)
Efficacy and safety of exenatide in
patients of Asian descent with type 2
diabetes inadequately controlled with
metformin
or
metformin
and
a
sulphonylurea.
Gao, Yan et al.
Diabetes Research and Clinical Practice,
83(1),69 (Jan., 2009)
Patients taking metformin (MET) alone or
with a sulphonylurea (SU) were randomly
assigned to exenatide 5 []g then 10 []g
twice-daily for 4 and 12 weeks, respectively,
or placebo. The primary endpoint was baseline
to endpoint HbA1c change. 466 patients (age
54 9 years, weight 68.7 11.2 kg, BMI
26.3 3.3 kg/m2, and HbA1c 8.3 1.1%;
mean S.D.) were enrolled in the full analysis
set. Endpoint HbA1c reduction (mean [95%
CI]) with exenatide was superior to placebo (1.2 [-1.3, -1.1]% vs. -0.4 [-0.5, -0.2]%,
p < 0.001). More exenatide- than placebotreated patients achieved HbA1c <=7% (48%
vs. 17%, p < 0.001). At endpoint, weight
reduction was greater with exenatide (-1.2 [1.5, -0.9] kg) than placebo (-0.1 [-0.3, 0.2] kg),
p < 0.001.
Nausea,
generally
mild-tomoderate, was the most common adverse event
with exenatide (25% vs. 1% with placebo).
The incidence of symptomatic hypoglycaemia
with exenatide and placebo were 36% and 9%,
respectively (p < 0.001). Hypoglycaemia rates
(events/patient-year) for patients taking
exenatide with MET or MET and SU were 1.8
(0.9, 3.7) and 4.7 (3.5, 6.5), respectively.
Exenatide treatment improved glycaemic
control in Asian patients with T2D and had a
similar safety profile as in non-Asian patients.
Prevalence and pattern of cardiac
autonomic dysfunction in newly detected
type 2 diabetes mellitus.
Jyotsna, Viveka P. et al.
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Diabetes Research and Clinical Practice,
83(1), 83 (Jan., 2009)
Cardiac autonomic functions were
assessed in 145 consecutive recently detected
type 2 diabetics. Ninety-nine healthy persons
served as controls. Criteria for normalcy were,
heart rate variation during deep breathing
>=15 beats/min, deep breathing expiratory to
inspiratory R-R ratio >=1.21, Valsalva ratio
>=1.21, sustained handgrip test >=16 mm of
mercury, cold pressor test >=10, BP response
to standing <=10 mm of mercury and 30:15 RR ratio on standing >=1.04. An abnormal test
was defined as the above parameters being
<10 beats/min, <1.21, <1.21, <=10 mm of
mercury, <10, >=30 mm of mercury and
<=1.0, respectively. A borderline test was
defined as, heart rate variation during deep
breathing 11-14, sustained handgrip test 1115 mm of mercury, BP response to standing
11-29 mm of mercury and 30:15 R-R ratio on
standing
1.01-1.03.
Parasympathetic
dysfunction was found in 44.2% and
sympathetic dysfunction in 51.9% diabetics.
Among healthy controls, these figures were
11.9% and 22.1%, respectively. Cardiac
autonomic function was normal in 7.8%
patients and 32.5% healthy controls.
Efficacy and safety of sitagliptin in the
treatment of patients with type 2 diabetes in
China, India, and Korea.
Mohan, Viswanathan et al.
Diabetes Research and Clinical Practice,
83 (1), 106 (Jan., 2009)
The efficacy and safety of sitagliptin as
monotherapy were evaluated in Chinese,
Indian, and Korean patients with type 2
diabetes inadequately controlled by diet and
exercise. In a randomized, placebo-controlled,
double-blind, 18-week trial, 530 patients with
HbA1c >=7.5% and <=11.0% (mean baseline
8.7%) received sitagliptin 100 mg once daily
or placebo. Compared with placebo, sitagliptin
significantly (p < 0.001) reduced mean HbA1c
(-1.0%), fasting plasma glucose (-1.7 mmol/L),
and 2-h postprandial glucose (-3.1 mmol/L),
Current R&D Highlights, Jan.-Mar. 2009

and a significantly (p < 0.001) greater


proportion of sitagliptin-treated versus
placebo-treated patients achieved HbA1c <7%
(20.6% versus 5.3%, respectively) at study
end. Efficacy of sitagliptin was demonstrated
in each country. Sitagliptin was generally welltolerated. Clinical adverse events (AEs) were
reported in 23.3% and 15.2% of sitagliptintreated
and
placebo-treated
patients,
respectively. The difference was primarily due
to increased gastrointestinal AEs in the
sitagliptin group, most of which were mild and
resolved on study drug. Serious AEs,
discontinuations due to AEs, and drug-related
AEs occurred with a low incidence in both
groups. No hypoglycemia was reported. In the
study, sitagliptin monotherapy for 18 weeks
significantly improved glycemic control and
was well-tolerated in patients with type 2
diabetes from China, India, and Korea.
Immediate impact of a diabetes training
programme for primary care physicians-An endeavour for national capacity building
for diabetes management in India.
Murugesan, N. et al.
Diabetes Research and Clinical Practice,
83(1), 140 (Jan., 2009)
India faces a huge burden from diabetes.
National capacity for management of diabetes
has to be strengthened by improving
knowledge of physicians treating diabetes,
especially in semi urban and rural areas. A
training programme was formulated and
conducted at national level, as a step towards
this goal. Physicians from 6 states of India
(n = 3023, M:F 2311:712), aged 30-55 years,
with service of >=3 years, (government
n = 1720, private n = 1303, semi urban and
rural areas (n = 1581:1442)) were trained in
diabetes care in 5-day workshops between
March 2004 to December 2006. Impact of
training was assessed by pre- and post-training
knowledge scores, feedback on usefulness of
training modules, prioritizing activities to be
introduced in their practice and methods to be
used for raising public awareness on diabetes.
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The training significantly improved knowledge
on treatment, complications, pathophysiology
and diagnosis of diabetes (p < 0.001). The
participants considered information on
preventive aspects of diabetes and foot care as
highly educative. Patient education and teamtraining were considered important in diabetes
management. Interest was evinced in raising
public awareness about the disease. Wellplanned short training programmes are useful
in improving knowledge and in creating
enthusiasm to improve diabetes care and
awareness.
Proton
magnetic
resonance
spectroscopy and biochemical investigation
of type 2 diabetes mellitus in Asian Indians:
observation of high muscle lipids and Creactive protein levels.
Sinha, Sanjeev et al.
Magnetic Resonance Imaging, 27(1), 94
(Jan., 2009)
Authors report the determination of
intramyocellular lipids (IMCLs) of the soleus
muscle of patients with type 2 diabetes
mellitus (T2DM) using proton magnetic
resonance spectroscopy. In addition, the
various anthropometric and biochemical
profiles of these patients were determined,
including estimation of C-reactive protein
(CRP), an inflammatory marker of coronary
heart disease, and insulin resistance
[Homeostasis Model Assessment (HOMAIR)]. The estimated CRP level and the IMCL
content in these patients were correlated with
body mass index, percentage of body fat, other
measures of abdominal obesity, serum
lipoproteins, fasting and post-oral glucose load
serum insulin levels and other surrogate
markers of insulin resistance. The IMCL
content (P=.04), CRP (P=.008) and insulin
resistance (P=.0007) were significantly higher
in T2DM patients compared to healthy
controls. However, IMCL content did not
correlate with values of fasting insulin,
HOMA-IR or CRP in either group. These
findings have strong implications of increased
96

cardiovascular risk in Asian Indians with


T2DM. The absence of relationship between
CRP and IMCL needs to be explored further in
a study using a large sample size.
Risk
factors
for
developing
osteomyelitis in patients with diabetic foot
wounds.
Lavery, Lawrence A et al.
Diabetes Research and Clinical Practice
Osteomyelitis worsens the prognosis in
the diabetic foot, but predisposing factors
remain largely undefined. In a prospectively
followed cohort authors assessed risk factors
for developing osteomyelitis. Consecutive
persons with diabetes who presented to a
managed-care diabetes disease management
program were enrolled. The patients
underwent standardized assessments and
monitored for all foot complications, defined
infections by criteria consistent with
International Working Group guidelines, and
defined osteomyelitis as a positive culture
from a bone specimen. 1666 persons were
enrolled, 50% male, mean age 69 years. Over a
mean of 27.2 months of follow-up, 151
patients developed foot infections, 30 (19.9%)
of which involved bone. Independent risk
factors for osteomyelitis were: wounds that
extended to bone or joint (relative risk
[RR] = 23.1), previous history of a wound
prior to enrollment (RR=2.2), and recurrent or
multiple wounds during the study period
(RR = 1.9). In this study population, managed
in a specialized diabetic foot care center, the
results suggest that independent risk factors for
developing osteomyelitis are deep, recurrent
and multiple wounds. These results may help
clinicians target their efforts at diagnosing foot
osteomyelitis to the highest risk patients.
(ScienceDirect)

Inter-relationship between low-density


lipoprotein phenotype and carotid intimamedia thickness in North Indian type 2
diabetic subjects.
Ahmad, Jamal et al.
Diabetes and Metabolic Syndrome:
Current R&D Highlights, Jan.-Mar. 2009

R & D Technology
Clinical Research and Reviews
Diabetic dyslipidemia is characterized by
a preponderance of small dense LDL which is
highly atherogenic. The aim of this study was
to examine the interrelationship between LDL
Phenotype and atherosclerosis; to determine
the factors determining LDL phenotype; and
evaluate LDLc:apo-B ratio as a surrogate for
the assessment of LDL phenotype in a group
of North Indian Type 2 diabetic subjects. 285
diabetic subjects attending the outpatient
Endocrine Clinic were subjected to detailed
anthropometry and fasting serum lipid and
apo-B was measured. The carotid intimamedia thickness (IMT) was determined using a
high resolution B-mode Ultrasonography.
LDLc:apo-B ratio was taken as a surrogate
index for LDL size. 29.5% patients with
normal triglyceride levels and 52.1% patients
with normal LDLc levels showed the presence
of small dense LDL or Phenotype B as
estimated by the LDL cholesterol/apo-B ratio.
The mean IMT in Phenotype B group was
higher (0.88 mm vs. 0.68 mm). Triglycerides
was the most important predictor variable
predicting
carotid
IMT
(R2 = 0.15,
[beta] = 0.376) as well as LDL phenotype B
(R2 = 0.28, [beta] = 0.561). Triglycerides and
HDLc contribute independently to the
variability in LDL particle size, and LDL
particle size was associated with preclinical
atherosclerosis as determined by carotid IMT
in North Indian Type 2 diabetic subjects. LDL
cholesterol/apo-B ratio serves as an easy
clinical tool to determine the elevated small
dense LDL. .
(ScienceDirect)
Vibration perception threshold and the
law of mobility in diabetic mellitus patients.
Manivannan, M et al.
Primary Care Diabetes (In Press)
Diabetic neuropathy is a family of nerve
disorders with progressive loss of nerve
function in 15% of diabetes mellitus (DM)
subjects. Vibration Perception Threshold
(VPT) is one of the modalities of testing loss
of protective sensation. Law of mobility for
Current R&D Highlights, Jan.-Mar. 2009

VPT is well known for normal subjects, but


not for diabetic subjects. This is a pilot study
to evaluate and plot the law of mobility for
VPT among DM subjects. Authors used
biothesiometer to find the VPT of several areas
in upper and lower extremities for normal and
diabetic subjects. VPT of normal and diabetic
subjects for different foot areas from proximal
to distal is evaluated for 30 subjects. All the
subjects are screened for peripheral artery
occlusive disease with ankle brachial pressure
index (0.9 or above). VPT values of different
areas are arranged in a proximal to distal order
for the analysis. VPT values monotonically
decrease from proximal to distal areas.
Vierodt's law of mobility holds well for normal
subjects in both feet areas. The law of mobility
does not hold good for the DM subjects in one
or both feet areas. The VPT value of diabetic
subjects reveals that the law of mobility do not
holds good for diabetic subjects in foot areas.
Though the number of subjects is small, all the
subjects defied the law.
Comparison of the glycemic control of
the normo- and hypertensive Chinese
patients with type 2 diabetes in a general
outpatient clinic in Hong Kong.
Go, Echo T.T. et al.
Diabetes and Metabolic Syndrome:
Clinical Research and Reviews
To describe and compare glycemic control
between normo- and hypertensive type 2
diabetic Chinese patients in outpatient setting.
This retrospective cross-sectional study was
performed by retrieving the records of 548
Chinese type 2 diabetic patients. HbA1c [less,
double equals] 6.5% was regarded as glycemic
good control. Linear and logistic regressions
were used to compare mean HbA1c levels and
the proportions with good glycemic control
between hypertensive and normotensive
patients while controlling for confounders. The
means HbA1c for all diabetic, hypertensive
and normotensive patients were 7.70, 7.55 and
8.01, respectively. The normotensive group
had a significant higher HbA1c (p = 0.004).
97

R & D Technology
Significantly higher HbA1c was associated
with lower age (CI of [beta]: -0.024 to -0.001,
p = 0.039), female gender (CI of [beta]: 0.0390.552, p = 0.024) and medication use (CI of
[beta]:
0.577-1.250,
p < 0.001).
The
proportions with good glycemic control for the
all diabetic, hypertensive, normotensive
subjects were 0.235, 0.249 and 0.207,
respectively. No significant difference was
shown for the two groups'proportions
(p=0.283). Lower proportions of good control
were shown in females (CI of OR: 0.3980.905, p=0.015) and those on medication (CI
of OR: 0.211-0.543, p<0.001) by stepwise
logistic regression. The hypertensive diabetic
patients had better glycemic control than the
normotensives.
Vildagliptin dose-dependently improves
glycemic control in Japanese patients with
type 2 diabetes mellitus.
Kikuchi, Masatoshi et al.
Diabetes Research and Clinical Practice,
83(2), 233 (Feb., 2009)
To assess the efficacy and tolerability of
vildagliptin (10, 25 or 50 mg bid) in Japanese
patients with type 2 diabetes mellitus (T2DM),
this 12-week, multicenter, randomized,
double-blind, placebo-controlled, parallelgroup study was performed in 291 patients.
The primary assessment was change from
baseline to endpoint in HbA1c. Baseline
HbA1c averaged 7.4%, and the betweentreatment difference (vildagliptin-placebo) in
the HbA1c adjusted mean change was -0.8%, 1.0% and -1.2% with vildagliptin 10, 25 and
50 mg bid, respectively (p < 0.001). Relative
to baseline, body weight did not change
significantly in vildagliptin groups. There was
no increase in incidence of adverse events in
the vildagliptin groups (62.0%, 62.5% and
61.8%, 10, 25 and 50 mg bid, respectively)
compared to placebo (73.6%). No deaths or
drug-related serious adverse events were
reported. Seven hypoglycemic events were
observed (four events (n = 3), two events
(n = 2), and one event (n = 1) in the
98

vildagliptin 10 and 50 mg bid, and placebo,


respectively) and none of them were severe or
dose related. Vildagliptin 50 mg bid was
considered to be the most effective and welltolerated dose, and therefore can be considered
the recommended clinical dose for Japanese
patients with T2DM.
Cost of medical care among type 2
diabetic patients with a co-morbid
condition--Hypertension in India.
Tharkar, Shabana et al.
Diabetes Research and Clinical Practice,
83(2), 263 (Feb., 2009)
The aim was to estimate the cost of
medical care among hospitalized diabetic
patients and to assess the influence of an
additional co-morbid condition--hypertension.
A pre tested and validated questionnaire was
interviewer
administered
among
443
(male:female, 235:208) hospitalized diabetic
patients. The JNC VII criteria for hypertension
was considered to divide the study population
into two groups; group I - diabetic patients
without hypertension (n = 269) and group II diabetic patients with hypertension (n = 174).
Details of cost of inpatient and out-patient care
and expenditure on hospitalization for the
previous 2 years were obtained. The
prevalence of hypertension among the study
subjects was 39.3% (174 subjects). Presence of
hypertension made a significant impact on the
expenditure pattern. On an average a diabetic
patient with hypertension spent 1.4 times more
than a diabetic subject without hypertension.
Median cost per hospitalization, length of stay
during admission, and cost of 2 years for
inpatient admission were all significantly
higher for diabetic patients with a co-morbid
condition. There is a need to develop a
protocol on cost effective strategy for diabetes
care. Strict control of hypertension should be
targeted to avoid excess treatment cost on
diabetes care.
Prevalence of diabetic retinopathy in
India:
Sankara
Nethralaya
diabetic
retinopathy epidemiology and molecular
Current R&D Highlights, Jan.-Mar. 2009

R & D Technology
genetics study report 2.
Raman, Rajiv et al.
Ophthalmology, 116(2), 311 (Feb., 2009)
The aim of the study was to estimate the
prevalence of diabetic retinopathy in an urban
Indian population older than 40 years. A
population-based cross-sectional study. Five
thousand nine hundred ninety-nine subjects
residing in Chennai, India, were enumerated.
A multistage random sampling, based on
socioeconomic
criteria,
was
followed.
Identified subjects with diabetes mellitus
(based on the World Health Organization
criteria) underwent detailed examination at the
base hospital. The fundi of all patients were
photographed using 45, 4-field stereoscopic
digital photography. The diagnosis of diabetic
retinopathy was based on Klein's classification
of the Early Treatment Diabetic Retinopathy
Study scale. These included age- and genderadjusted prevalence of diabetes and diabetic
retinopathy, and correlation of prevalence with
history-based risk factors. The age- and
gender-adjusted prevalence rate of diabetes in
an urban Chennai population was 28.2% (95%

confidence interval [CI], 27.0-29.3), and the


prevalence of diabetic retinopathy in general
population was 3.5% (95% CI, 3.49-3.54). The
prevalence of diabetic retinopathy in the
population with diabetes mellitus was 18.0%
(95% CI, 16.0-20.1). History-based variables
that were significantly associated with
increased risk of diabetic retinopathy included
gender (men at greater risk; odds ratio [OR],
1.41; 95% CI, 1.04-1.91); use of insulin (OR,
3.52; 95% CI, 2.05-6.02); longer duration of
diabetes (>15 years; OR, 6.43; 95% CI, 3.1812.90); and subjects with known diabetes
mellitus (OR, 2.98; 95% CI, 1.72-5.17).
Differences in the socioeconomic status did
not influence the occurrence of diabetic
retinopathy. The prevalence of diabetic
retinopathy was 18% in an urban population
with diabetes mellitus in India. The duration of
diabetes is the strongest predictor for diabetic
retinopathy. The author(s) have no proprietary
or commercial interest in any materials
discussed in this article.

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Current R&D Highlights, Jan.-Mar. 2009

99

New Leads

Antidiabetic effect through islet cell


protection in streptozotocin diabetes: A
preliminary assessment of two thiazolidin-4ones in Swiss albino mice.
Kishore, Anoop et al.
Chemico-Biological Interactions, 177(3),
242 (Feb., 12, 2009)
This study was undertaken on the basis of
several reports in the literature that pancreatic
beta cells are capable of replication/
regeneration and also being afforded
protection against damage induced by
streptozotocin. Nicotinamide was reported to
give protection against streptozotocin-induced
damage in rats. In the present study, two
thiazolidine-4-ones
with
nicotinamide
substitution were administered to Swiss albino
mice with streptozotocin diabetes for 15 days.
Concurrently, one group received nicotinic
acid. Both the test compounds reversed the
hyperglycaemia diabetic mice. Damage to
pancreatic islets was also reduced in these
groups compared to diabetic control and
nicotinic acid treated groups. Since these
compounds have been earlier found have
antioxidant activity, one of the possible
mechanisms of action could be by reducing
oxidative stress in pancreas. Further, possibly
by releasing nicotinamide in vivo, the
molecules could have contributed to the NAD
pool in pancreas and afforded protection. It is
concluded that the test compounds have
potential to be developed for multiple
beneficial action in conditions like metabolic
syndrome.
Alogliptin benzoate [2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4tetrahydropirimidin-1-ylmethyl]
benzonitrile benzoate- dipeptidyl-peptidase IV
(DPP IV) inhibitor treatment of type 2
diabetes.
Wang Y et al.
100

Drugs of the Future, 33(1): 7-12 (2008)


Alogliptin (SYR-322), a potent, highly
selective inhibitor of the serine protease
dipeptidyl-peptidase IV (DPP IV), is a new
investigational drug developed for the
treatment of type 2 diabetes. Orally
administered alogliptin demonstrated antidiabetic effects in preclinical studies in mice, rats,
dogs and monkeys, as well as a good safety
profile. Early clinical studies demonstrated that
alogliptin can be safely co-administered with
antidiabetic drugs such as pioglitazone,
glyburide, metformin and warfarin without the
need for dose adjustment. Alogliptin also
demonstrated efficacy in reducing glucose and
increasing insulin levels and proved to be well
tolerated in healthy subjects and patients with
type 2 diabetes. Global phase III clinical trials
of alogliptin as monotherapy and in
combination with other antidiabetic drugs for
the treatment of type 2 diabetes are currently
ongoing, and an NDA was recently submitted
to the FDA.
Liraglutide [N-[ (N-hexadecanoyl)--L
-Glu]-L -Lys26 ,L -Arg34]-GLP-1 (7-37)]
GLP-1 receptor agonist treatment of type 2
diabetes treatment of obesity.
Gallwiz B et al.
Drugs of the Future. 33(1): 13-20(2008)
Liraglutide (NN-2211), a novel glucagon-like
peptide-1 (GLP-1) analogue for once-daily s.c.
injection, is in advanced clinical phase III
development for type 2 diabetes therapy. It is a
GLP-1 derivative with two amino acid chains
and a fatty acid side-chain. The effects of
liraglutide are mediated exclusively by
activation of the GLP-1 receptor. It reduces
hemoglobin A1c (HbA1c), fasting and
postprandial glucose by glucose-dependent
stimulation of insulin secretion and inhibition
of glucagon secretion, both as monotherapy
and in combination with oral antidiabetic
drugs. Weight loss has also been observed in
obese patients and indirect measures show a
possible improvement in -cell function.
Liraglutide does not cause hypoglycemia. The
Current R&D Highlights, Jan.-Mar. 2009

New Leads
main adverse events are nausea and diarrhea at
the beginning of treatment, which are mild to
moderate and transient. The formation of antiliraglutide antibodies has not been observed.
Dapagliflozin [1-[4-Chloro-3-(4ethoxybenzyl) phenyl]-1-deoxy-
-D-glucopyranose
(1S)-1
,5-anhydro-1-C-[4-chloro-3-(4ethoxybenzyl) phenyl]- D -glucitol (2S, 3R,
4R, 5S, 6R)-2 -[ 4-chloro-3-(4-ethoxybenzyl)
phenyl]-6-(hyd roxymethyl)tetrahydro-2Hpyran-3,4,5-triol-] SGL T2 inhibitor
antidiabetic agent.
Cole P et al.
Drugs of the Future, 33(9): 745-751
(2008)
One potential means of treating diabetes is
via modulation of glucose uptake. A novel
strategy for achieving this is through inhibition
of sodium-dependent glucose transporters
(SGL Ts), which mediate the process by which
plasma glucose filtered in the kidney
glomerulus is reabsorbed. The great majority
of this process of reabsorption is mediated by
SGL T2 and SGL T2 inhibitors have therefore
been sought and identified in order to prevent
renal glucose reabsorption and increase
glucose excretion in urine. The compound that
has advanced the furthest is dapagliflozin,
which demonstrated superior metabolic
stability
compared
to
early
agents.
Dapagliflozin also exhibited potent inhibition
of SGL T2 and selectivity over SGL T1 in
vitro, and was associated with reduced plasma
glucose levels in animal models of diabetes
after acute and chronic dosing. Dapagliflozin
has proven safe and well tolerated in humans,
with pharmacokinetic and pharmacodynamic
variables indicating that daily dosing is
appropriate. Double-blind trials in patients
with type 2 diabetes revealed reductions in
fasting and postprandial glucose, as well as
significant reductions in HbA 1 c.
Dapagliflozin has entered phase III evaluation.
Saxagliptin [(1 S,3S,5S)-2-[2( S)-amino2-(3-hydroxyadamantan-1-yl)acetyl]-2azabicyclo [3.1.0] hexane-3-carbonitrile]
Current R&D Highlights, Jan.-Mar. 2009

dipeptidyl
peptidase
IV
inhibitor
antidiabetic agent.
Cole P et al.
Drugs of the Future, 33(7), 577 (2008)
Targeting glucagon-like peptide 1 (GLP1) is an attractive strategy for the treatment of
type 2 diabetes, as this incretin hormone
enhances postprandial insulin secretion in a
manner dependent on glycemia. Evidence also
indicates that GLP-1 reduces glucagon
secretion, induces satiety, delays gastric
emptying and enhances -cell functio'n
through stimulation of neogenesis and
inhibition of apoptosis. One means of utilizing
this target is by inhibiting its degradation,
which is mediated by dipeptidyl peptidase IV
(DPP IV). Saxagliptin is a DPP IV inhibitor
that has displayed promising preclinical
characteristics, such as dosedependent
clearance of glucose in animal models of
diabetes. Data from clinical trials show
significantly
improved
glycosylated
hemoglobin (HbA1c) and fasting serum
glucose in diabetes patients with saxagliptin
alone and in combination with metformin, and
the agent was well tolerated. Results from
phase III studies are expected to soon provide
a comprehensive view of saxagliptin's role in
the expanding effort to improve the lives of
diabetic patients.
B1-1356 [ 8-[3(R)-aminopiperidin-1-yl]7-(2-butynyl)-3-methyl-1-(4methylquinazolin-2-ylmethyl)xanthine,]
dipeptidyl-peptidase
IV
inhibitor
antidiabetic agent.
Wang Y et al.
Drugs of the Future, 33(6): 473-477
(2008)
BI-1356 is a dipeptidyl-peptidase IV (DPP
IV, or CD26) inhibitor developed at for the
treatment of type 2 diabetes. BI-1356
demonstrated long-lasting DPP IV inhibition
both in vitro and in vivo. In vitro, BI-1356 was
at least 10,000-fold more selective for DPP IV
than for DPP-8 and DPP-9. High potency and
long-lasting inhibitory effects were also
101

New Leads
observed in vivo in' mice and rats, the
inhibition induced by BI-1356 being longer
lasting than that induced by any other DPP IV
inhibitor tested. BI-1356 exhibited nonlinear
pharmacokinetics in healthy volunteers and
patients with type 2 diabetes. Oral BI-1356
administered once daily proved to be well
tolerated in healthy volunteers and patients
with type 2 diabetes. Treatment with BI-1356
increased concentrations of GLP-1 and
reduced concentrations of glucose in patients
with type 2 diabetes, and it also significantly
reduced Hb1Ac in diabetic patients. Phase III
clinical trials are under way.
Taspoglutide--[L-Histidyl-2methylalanyl-L-glutamyl-glycyl-L-threonylL-phenylalanyl-L-threonyl-L-seryl-Laspartyl-L-valyl-L-seryl-L-seryl-L-tyrosylL-Ieucyl-L-glutamyl-glycyl-L-glutaminyl-L
alanyl-Lalanyl-L-lysyl-L-glutamyl-Lphenyl-alanyl-LisoleucylL-alanyl-Ltryptophyl-L-leucyl-L-valyl-L-lysyl-2methylalanyl- L-argininamide ] GLP-1
analogue for the treatment of diabetes.
Arjona A et al.
Drugs of the Future, 33(11): 938-943
(2008)
Incretin agonists and analogues are
receiving increasing attention as potential
antidiabetic agents due to their ability to
stimulate insulin secretion only during
hyperglycemic states. Exploitation of the
incretin effect reduces the risk of rebound
hypoglycemia that accompanies many
antidiabetic treatments. Taspoglutide (R-1583,
BIM-51077, ITM-077) is a long-acting
glucagon-like peptide 1 (GLP-1) analogue that
shows promise for the treatment of type 2
diabetes. In addition to having enhanced
resistance to enzymatic degradation by the
protease dipeptidyl peptidase 4 (DPP4),
clinical studies have shown that taspoglutide
increases insulin levels and lowers glycemia.
Phase II trials have also demonstrated that
weekly administration of a slowrelease
formulation was associated with enhanced
102

glycemic control, reduced body weight and


improved-cell function. Taspoglutide is
generally
well
tolerated,
with
mild
gastrointestinal symptoms being the most commonly reported adverse events. Several phase
III clinical trials of this novel GLP-1 analogue
are under way.
Antihyperglycemic effects of ginseng
and possible mechanisms.
D.C. Peng1 et al.
Drugs of the Future,33(6): 507-514
(2008)
Ginseng is a medicinal plant valued
throughout the world and is considered the
king of herbs in traditional Chinese/Oriental
medicine. Ginseng has gained popularity as a
dietary supplement in the United States and
Canada in recent decades. The multiple
constituents of ginseng possess equally
multifaceted pharmacological functions, as
demonstrated by numerous studies. According
to previous reports, ginseng root and its
constituents influence the central nervous
system (CNS), endocrine, cardiovascular,
gastrointestinal, sexual, renal and immune
systems, etc. One important function of the
ginseng plant is its antihyperglycemic effect.
Ginseng extracts have been commonly used in
Chinese/Oriental medicine to treat diabeteslike conditions. Our recent data suggest that all
the main parts of the ginseng plant (including
berry, root, leaf and stem) exhibit potent
antihyperglycemic effects and may provide an
opportunity to develop a novel class of
antidiabetic agents. In the current article,
authors have discussed on the anti
hyperglycemic effects of ginseng root, berry
and leaf extracts, as well as on the possible
mechanisms of the anti hyperglycemic action.
Drugs for the treatment of diabetes
complications. zycose: a new player in the
field?
Alin Stirban et al.
Drugs of Today, 2008,44 (10): 783-796
Zycose is a newly released (2006)
combined medication containing folic acid (1
Current R&D Highlights, Jan.-Mar. 2009

New Leads
mg) benfotiamine (150 mg) and benzamine
(850 mg), a proprietary blend of paraaminobenzoic acid (PABA), vitamin E and a.lipoic acid (ALA). Zycose protects vascular,
retinal and kidney function by improving
cellular health and promoting peripheral nerve
health in people with diabetes. Zycose's
therapeutic benefit is believed to be due to the
additive effects of its compounds on lowering
homocysteine levels (folic acid), reducing the
production of advanced glycation end products
(benfotiamine), improving endothelial function
(folic acid, benfotiamine, ALA), reducing
oxidative stress (ALA, vitamin E) and
reducing carbonyl stress (benzamine). The
complex composition of Zycose allows the
therapeutic
intervention
of
several
hyperglycemiamediated
disorders.
The
compound consists mainly of vitamins,
therefore explaining, in part, the good safety
profile and reduced adverse effects.
People with type 2 diabetes have a 2- to 5fold increased risk for cardiovascular mortality
when compared to the nondiabetic population.
The
main
causes
are
accelerated
atherosclerosis, microvascular disease causing
complications
such
as
neuropathy,
nephropathy and retinopathy, as well as a
prothrombotic status. Pathomechanisms of
diabetes are related to hyperglycemia,
hyperlipidemia, hyperinsulinemia, increased
oxidative stress and accelerated aging. An
important role in triggering these changes is
attributed to the endothelium. Endothelial cells
are mainly responsible for the production of
nitric oxide (NO), a key mediator contributing
to vascular health. NO promotes vasodilatation
and has antiatherosclerotic, anti oxidative and
antithrombotic properties. Endothelial NO
results from the transformation of L-arginine
into citrullin and NO by the enzyme NO
synthase (NOS).
AVE-0010[H-His-GIy-Glu-GlyThrPhe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-G
lu-Glu-Glu-Ala-Val-Arg-Leu-Phe-lle-GluTrp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-SerCurrent R&D Highlights, Jan.-Mar. 2009

Gly-Ala-Pro-Pro-Ser-Lys- Lys- Lys- LysLys- Lys-NH2. ] --- GLP-1 receptor agonist


for the treatment of diabetes.
Campas C et al.
Drugs of the Future, 33(10): 838-840
(2008)
Type 2 diabetes is associated with
progressive decreases in pancreatic -cell
function. Most patients require increasingly
intensive
treatment,
including
oral
combination therapies followed by insulin.
Fear of hypoglycemia is a potential barrier to
treatment adherence and glycemic control,
while
weight
gain
can
exacerbate
hyperglycemia
or
insulin
resistance.
Administration of insulin can roughly mimic
physiological insulin secretion but does not
address the underlying pathophysiology.
AVE-0010 (ZP-10) is a glucagon-like
peptide 1 (GLP-1) receptor agonist and an
insulin secretagogue. In preclinical studies,
AVE-0010 improved glucose tolerance,
decreased water intake and produced a
dosedependent decrease in glycosylated
hemoglobin (HbA1c), without the risk of
hypoglycemia. AVE-0010 has shown glucoselowering activity similar to that of other GLP1 agonists, while being devoid of nausea
related side effects, and it has been shown to
be safe and well tolerated in large clinical
studies. AVE-0010 is currently in phase III
clinical trials for the treatment of type 2
diabetes in patients treated with or without
metformin, either alone or in combination with
sulfonylureas, insulin or pioglitazone. A phase
II clinical trial comparing AVE-0010 with the
already marketed GLP-1 analogue exenatide is
also under way.
Emerging drug candidates of dipeptidyl
peptidase IV (DPP IV) inhibitor class for
the treatment of Type 2 Diabetes.
Gupta Rajesh et al.
Current Drug Targets (2009), 10(1), 7187.
Dipeptidyl peptidase IV (DPP IV) is a key
regulator of insulin-stimulating hormones,
103

New Leads
glucagon-like peptide (GLP-1) and glucosedependent insulinotropic polypeptide (GIP),
thus it is a promising target for the treatment of
Type 2 Diabetes mellitus (T2DM). Inhibition
of plasma DPP IV enzyme leads to enhanced
endogenous GLP-1 and GIP activity, which
ultimately results in the potentiation of insulin
secretion by pancreatic beta-cells and
subsequent lowering of blood glucose levels,
HbA[1(c)], glucagon secretion and liver
glucose production.
Various classes of
structurally different DPP IV inhibitors are
currently being explored and few of them such
as Sitagliptin and Vildagliptin were
successfully launched. These drugs have been
approved as a once-daily oral monotherapy or
as a combination therapy with current antidiabetic
agents
like
pioglitazone,
glibenclamide, metformin etc. for the
treatment of T2DM. Several other novel DPP
IV inhibitors are in pipeline. The present
review summarizes the latest preclinical and
clinical trial data of different DPP IV
inhibitors with a special emphasis on their
DPP8/9 fold selectivity and therapeutic
advantages over GLP-1 based approach.
New frontiers in the management of
type 2 diabetes.
Mudaliar Sunder
The Indian Journal of Medical Research
(2007), 125(3), 275-96
.
Type 2 diabetes is a chronic, debilitating
disease characterized by insulin resistance,
impaired
insulin
secretion,
and
hyperglycaemia, and afflicting at least 171
million people worldwide (31.7 million in
India). This chronic disease is not benign and
patients with diabetes suffer from numerous
microvascular
and
macrovascular
complications which cause a lot of morbidity
and mortality. Results from the UKPDS
(United Kingdom Prospective Diabetes Study)
clearly demonstrate that tight glucose and
blood pressure control in patients with type 2
diabetes prevents the development of and
delays the progression of microvascular
104

complications and possibly macrovascular


disease. In addition, results from the UKPDS
and other studies like the Heart Protection
Study (HPS) have also shown that treatment of
concomitant risk factors like lipids and blood
pressure and the use of aspirin have favourable
effects on cardiovascular complications and
mortality in patients with type 2 diabetes. In
order to achieve glycaemic goals, we have
several anti-hyperglycaemic agents in our
therapeutic armamentarium today. However,
despite their availability, we have not been
able to achieve glycaemic goals in our patients
with diabetes due to a variety of reasons.
However, there appears to be hope for the
future. The progress of research in all fields of
diabetes therapeutics from diabetes treatment
to continuous glucose monitoring systems to
novel insulin delivery systems has been
spectacular. These advances have resulted in
newer pharmacologic agents, implantable
glucose sensors and inhaled insulin. There is
also hope that large scale implementation of
intensive lifestyle programmes and education
efforts may help to prevent diabetes in high
risk individuals. Indeed, the repertoire of
options and strategies currently available (and
in the pipeline) to treat and prevent/delay
diabetes and its complications is impressive. In
this review, we will discuss the evolving
cardiovascular
benefits
of
the
thiazolidinediones (TZDs); describe in detail
the newer glucose lowering gut hormones with
novel mechanisms of action; delineate the
recent advances in non invasive insulin
delivery systems (including inhaled insulin);
review the ongoing developments in
continuous glucose measuring devices and
finally present an update on the prevention of
diabetes.
Diabetes: assessing the pipeline.
Lebovitz Harold
Atherosclerosis. Supplements (2006), 7(1),
43-9.
Type 2 diabetes is recognised as a major
cardiovascular risk factor, and future therapies
Current R&D Highlights, Jan.-Mar. 2009

New Leads
must therefore address more than just blood
glucose levels. Novel approaches to the
treatment of type 2 diabetes are now at various
stages of development or regulatory approval.
Exenatide and pramlintide, analogues of gutderived hormones glucagon-like peptide-1
(GLP-1) and amylin, respectively, have
demonstrated improvements in glycaemic
control and bodyweight in clinical studies and
have been recently approved for treatment of
type 2 diabetes. Initial studies have indicated
that agents that activate both peroxisome
proliferator-activated receptor (PPAR)alpha
and gamma improve glycaemic control and
have beneficial effects on lipid profiles. Two
dual PPARalpha/gamma agonists, muraglitazar
and tesaglitazar, are under regulatory review
and in phase III trials, respectively.

Modulation
of
the
endogenous
endocannabinoid system by rimonabant, which
is under regulatory review, has been shown to
improve body weight, atherogenic lipid
profiles and glycaemic control. In addition,
enhanced
understanding
of
the
pathophysiology underlying the microvascular
complications of type 2 diabetes has led to the
development of targeted therapies for
conditions such as diabetic retinopathy,
including the protein kinase C (PKC)antagonist ruboxistaurin, now in phase III
trials. Such therapies should enable physicians
to achieve more for their patients with type 2
diabetes.

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Current R&D Highlights, Jan.-Mar. 2009

105

Natural Products

Withania coagulans: Role in Diabetes


Akankshaa, Jayendraa, Arvind K. Srivastavab, Rakesh Mauryaa,*
a

Divisions of Medicinal and Process Chemistry and bBiochemistry


Central Drug Research Institute, Lucknow- 226001, India

Withania coagulans, is well known in the


Ayurvedic system of medicine for the
treatment of various diseases. Withanolides are
the major constituents of the plant. Its
hepatoprotective,
anti-inflammatory,
antihyperglycemic, hypolipidemic, free radical
scavenging and antimicrobial activities have
been reported. Aqueous decoction of the fruit
is used by traditional medical practitioner to
treat diabetes. However, the active principle
responsible for this activity had not been
identified yet. We have reported the compound
responsible for its antidiabetic activity. Our
results show that it should be studied more
extensively to develop it as a antidiabetic drug.

Introduction
Since ancient time plants are being used
for their medicinal properties. Natural products
have been the basis of treatment of human
diseases. Many of todays drugs are of plant
origin, e.g., penicillin, morphine and paclitaxel
(taxol), artemisinin etc. Plant derived drugs
have safer side over synthetic drugs as they
show lesser or no side effects. Withania
coagulans Dunal (family Solanaceae), is
reported in Ayurveda for its biological
potentials. It is commonly known as Paneer
ke phool in Hindi and Indian cheese maker
or Vegetable rennet in English, distributed in
drier parts of India [1]. The effective treatment
of diabetes is dependent on active constituents
of medicinal plants capable of controlling
106

hyperglycaemia as well as its secondary


complications. The natural active principles of
W. coagulans contributing to antihyperglycemic activity were not determined. It was
therefore, necessary to determine the active
antihyperglycemic agent. We have reported the
withanolides
responsible
for
its
antihyperglycemic activity [2].
In India two species of genus Withania,
Withania somnifera and Withania coagulans
are found [3]. Withania somnifera is famous by
the name Ashwagandha in Hindi and Indian
Ginseng, Winter cherry in English. The
morphologies of both the species are near
about same.

Chemical Costituents
Withania coagulans is rich in steroidal
lactones, which are known as withanolides (137). Withanolides are naturally occurring
polyhydroxy C28 steroidal lactones. In the
basic structure of all withanolides six- or fivemembered lactone ring is attached to an intact
or rearranged ergostane skeleton.

Chemical constituents from the whole


plant of Withania coagulans
Previous phytochemical examination of
this plant indicated the presence of
withanolides. The ethanolic extracts of the
whole plant have resulted in the isolation of
one withanolide named coagulin (17,27Current R&D Highlights, Jan.-Mar. 2009

Natural Products
dihydroxy-14,20-epoxide-1-oxo-(22R)-witha3,5,24-trienolide (1) [4]. Two withanolides,
14,15-epoxywithanolide
I
[(20S,22R)
17,20-dihydroxy-14,15-epoxy-1-oxowitha-3,5,24-trienolide] (2)
and
17hydroxywithanolide K [(20S,22R) 14,7,20trihydroxy-1-oxo-witha-2,5,24-trienolide] (3) [5,6].
Four withanolides, coagulin B (4), coagulin C (5),
coagulin D (6), coagulin E (7) [7], two withanolides
(steroidal lactones) named coagulin F (27-hydroxy14,20-epoxy-1-oxo-(22R)-witha-3,5,24-trienolide)
(8) and coagulin G (17,27-dihydroxy-14,20epoxy-1-oxo-(22R)-witha-2,5, 24-trienolide) (9) [8],
five
withanolides,
namely
coagulin
H
(17S,20S,22R)-5,6,14,15,17,20hexahydroxy-1-oxowitha-2,24-dienolide
(10),
coagulin
I
(14R,17S,20S,22R)-5,6,17trihydroxy-14,20-epoxy-1-oxowitha-2,24-dienolide
(11), coagulin J (14R,17R,20R,22R)-3,27dihydroxy-14,20-epoxy-1-oxowitha-5,24-dienolide
(12), coagulin K (14R,17R,20R,22R)-14,20-epoxy3-(O--D-glucopyranosyl)-1-oxowitha-5,24dienolide (13), coagulin L (14R,17S,20S,22R)14,17,20-trihydroxy-3-(O--D-glucopyranosyl)[9]
1-oxowitha-5,24-dienolide
(14)
.
Three
withanolides, coagulin M (14R,17R,20,22R)5,6,27-trihydroxy-14,20-epoxy-1-oxo-with
a24-enolide) (15), coagulin N (14R,17S,20,22R)15,17-dihydroxy-14,20-epoxy-3-(O-b-Dglucopyranosyl)-1-oxo-witha-5,24-dienolide) (16),
coagulin O (14R,20,22R)-14,20-dihydroxy-3(O--D-glucopyranosyl)-1-oxo-witha-5,24dienolide) (17) [10]. Three withanolides, coagulin P
(20,27-dihydroxy-3-(O--D-glucopyranosyl)-1oxo-(20S,22R)-witha-5,14,24-trienolide)
(18),
coagulin Q (1,20-dihydroxy-3- (O--Dglucopyranosyl)-(20S,22R)-witha-5,24-dienolide)
(19), coagulin R (3,17-dihydroxy-14,20-epoxy
1-oxo-(22R)-witha-5,24-dienolide) (20) [11]. Three
withanolides,
20-hydroxy-1-oxo-(22R)-witha2,5,24-trienolide (21), withacoagulin (22), and
17-hydroxy-14, 20-epoxy-1-oxo-(22R)-witha3,5,24-trienolide (23) [12]. A withanolide, coagulin
S (24) and dimeric lignan, bispicropodophyllin
glucoside (25) have been isolated from the
ethanolic extract of whole plant of Withania
coagulans [13].
Current R&D Highlights, Jan.-Mar. 2009

Fig 1: Compounds isolated from the whole plant of


Withania coagulans.

Chemical constituents from the fruits of


Withania coagulans
The aqueous extract of fruits of Withania
coagulans have resulted in the isolation of
withanolides, 3,14,17,20F-tetrahydroxy-1oxo-20S,22R-witha-5,24-dienolide (26) and
[14]
ergosta-5,25-diene-3,24-diol
(27)
.
3,14,20F,27-Tetrahydroxy-1-oxo-20R,22Rwitha-5,24-dienolide (or 3-hydroxy-2,3dihydrowithanolide H) (28), sitosterol--D[15]
glucoside
(29)
,
coagulanolide
(17S,20S,22R)-14,15,17,20-tetrahydroxy1-oxowitha-2,5,24-trienolide)
(30)
and
withanolide F (31) [2].

107

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CH3
H3C
H 3C HO
O

CH3
CH3

HO

CH 3 H

H3 C
H 3C

O
O

CH2 OH

HO

CH 3 H

OH
OH
11 : Coagulin I

HO
12: Coagulin J

CH 3

CH 3
H 3C
H3C H
O

CH3 H

HO
O

HO
HO

H O
O

O
HO

OH

H 3 C OH
H 3C
H O
O
OH
CH 3 H

CH 3

HO
HO

OH

13: Coagulin K

H3 C
O

OH

14: Coagulin L

CH 3 H

CH 3
H 3C

CH 2OH
HO

CH3

H 3C HO
O

O
HO

HO
HO

OH
OH

CH 3 H

HO

OH

O
OH
16 : Coagulin N

CH3

CH3
H3 C OH
H 3C
O
HO
O

HO

H 3C OH

CH 3
H3 C
O

CH 3 H
H

O
OH

17: Coagulin O

108

15: Coagulin M

HO
HO

CH3
H3 C

CH 3

HO
OH

HO
HO

CH 3 H

HO
H

CH 2OH
O

H
O

OH

18: Coagulin P

Current R&D Highlights, Jan.-Mar. 2009

Natural Products
CH3
H3C OH
H3C
HO

HO
HO

H3C

CH3

HO
H

OH
CH3 H

CH3

CH3 H

H3C OH

CH3
H3C OH

CH3

HO
H

H3 C
O

HO
H

CH3 H

CH2OH
O

22: Withacoagulin

21

CH3

CH3
H3C
H3C HO
O

20: Coagulin R

CH3

CH3 H

HO

19: Coagulin Q

HO

OH

H3C

CH3

H3C HO

CH3 H

H3C OH

CH3
HO

CH3
O

CH3 H

H O
OH

CH2OH
O

O
H

OH OH

OH
OH
23

24:Coagulin S
OH

H3CO

HO
HO

OH
O

O
O

O
O
H3CO

OCH3
OCH3

OCH3
OCH3

O
HO
O

OH
OH

O
HO

25: Bispicropodophyllin glucoside

Current R&D Highlights, Jan.-Mar. 2009

109

Natural Products
28
CH 3
H 3C OH
H3C
O

CH 3

HO
OH

CH 3 H
H

OH
24
CH3

26

CH3 H
H

OH

OH

HO

HO
26:3Hydroxy-2,3-dihydro-withanolide F

27:Ergosta-5,25-diene-3,24-diol

CH 3
H 3C OH
H3C
O

CH3

OH

HO

CH3 H
H

HO
HO

OH

CH3 H

HO
O
OH

HO

H
O

28: 3-hydroxy-2,3-dihydrowithanolide H

29: Sitosterol--D-glucoside

CH3

H3 C OH
CH 3 H O
OH
H

CH 3

OH

CH3
H 3C OH
CH 3 H O
OH
H

CH 3
O

CH 3

30: coagulanolide

CH 3
O

OH

OH

31:Withanolide F

Fig 2: Compounds isolated from the fruits of


Withania coagulans
CH 3

CH 3
H 3C OH
CH 3
O

CH 3

HO

CH3 H
H

H 3C H

CH3
O

CH3 H
H

H
O

OH

OH

CH2OH

HO
H

33: Withaferin A

CH3
H 3C H
CH3
O

CH 3 H
H
OH

32

CH 3
CH 2OH

HO
H

H 3C OH
CH 3

CH 3 H

CH3

HO
H

OH

34

35: Withacoagin
CH 3
H 3C OH
CH3

HO

CH 3

CH3 H
H
OH

H 3C H

CH 3

H
O

CH3
O

36

CH3
HO

CH3 H
H
OH

H
O

37

Fig 3: Compounds isolated from the root of


Withania coagulans.

Pharmacology
It has a prominent place in Ayurvedic,
Unani, and ancient Indian systems of
medicine. The berries of the plant are used for
milk coagulation [3]. A number of reports
reveal that the withanolides isolated from
110

Chemical constituents from the root of


Withania coagulans
Chemical investigation of methanolic
extract of roots of Withania coagulans have
resulted in the isolation of withanolides,
5,20(R)-dihydroxy-6,7-epoxy-1-oxo-(5)witha-2,24-dienolide (32) and withaferin A
(33) [16, 17, 18]. 5,27-Dihydroxy-6,7-epoxy-1[19]
.
oxo-(5)-witha-2,24-dienolide
(34)
Defatted methanolic extract of roots of
Withania coagulans have afforded withacoagin
(20R,22R)-5,20-dihydroxy-1-oxowitha2,6,24-trienolide (35), (20R,22R)-6,7epoxy-5-20-hydroxy-1-oxowitha-2,24dienolide (36) and (20S,22R)-6,7-epoxy5-dihydroxy-1-oxowitha-2,24-dienolide (37)
[20]
.
Withania coagulans Dunal possess interesting
biological activities. The fruits of the plant are
sweet and are reported to be sedative, emetic,
alterative and diuretic. They are useful in the
chronic complaints of liver. In some places
they are used as blood purifier. It is also used
in dyspepsia, flatulent colic and other intestinal
infections. These are used for the treatment of
asthma, biliousness and stranguary [21]. In the
Unani system of medicine, they are used for
the treatment of wounds and ulcers. In the
fruits of Withania coagulans high degree of
proteolytic activity has been reported. Acetone
and alcohol precipitated fractions of the plant
showed 50.0 and 33.0 units of activity per
gram respectively, which is about half of that
found for papain [22]. This plant is reported to
possess hepatoprotective, anti-inflammatory,
antihyperglycemic, hypolipidemic, free radical
scavenging, antimicrobial, cardiovascular,
central
nervous
system
depressant,
immunomodulating, antitumor and cytotoxic
activities.
Antihyperglycemic activity
Administration of an aqueous extract of
fruits of W. coagulans (1 g/kg; p.o.)
significantly lowered the blood sugar, serum
cholesterol, serum LPO and hepatic LPO
Current R&D Highlights, Jan.-Mar. 2009

Natural Products
levels in streptozotocin induced diabetic rats
after 7 days of treatment (p<0.001). Such lipid
lowering activity in streptozotocin induced
diabetic rats may also help in preventing
associated atherogenesis and other secondary
complications of diabetes mellitus. Its serum
LPO and liver LPO reducing activity suggests
that it may prevent lipid peroxidation and may
protect tissues from free radicals. It also
significantly (p<0.01) decreased blood glucose
level in normal rats (at the dose 1 g/kg; po) [23].
We
have
demonstrated
significant
antihyperglycemic activity in the aqueous
extract of W. coagulans fruits in
normoglycemic as well as in STZ-induced
diabetic rat models at 250 mg/kg po dose level.
We have isolated five withanolides identified
as coagulin C (5), 17-hydroxywithanolide K
(3), withanolide F (31), coagulanolide
[(17S,20S,22R)-14,15,17,20tetrahydroxy-1-oxowitha2,5,24-trienolide]
(30), which is a new compound and coagulin L
(14) from the aqueous extract of its fruits. The
compounds were evaluated for their
antihyperglycemic activity in normoglycemic
rat model (SLM) and in streptozotocin induced
diabetic rat model (STZ) as well as in a well
characterized model of type 2 diabetes, that is,
C57BL/KsJ-db/db mice. Compound 14 was
most active, it was found to improve glucose
tolerance up to the tune of 29.8% in SLM and
23.3% in STZ-induced diabetic rats at a dose
of 100 mg/kg body weight. Compounds 5, 3,
31
and
30
exhibited
significant
antihyperglycemic activity, 22.8%, 20.4%,
24.9% and 28.1% in SLM and 16.9%, 15.8%,
18.2% and 19.3% in STZ, models,
respectively. Compound 14 was further
evaluated in db/db mice. The C57BL/KsJdb/db mice at 12 weeks of age exhibited most
of the human characteristics of type 2 diabetes
including hyperglycemia in the fasting and fed
states, hyperinsulinemia and insulin resistance.

Current R&D Highlights, Jan.-Mar. 2009

The db/db mice supplemented with compound


5 at a dose of 50 mg/kg body weight for 10
consecutive days, significantly lowered the
postprandial blood glucose level by 22.7% (p <
0.01), whereas metformin declined the
postprandial blood glucose by 18.6% (p <
0.05), when compared to vehicle-treated
control group. After 10 days of treatment, the
glucose tolerance significantly improved in the
compound 14 treated group, compared to the
vehicle-treated group. It was observed that
significant (p < 0.05) inhibition in rise of
postprandial blood glucose level at time
interval 90 min and 120 min in compound 14
as well as metformin treated group. For the
compound 14 db/db mice group, the area under
the curve (AUC) of blood glucose decreased
by approximately 40.5% compared to vehicle
treated group. In the other experiment,
compound 5 at a dose of 50 mg/kg body
weight, showed significant improvement in
plasma lipid profiles of dyslipidemic db/db
mice after 10 days of consecutive treatment.
The effect of increasing oral doses of
compound 14 declined the postprandial
glucose level, was dose-dependent with a
calculated ED50 of around 25 mg/kg of body
weight following oral administration [2].
Discussion
Withania coagulans Dunal has variety of
pharmacological acivities. Extracts, fractions
and isolated withanolides from Withania
coagulans Dunal have been reported for their
various biological potentials. More extensive
research on the chemistry and pharmacology
of the withanolides should be carried out.
Isolation
at
large
scale,
chemical
transformations and synthesis of the active
compounds will definitely enhance its
pharmacological value. Clinical trials should be
carried out on the active principles.

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References
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Plants; International Book Distributors, Dehradune,
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[12] Rahman, Atta-Ur., Shabbir, M., Yousaf, M.,


Qureshi, S., Shahwar, Dur-E., Naz, A., Rahman, AttaUr., Shahwar, Dur-E., Naz, A., Choudhary, M.I., 2003;
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[2] Maurya, R., Akanksha, Jayendra, Singh, A.B.,


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[13] Alam, Nur-e., Yousaf, M., Qureshi, S., Baig, I.,


Nasim, S., Rahman, Atta-Ur., Choudhary, M.I., 2003;
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[3] Chadha, Y.R., 1976; The Wealth of India, Raw


Materials; CSIR, New Delhi; 10; 580-581.

[14] Velde, V.V., Lavie, D., Budhiraja, R.D., Sudhir, S.,


Garg, K.N.; 1983; Phytochemistry; 22(10); 2253-2257.

[4] Rahman, Atta-Ur., Abbas, S., Shahwar, Dur-E.,


Jamal, S.A., Choudhary, M.I., 1993; Journal of Natural
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[15] Ramaiah, P.A., David, L., Budhiraja, R.D., Sharan,


S., Garg K.N., 1984; Phytochemistry; 23; 143-149.

[5] Choudhary, M.I., Shahwar, Dur-E., Zeba, P., Jabbar,


A., Ali, I., Rahman, Atta-Ur., 1995; Phytochemistry; 40;
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Applied Chemistry; 70; 385-389.
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Choudhary. M. I., Voelter, W., Hohnholz, D., 1998a;
Heterocycles; 47; 1005-1011.
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Gul, W., Yousaf, M., 1998b; Journal of Natural
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Choudhary, M.I., Voelter, W., Hoff, A., Jens, F., Naz,
A., 1998c; Heterocycles; 48; 1801-1811.

[16] Subramanian, S.S., Sethi, P.D., 1969; Current


Science; 38; 267-68.
[17] Kupchan, S.M., Anderson, W.K., Bollinger, P.,
Doskotch, R.W., Smith, R.M., Renauld, J.A.S., Schnoes,
H.K., Burlingame, A.L., Smith, D.H.; 1969; Journal of
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Suzuki, M., 1988; Bulletin of the Chemical Society of
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112

P.N.,
of

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Marine Biota and Diabetics


The Ocean, which is called the mother of
origin of life, is also the source of structurally
unique natural products that are mainly
metabolised/accumulated in living organisms.
Among 34 fundamental phyla of life, 17 occur
on land whereas 32 occur in the sea (with
some overlap). From the fundamental point of
view of biodiversity, the ocean is far more
diverse and really would have been the better
place to start to develop a natural Pharmacy.
To
date,
researchers
have
isolated
approximately 7000 marine natural products,
25 percent of which are from algae, 33 percent
from sponges, 18 percent from coelenterates
(sea whips, sea fans and soft corals), and 24
percent from representatives of other
invertebrate phyla such as ascidians (also
called tunicates), opisthobranch molluscs
(nudibranchs, sea hares etc), echinoderms
(starfish, sea cucumbers etc) and bryozoans
(moss animals). Thus lifesaving drugs are
mainly found abundantly in microorganisms,
algae and invertebrates, while they are scarce
in vertebrates. A simplistic analysis of these
data reveals that as the search for Drugs from
the Sea progresses at the rate of a 10 percent
increase in new compounds per year,
researchers are concentrating their efforts on
slow-moving or sessile invertebrate phyla that
have soft bodies, and lack of spines or a shell,
i.e. animals that require a chemical defence
mechanism.
Studies on marine natural products has led
to the discovery of many potently active
agents/chemical compounds. The marine
environment, due to its hostilities towards
almost every class of marine organism,
induces the inhabitants to produce/metabolise
Current R&D Highlights, Jan.-Mar. 2009

a variety of molecules with unique structural


features to survive in the adverse physical and
chemical
conditions
in
the
marine
environment. Thus marine environment is an
exceptional reservoir of bioactive natural
products,
many
of
which
exhibit
structural/chemical features not found in
terrestrial natural products. Marine organisms
have evolved biochemical and physiological
mechanisms that include the production of
bioactive compounds for such purposes as
reproduction, communication, and protection
against predation, infection and competition.
Beyond the chemical diversity, the sea also
provides amazing biological diversity. This
diversity has been the source of unique
chemical compounds with the potential for
industrial development as pharmaceuticals,
cosmetics, nutritional supplements, molecular
probes, fine chemicals and agrochemicals.
In recent years, a significant number of
novel metabolites with potent pharmacological
properties havebeen discovered from the
marine organisms. Although there are only a
few marine-derived products currently on the
market, several robust new compounds derived
from marine natural products are now in the
clinical pipeline, with more clinical
development. While the marine world offers
an extremely rich resource for novel
compounds, it also represents a great challenge
that requires inputs from various scientific
areas to bring the marine chemical diversity up
to its therapeutic potential.
There is a need for consorted efforts
towards the antidiabetic agents of marine
origin. If required we must modify SOPs for
113

Natural Products
sample collection, preservation, extract
preparation and newer test models. In future,
Bioinformatics is going to play a very

significant role in pinpointing the bioactive


biota for particular medicinal properties.

Selected Bibliography (Patents)


Bryhn, M., Holmeide, A. K., & Kopecky, J.
New DHA derivatives and their use as medicaments
for the treatment of diabetes type 2.
ed. (Pronova Biocare A/S, N. 2006-IB1155
[2006117664], 97pp-20061109. WO. 5-4-2006.
Bulawa, C.
Compounds and methods for modulating protein
trafficking.
ed. (Foldrx Pharmaceuticals, I. U. 2007-US84257
[2008058269], 97pp-20080515. WO. 11-9-2007.
Fan, X., Ma, C., Han, L., Shi, D., & Liu, Q.
Extraction of bromophenol compounds from red
algae and their uses in the treatment of diabetes and
obesity.
ed. (Institute of Oceanology, C. A. o. S. P. R. C. 200510046293[1853618], 10pp-20061101. CN. 4-20-2005.

Liquid dosage compositions of stable nanoparticulate


drugs.
ed. (Elan Pharma International, L. I. 2003-US22187
[2004006959], 68-20040122. WO. 7-16-2003.
Gaitanaris, G. A.
Nuclear receptors as diagnostic and risk markers for
disease and as targets for therapy.
ed. (Nura, I. U. 2003-US36229[2004045369], 50820040603. WO. 11-12-2003.
Holmeide, A. K. & Rosman, J.
Fatty acid alcohols as prodrugs for the treatment of
elevated triglyceride levels.
ed. (Pronova Biopharma Norge AS, N. 2007-IB4590
[2008139261], 59pp-20081120. WO. 11-2-2007.

Foong, F. W. & Kuwabara, M.


Sea
slug-derived
immunopotentiating,
nerve
repairing,
antiulcerative,
antidiabetic
and
neurogenic pain preventing agent.
ed. (Imex Japan Co.Ltd., J. 2006-JP317254
[2007026836], 45pp-20070308. WO. 8-31-2006.

Hovey, D., Pruitt, J., & Ryde, T.


Nanoparticulate megestrol formulations containing
surface stabilizer.
ed. (Elan Pharma International Ltd., U. 2004-878623
[2005008707], 38-20050113. US. 6-29-2004.

Hwang, C. G.
System and method for modifying a fluid for oral
administration.
ed. (Remote Clinical Solutions, I. U. 2005-US30146
[2006023985], 41-20060302. WO. 8-23-2005.

Marshall, W. S.
IgG Fc-domain peptide conjugates as glucagon
antagonists.
ed. (Amgen Inc., U. 2001-US14321[2001083527], 5420011108. WO. 5-3-2001.

Bosch, H. W.
Novel nanoparticulate nimesulide compositions.
ed. (Elan Pharma International Ltd., I. 2003US32731[2005051356], 87-20050609. WO. 10-312003.
Bosch, W. H.

Mayer, A. M. S. & Hamann, M. T.


Marine pharmacology in 2001-2002: Marine
compounds
with
anthelmintic,
antibacterial,
anticoagulant,
antidiabetic,
antifungal,
antiinflammatory,
antimalarial,
antiplatelet,
antiprotozoal, antituberculosis, and antiviral

114

Current R&D Highlights, Jan.-Mar. 2009

Natural Products
activities; affecting the cardiovascular, immune and
nervous
systems
and
other
miscellaneous
mechanisms of action.
Comp.Biochem.Physiol., Part C: Toxicol.Pharmacol.
140C[3-4], 265-286. 2005.

The curcuminoids- and anthocyanins-responsive


genes in human adipocytes and their use in
screenings of anti-obesity and anti-diabetes drugs.
ed. (Biomarker Science Co., L. J. 200453258[2005198640], 85-20050728. JP. 2-27-2004.

Negreanu-Pirjol, T., Sirbu, R., & Guran, C.


New transitional metal complexes of biguanide
derivatives - biological activity on marine organisms.
J.Environ.Prot.Ecol. 6[4], 827-837. 2005.

Urakami, T. et al.
Process for producing oxazopyrroloquinolines, novel
oxazopyrroloquinolines, and use of oxazopyrroloquinolines.
ed. (Mitsubishi Gas Chemical Co., I. J. 90-403176
[429333], 59-19910529. EP. 11-8-1990.

Sato, N.
Health food compositions for prevention and
treatment of obesity.
eds. (Someya, H. J. & Tangolwood K.K.). 2004203833[2006020606], 12-20060126. JP. 7-9-2004.

Van Kaer, L.
Drugs from the sea: A marine sponge-derived
compound prevents type 1 diabetes.
The Scientific World 1, 630-632. 2001
(Compiled byDr. RK Sharma,Botany Division, Central Drug
Research Institute, Lucknow)

Ueno, Y., Tsuda, T., Takanori, H., Yoshikawa, T., &


Osawa, T.

Antidiabetic effect of Punica granatum


flowers:
Effect
on
hyperlipidemia,
pancreatic cells lipid peroxidation and
antioxidant enzymes in experimental
diabetes.
Bagri, Priyanka et al.
Food and Chemical Toxicology, 47(1), 50
(Jan., 2009)
The study investigated the effects of
Punica granatum aqueous extract (PgAq) on
streptozotocin (STZ) induced diabetic rats by
measuring fasting blood glucose, lipid profiles
(atherogenic index), lipid peroxidation (LPO)
and activities of both non-enzymatic and
enzymatic antioxidants. Diabetes was induced
by single intraperitoneal injection of STZ
(60 mg/kg) to albino Wistar rats. The increase
in blood glucose level, total cholesterol (TC),
triglycerides (TG), low-density lipoprotein
cholesterol (LDL-C), very low density
lipoprotein (VLDL), LPO level with decrease
in high density lipoprotein cholesterol (HDLC), reduced glutathione (GSH) content and
antioxidant enzymes namely, glutathione
peroxidase (GPx), glutathione reductase (GR),
Current R&D Highlights, Jan.-Mar. 2009

glutathione-S-transferase (GST), superoxide


dismutase (SOD) and catalase (CAT) were the
salient features observed in diabetic rats. On
the other hand, oral administration of PgAq at
doses of 250 mg/kg and 500 mg/kg for 21 days
resulted in a significant reduction in fasting
blood glucose, TC, TG, LDL-C, VLDL-C and
tissue LPO levels coupled with elevation of
HDL-C, GSH content and antioxidant enzymes
in comparison with diabetic control group. The
results suggest that PG could be used, as a
dietary supplement, in the treatment of chronic
diseases characterized by atherogenous
lipoprotein profile, aggravated antioxidant
status and impaired glucose metabolism and
also in their prevention.
Effect of bitter gourd and spent
turmeric on glycoconjugate metabolism in
streptozotocin-induced diabetic rats.
Vijayalakshmi, B. et al.
Journal
of
Diabetes
and
its
Complications, 23(1), 71 (2009)
Changes in glycoconjugate metabolism
during the
development of
diabetic
complications and their modulation by feeding
bitter gourd and spent turmeric as fiber-rich
115

Natural Products
source. This was studied by measuring the
contents of total sugar, uronic acid, amino
sugar, and sulfate in the streptozotocin-induced
diabetic rats. Total sugar content decreased in
liver, spleen, and brain, while an increase was
observed in heart and lungs. Uronic acid
content in liver, spleen, and brain decreased,
and marginal increase was observed in testis.
Amino sugar content decreased in liver,
spleen, lungs and heart during diabetes, and
augmentation was observed to different
extents.
Decrease
in
sulfation
of
glycoconjugates was observed in liver, spleen,
lungs and heart during diabetes and was
significantly ameliorated by bitter gourd and
spent turmeric, except brain. Protein content
decreased in liver, while an increase was
observed in brain. The studies clearly showed
alteration in glycoconjugate metabolism during
diabetes and amelioration to different extents
by feeding bitter gourd and spent turmeric.
Improvement is due to slow release of glucose
by fiber in the gastrointestinal track and shortchain fatty acid production from fiber by colon
microbes.
Protective role of arjunolic acid in
response to streptozotocin-induced type-I
diabetes via the mitochondrial dependent
and independent pathways.
Manna, Prasenjit et al.
Toxicology (In Press)
Increasing evidences in both experimental
and clinical studies suggest that oxidative
stress is involved in the pathogenesis of
diabetic tissue damage. Pancreatic [beta]-cell
death is the cause of decreased insulin
production in diabetes. Streptozotocin (STZ) is
widely used to induce experimental diabetes
due to its ability to selectively target and
destroy insulin producing pancreatic [beta]cells via the formation of both reactive oxygen
species (ROS) and RNS (reactive nitrogen
species). This study investigated the
prophylactic role of arjunolic acid (AA)
against STZ-induced diabetes in the pancreas
tissue of the Swiss albino rats (as a working
116

model). We observed that STZ administration


(at a dose of 65 mg/kg body weight, injected in
the tail vain) caused increased production of
both ROS and RNS in the pancreas tissue of
experimental animals. Formation of these
reactive
intermediates
decreased
the
intracellular antioxidant defense, increased the
levels of lipid peroxidation, protein
carbonylation, serum glucose and TNF[alpha]. Investigating the signaling pathways,
we found that STZ administration caused the
activation of phospho-ERK1/2, phospho-p38,
NF-[kappa]B and destruction of mitochondrial
transmembrane
potential,
release
of
cytochrome c as well as activation of caspase 3
in the pancreas tissue keeping the levels of
total ERK1/2 and p38 significantly unchanged.
Treatment of animals with AA (at a dose of
20 mg/kg body weight, orally) both prior and
post to the STZ administration effectively
reduced these adverse effects by inhibiting the
excessive ROS and RNS formation as well as
by down-regulating the activation of phosphoERK1/2, phospho-p38, NF-[kappa]B and
mitochondrial dependent signal transduction
pathways leading to apoptotic cell death.
Combining all, these results suggest that AA
plays some beneficial roles against STZinduced diabetes.
Modification
of
psyllium
polysaccharides for use in oral insulin delivery.
Singh, Baljit et al.
Food Hydrocolloids, 23(3), 928 (May
2009)
There is no doubt that fibers, in particular
viscous dietary fibers, have positive effects on
human health, both in the prevention and in
treatment of chronic diseases. Psyllium, a
medicinally important serum glucose reducing
natural polysaccharide, if suitably tailored to
prepare the hydrogels for controlled release of
insulin; it can act as double potential candidate
for cure of diabetes mellitus. Keeping in view
the therapeutic importance of psyllium and its
gel-forming nature we have prepared psyllium
and methacrylamide based hydrogels by using
Current R&D Highlights, Jan.-Mar. 2009

Natural Products
N,N'-methylenebisacrylamide as crosslinker.
The present paper discusses the effect of pH on
swelling kinetics of the hydrogels and release
dynamics of insulin from drug-loaded
hydrogels, for the evaluation of the swelling
mechanism and drug release mechanism from
the
hydrogels.
Non-Fickian
diffusion
mechanism has been observed for the release
of insulin in pH 2.2 buffer and pH 7.4 buffer.
Inhibition of 11[beta]-hydroxysteroid
dehydrogenase type 1 by plant extracts used
as traditional antidiabetic medicines.
Gumy, Christel et al.
Fitoterapia
Elevated glucocorticoids are a key risk
factor for metabolic diseases, and the
glucocorticoid-activating enzyme 11[beta]hydroxysteroid dehydrogenase 1 (11[beta]HSD1) represents a promising therapeutic
target. Authors have measured the potential of
six traditional antidiabetic medicinal plants
extracts to inhibit 11[beta]-HSD1 activity and
glucocorticoid receptor (GR) activation in
transfected HEK-293 cells. Leave extracts of
Eriobotrya japonica preferentially inhibited
11[beta]-HSD1 over 11[beta]-HSD2. Extracts
of roasted but not native coffee beans
preferentially inhibited 11[beta]-HSD1 over
11[beta]-HSD2, emphasizing the importance
of sample preparation. Thus, natural
compounds inhibiting 11[beta]-HSD1 may
contribute to the antidiabetic effect of the
investigated plant extracts. (ScienceDirect)
Antihyperglycemic
and
insulin
secretory activity of Costus pictus leaf
extract in streptozotocin induced diabetic
rats and in in vitro pancreatic islet culture.
Gireesh, G. et al.
Journal of Ethnopharmacology
The leaves of Costus pictus D Don were
used extensively for its anti hyperglycemic
activity by the people in Kerala, India. In the
present study, the antihyperglycemic and
insulin secretory activity of an aqueous extract
of Costus pictus leaf extract was investigated
in streptozotocin induced diabetic rats. Oral
Current R&D Highlights, Jan.-Mar. 2009

Glucose Tolerance Test was done to determine


the effective dose of Costus pictus extract.
Aqueous extract of Costus pictus leaves was
given orally to the diabetic rats for 14 days.
The insulin secretory action of the leaf extract
was investigated using isolated pancreatic
islets from rat. Liver glucose uptake activity
was measured using D-[14C] glucose. The oral
administration of an aqueous extract of Costus
pictus at a dose of 250 mg/kg body weight
significantly decreased the blood glucose with
significant increase in plasma insulin level in
diabetic rats at the end of 14 days treatment.
The Costus pictus leaf extract significantly
increased glucose induced insulin secretion at
both 4 mM and 20 mM glucose concentrations
which represents normal physiological and
diabetic condition respectively. The decreased
glucose uptake activity of the liver of diabetic
rats were reverted back to near normal levels
after the treatment with Costus pictus leaf
extract. Our results suggest the glucose
lowering effect of Costus pictus to be
associated with potentiation of insulin release
from pancreatic islets and enhancement of
peripheral utilization of glucose. (ScienceDirect).
A novel compound from Casearia
esculenta (Roxb.) root and its effect on
carbohydrate metabolism in streptozotocindiabetic rats.
Chandramohan, Govindasamy et al.
European Journal of Pharmacology,
590(1-3), 437 (Aug., 20, 2008)
Casearia esculenta root (Roxb.) is widely
used in traditional system of medicine to treat
diabetes in India. An active compound 3hydroxymethyl xylitol (3-HMX) has been
isolated and its optimum dose has been
determined in a short duration study and
patented. In the present study, the long-term
effect of 3-HMX in type 2 diabetic rats has
been investigated. An optimum dose of 3HMX (40mg/kg body weight) was orally
administered for 45days to streptozotocindiabetic rats for the assessment of glucose,
insulin,
hemoglobin
(Hb),
glycated
117

Natural Products
hemoglobin (HbA1c), hepatic glycogen, and
activities of carbohydrate metabolizing
enzymes, such as glucokinase, glucose 6phosphatase, fructose 1,6-bisphosphatase and
glucose-6-phosphate
dehydrogenase
and
hepatic marker enzymes, such as aspartate
aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP)
and gammaglutamyl transferase (GGT) in
normal and streptozotocin-diabetic rats. 3-

HMX at 40mg dose produced similar effects


on all biochemical parameters studied as that
of glibenclamide, a standard drug. Histological
study of pancreas also confirmed the
biochemical findings. These results indicate
that 3-hydroxymethyl xylitol, the compound
from C. esculenta, possesses antihyperglycemic effect on long-term treatment also.

Drugs & Pharmaceuticals

Current R&D Highlights


Form IV (See rule 8)
1.

Place of Publication

: Lucknow

2.

Periodicity of its publication

: Bi-Monthly

3.

Printer's Name
(Whether citizen of India?)
Address

: Dr. Sheela Tandon


: Yes
: CDRI, Chattar Manzil Palace,
Lucknow-226 001.

4.

Publisher's Name
(Whether citizen of India?)
Address

: Dr. Sheela Tandon


: Yes
: CDRI, Chattar Manzil Palace,
Lucknow-226001.

5.

Editor's Name
(Whether citizen of India?)
Address

: Dr. Sheela Tandon


: Yes
: CDRI, Chattar Manzil Palace,
Lucknow-226001.

6.

Names and Addresses of individuals who own : Government publication


the newspaper and partners or shareholders
holding more than one per cent of the total capital.

I, Dr. Sheela Tandon, hereby declare, that the particulars given above are true to the best of my
knowledge and belief.
Dated: 31.03.2009

Signature of Publisher
NOT TO BE RETURNED TO THE PRESS REGISTRAR

118

Current R&D Highlights, Jan.-Mar. 2009

Biotechnology

Latent Autoimmune Diabetes in Adults (LADA)


Introduction
Latent autoimmune diabetes in adults
(LADA) is the term that was coined to
describe
a
condition
that,
although
phenotypically identical to type 2 diabetes,
also features circulating pancreatic islet cell
antibodies (ICAs) and a slow progression to
autoimmune -cell failure. Thus, LADA
shares features with both type 1 and type 2
diabetes. The acronynm LADA has generally
been surrounded by controversy since it has
been difficult to define the disorder as a
distinct etiological entity and not a mere
subtype of type 1 diabetes. The term latent has
also been questioned, as the disease is not
typically latent (i.e., existing but not yet
apparent) since autoimmune serology is
present and is required for diagnosis.
Therefore, other acronyms and names have
been proposed, such as ADA (autoimmune
diabetes in adults) or autoimmune diabetes not
requiring insulin at diagnosis, among others.
Regardless of the term used, the diagnosis
of LADA is based on three criteria: 1) diabetes
onset occurs at adult age (25-40 years); 2) the
presence of circulating ICAs; and 3) insulin
therapy is not required for at least 6 months
after diagnosis. The serology of LADA
patients at diagnosis typically shows
circulating islet cell antibodies of the IgG type
and antibodies to glutamic acid decarboxylase
(GAD), the presence of which has been
correlated with further insulin dependence.
Moreover, the clinical picture of LADA
patients may be associated with titers of
diabetes-associated autoantibodies, as some
authors have proposed. Thus, combined antiCurrent R&D Highlights, Jan.-Mar. 2009

GAD/ICA positivity and/or high-titer antiGAD was found to correlate with an early age
of onset, reduced -cell function, the presence
of other autoimmune disorders, fewer markers
of metabolic syndrome (high body mass index,
hypertension, dyslipidemia) and increased
frequency of high-risk diabetes type 1associated HLA class II alleles (discussed
below).

Clinical Symptoms
As mentioned earlier, LADA shares
metabolic features with type 1 and type 2
diabetes. Thus, type 2 diabetes and LADA
patients have been shown to present with a
similar degree of insulin resistance and
elevated glucagon levels, but the latter exhibit
severe and progressive defects in -cell
function, hence resembling type 1 diabetes.
However, unique clinical features may be
associated with this form of diabetes.
Fourlanos et al. found that, compared to
patients with type 2 diabetes, most patients
with LADA exhibited at least two of the
following five clinical parameters: 1) age of
onset < 50 years; 2) acute symptoms; 3) body
mass index (BMI) < 25 kg/m2; 4) personal
history of autoimmune disease; or 5) family
history of autoimmune disease. Moreover, the
presence of at least two of these features at
diagnosis had a sensitivity and specificity for
LADA detection of 90% and 70%,
respectively. Alternatively, the presence of less
than two distinguishing clinical parameters
resulted in a negative predictive value of 99%,
hence representing a highly reliable method for
excluding the disease. When compared to type
1 diabetes patients, LADA subjects have been
119

Biotechnology
noted to show higher BMI, elevated
triglycerides and HDL cholesterol, greater
insulin resistance, as well as greater plasma Cpeptide concentrations, an indicator of insulin
production by -cells.
The criterion of insulin independence in
LADA can be rather subjective and may
depend on insulin-prescribing trends, among
other factors. A recent study showed that the
time to insulin treatment depended on whether
autoantibody testing was performed or not,
thus being shorter in those centers that
routinely performed laboratory tests for
diabetes-associated autoantibodies.

Pathophysiology of LADA
The loss of tolerance to self-antigens
present in insulin-secreting -cells in
pancreatic islets appears to be the underlying
pathogenic process in LADA, as well as in
type 1 diabetes. However, both LADA and
type 1 diabetes present with specific
serological markers. The four islet antibody
subtypes, namely ICAs, GAD antibodies,
insulinoma antigen 2 (IA-2) antibodies and
insulin autoantibodies, are also present in type
1 diabetes, whereas IA-2 and insulin
autoantibodies are rarely seen in LADA
patients. Detection of ICAs and GAD
antibodies is thus key in the diagnosis of
LADA. The enzyme GAD has two isoforms,
GAD65 and GAD67, which catalyze the
formation of -aminobutyric acid (GABA) in
neurons and pancreatic Langerhans islets. The
GAD65 isoform appears to be particularly
important in the detection of type 1 diabetes,
since it is found in up to 80% of patients and is
considered a predictive marker. GAD65 antibodies appear to bind specific epitopes
comprised in the N-terminal region of the
GAD enzyme (the membrane anchoring site),
according to a study in patients with "slowly
progressive type 1 diabetes". In contrast,
GAD65 antibodies from the sera of type 1
diabetes patients did not react with this
specific N-terminal site.
120

Moreover, N-terminal binding by GAD65


antibodies was inversely correlated with the
time to insulin requirement. However,
reactivity against C-terminal and middle
epitopes of GAD65 has also been described in
LADA patients, with no relationship found
between binding and time to treatment or
disease progression. This study confirmed the
long-term persistence of GAD antibodies (6
years) after diagnosis, indicating that it is a
valid criterion for the diagnosis of LADA
several years after the onset of hyperglycemia.

Genetics
Similarly to what occurs in type 1
diabetes, certain HLA class II genes appear to
be associated with higher LADA risk.
Particularly, HLA DR3 and/or DR4 and DQ2
and/or DQ8 are the highest-risk HLA alleles
for type 1 diabetes, which have also been
found in LADA patients, hence suggesting a
similar genetic basis. For instance, LADA and
type 1 diabetes patients exhibited an increased
prevalence of the high-risk HLA-DQB1*0302,
-DR4, -D3 and -DR3/DR4 genotypes and the
high-risk DR3/DR4-DQB1*0302 haplotype
compared
to
a
control
population.
Interestingly, another study evaluating the
genotypes of patients with LADA and
nondiabetic individuals found that DR4
antigen specificity subtypes may confer a
differential risk for LADA, with DRB1*0401
and DRB1*0403(06/07) being predisposing
and protective, respectively. Besides HLA
genes, LADA has also been associated with
other genetic factors. Thus, variations in the
variable number of tandem repeats (VNTR)
minisatellite upstream of the insulin gene
region 100M2, which accounts for about 10%
of familial risk for type 1 diabetes, have also
been
significantly
associated
with
susceptibility to LADA. However, these
genetic variations did not help to distinguish
between type 1 diabetes and LADA. Also,
outside the HLA region, the tyrosine-protein
phosphatase non-receptor type 22 gene
(PTPN22) encoding a lymphoid-specific
Current R&D Highlights, Jan.-Mar. 2009

Biotechnology
phosphatase known as LyP, which is a
powerful inhibitor of T-cell activation, has
been identified with type 1 diabetes in young
subjects. A recent study has demonstrated an
association between the PTPN22 C1858T gene
polymorphism and patients with adult-onset
diabetes and high GAD antibody titers,
compared to those with low antibody titers,
type 2 diabetes and a control population. Other
authors have encountered a higher frequency
of the C1858T gene polymorphism in LADA
patients compared to type 1 diabetes and
nondiabetic subjects. The PTPN22 C1858T
gene variant has also been linked to other
autoantibody-producing autoimmune diseases.
A recent study confirmed these findings
and showed that LADA shared genetic features
with type 1 diabetes, namely associations with
HLA-DQB1, insulin gene (INS) VNTR and
PTPN22, but LADA patients also presented
with a variant of the transcription factor 7 -like
2 (TCF7L2) gene, which is strongly associated
with type 2 diabetes. The authors concluded
that these results support the hypothesis that
LADA is a combination of type 1 and type 2
diabetes, rather than just a form of type 1
diabetes. Another study investigated the
potential relationship of LADA with cytokine
genes involved in the pathogenesis of other
autoimmune disorders and found an increased
frequency in the interleukin 1L10-1082A1G
gene variant in LADA compared to type 2
diabetics. Other studies have shown
associations of LADA with insulin resistance
genes (lRS1, IRS2) and vitamin D receptor
(VOR) gene polymorphisms.

Treatment
In general, the treatment of LADA, as
well as the major diabetes types, is aimed at
providing optimal glycemic control and
preserving -cell function. However, it is not

Current R&D Highlights, Jan.-Mar. 2009

yet clear which are the best treatments for this


condition.Lifestyle intervention (diet and
exercise) together with insulin therapy is
usually the strategy of choice. Although
efficacy for early insulin treatment (at
diagnosis) in preventing -cell failure has been
reported , some evidence suggests that it may
not be superior to diet or oral hypoglycemic
control. A randomized, open study is currently
examining the clinical efficacy of early insulin
treatment in patients with LADA compared to
oral hypoglycemic agents (metformin,
sulfonylureas, rosiglitazone).
The
efficacy
of
thiazolidinedione
treatment in LADA has not been thoroughly
studied. Nevertheless, a pilot study evaluating
23 LADA patients randomized to receive
premixed human insulin twice daily alone or
rosiglitazone (4 mg/day) plus insulin found
that this latter approach may be more effective
in preserving -cell function than insulin
alone. Combined insulin and rosiglitazone
treatment stabilized C-peptide levels after
glucose load (PCP) and glucagon-stimulated
11 C-peptide (I1CP) at 12 and 18 months after
treatment onset, while both parameters
declined with insulin monotherapy at those
time points (Table I).
Current investigations are focusing on two
vaccine candidates, which attempt to provide
better prevention of islet -cell destruction
(Table I). DiamydID is a recombinant human
DNA vaccine consisting of the recombinant
human GAD 65-kD isoform (rhGAD65) that is
currently in phase 11/111 clinical trials for the
subcutaneous (s.c.) treatment of type 2
diabetes at Diamyd Medical, and in phase III
trials for the treatment of children and
adolescents with type 1 diabetes, also as an s.c.
formulation.

121

Biotechnology
Table 1: Summary of Therapeutic Strategies in LADA
Drug

Design

Treatments

Rosiglitazone

Randomized

Rosiglitazone,

Unblinded

Human
recombinant
GAD65

mg/d

Conclusions / Objectives

23

In comparison with insulin monotherapy,


combined insulin plus rosiglitazone
treatment preserved l3-cell residual
function at 12 and 18 months of follow-up.
No severe hypoglycemic attacks or other
adverse events were reported during the
study period
This phase II/III study will investigate the

Insulin,

b.Ld Insulin, b.Ld.

160

Randomized

Human recombinant

Double-blind

GAD65, 4, 20, 100

safety

or500 Ilg s.c. at wks

(rhGAD65) for the treatment of LADA.

1 and 4 Placebo

The primary outcome measure will assess

and

efficacy

of

DiamycfID

the change in glycosylated hemoglobin


(HbA1c) at 18 months (main study period)
after the prime injection of Diamyd@ 20
Ilg versus baseline in comparison with
placebo.

Randomized
Double-blind

Human recombinant

47

This

randomized,

double-blind,

dose-

GAD65 , 20 Ilg s.c.

escalation trial of Diamyd@ showed

at wks 1 and 4

increased C-peptide levels at 24 weeks at a

Placebo

dose of 20 Ilg in LADA patients. No safety


issues were reported.

DiaPep277

Randomized

DiaPep277,

Double-blind

Placebo

s.c.

100

This study will assess the safety,


immunological and clinical efficacy of
DiaPep277 versus placebo. DiaPep277 will
be administered at 0, 1 and 3 months, and
then every 3 months for a total of 8
administrations. The duration of the trial
will be 18 months of treatment plus 6
months of follow-up

(Based on the article written by E. Ferrer, C. Dulsat and published in Drugs of the Future 2008, 33(11): 963-967)

122

Current R&D Highlights, Jan.-Mar. 2009

Patents

Therapeutic agent for diabetes mellitus.


Kamiya , et al.
Kyowa Hakko Kogyo Co., Ltd. ,Tokyo,
Japan
US Patent 7,485,662 February 3, 2009
Appl. No.: 10/549,155 March 19, 2004
An object of the invention is to provide a
therapeutic agent for diabetes mellitus and an
insulin resistance improving agent. In order to
achieve such an object, the agents comprised
of hydroxyproline and derivatives were used.
Peptides acting as both GLP-1 receptor
agonists and glucagon receptor antagonists
and their pharmacological methods of use.
Pan; Clark , et al.
Bayer Pharmaceuticals Corporation, West
Haven, Connecticut, US
US Patent 7,488,714 February 10, 2009
Appl. No.:11/212,439 August 26, 2005
The invention provides polypeptides that
act both as an agonist of the GLP-1 receptor
and an antagonist of the glucagon receptor.
Such polypeptides are useful for treating
individuals with type-2 diabetes or other
metabolic disorders.
Cannabinoid receptor antagonists/
inverse agonists useful for treating
metabolic disorders, including obesity and
diabetes.
McElroy , et al
Jenrin Discovery, Inc., West Chester,
Pennsylvania, US
US Patent 7,482,470 January 27, 2009 Appl.
No.: 11/745,162 May 7, 2007

The invention provides novel pyrazoles


that are useful as cannabinoid receptor
antagonists and pharmaceutical compositions
thereof and methods of using the same for
treating
obesity,
diabetes,
and/or
cardiometabolic disorders.
Natural

herb

composition

Current R&D Highlights, Jan.-Mar. 2009

for

treatment of diabetes and manufacturing


method thereof.
Mansilla; Audino et al.
US Patent 7,482,030 January 27, 2009
Appl. No.:11/809,747 June 1, 2007
The invention refers to a new composition
comprising natural herbs for the treatment of
diabetes, and to a method for preparing said
composition. The composition contains the
herb Mulinum spinosum and Chamaemelum
nobile mixed in a specific proportion using
mineral water as solvent.
Systems and methods for modulation of
pancreatic
endocrine
secretion
and
treatment of diabetes.
Whitehurst ,TK et al
Boston
Scientific
Neuromodulation,
Valencia, California, US
US Patent 7,477,944 January 13, 2009;
19.12.2004
Systems and methods for introducing one
or more stimulating drugs and/or applying
electrical stimulation to the pancreas and/or
nerve fibers innervating the pancreas to treat or
prevent diabetes and/or to modulate pancreatic
endocrine secretions uses at least one system
control unit (SCU) producing electrical pulses
delivered via electrodes and/or producing drug
infusion pulses, wherein the stimulating
drug(s) are delivered via one or more pumps
and infusion outlets.
Glycinamide derivatives as raf-kinase
inhibitors.
Buchstaller , HP et al
Merck
Patent
GmbH,
Darmstadt,
Germany
US Patent 7,476,683 January 13, 2009
The invention relates to glycinamide
derivatives of formula (I), the use of the
compounds of formula (I) as inhibitors of rafkinase, the use of the compounds of formula
(I) for the manufacture of a pharmaceutical
composition and a method of treatment,
comprising administering said pharmaceutical
composition to a patient.

the
123

Patents
Bicyclic pyrazolo protein kinase
modulators
Bounaud , et al.
SGX Pharmaceuticals, Inc. San Diego,
California, US
US Patent 7,473,783 January 6, 2009
Appl. No. 11/016,126 December 17, 2004
The invention provides novel bicyclic
pyrazolo kinase modulators and methods of
using the novel bicyclic pyrazolo kinase
modulators to treat diseases mediated by
kinase activity.
Pyrazole compounds useful as protein
kinase inhibitors.
Davies; Robert , et al.
Vertex Pharmaceuticals Incorporated
Cambridge, Massachussetts, US
US Patent 7,473,691 January 6, 2009
Appl. No.: 09/952,875 September 14, 2001
This invention describes novel protein
kinase inhibitors of formula are useful for
treating diseases such as cancer, diabetes and
Alzheimer's disease.
Metastable benzoxepne derivatives
which can be used in the treatment of
dyslipidaemia atherosclerosis and diabetes,
pharmaceutical compositions comprising
them and processes for the preparation
thereof..
Bosc; Nathali et al.
Merck
Patent
GmbH
,Darmstadt,
Germany
US Patent 7,470,719 December 30, 2008
Appl. No.: 10/530,571 September 1, 2003
The present invention relates to novel
metastable derivatives of benzoxepines of the
formula (I) in which n represents 0, 1 or 2; and
the radicals R, which may be identical or
different, are alkyl or alkoxy groups, or
halogen atoms, which can be used in the
treatment of dyslipidaemia, atherosclerosis and
diabetes.
Proteins in type 2 diabetes.
Hojlund; Kurt et al.
Pride Proteomics A/S ,Odense M,
124

Denmark
US Patent 7,470,542 December 30, 2008
The invention relates to the use of
naturally occurring compounds and derivatives
thereof as markers for predisposition of
diabetes related diseases. The invention also
relates to a pharmaceutical composition for
treatment of the diabetes related diseases.
Use of gp130 activators in diabetic
neuropathy.
Dreano; Michel, et al.
Laboratoires
Serono
SA
,Vaud,
Switzerland
US Patent 7,465,441 December 16, 2008
Appl. No.: 10/492,087 October 10, 2002
The invention relates to the use a
substance signaling through gp130 for the
manufacture of a medicament for the treatment
and/or prevention of diabetic neuropathy. The
use of IL-6 is preferred.
System and method for evaluating
impaired glucose tolerance and diabetes
mellitus within a patient using an
implantable medical device.
Bharmi; Rupinder et al.
Pacesetter, Inc., Sylmar, California, US
US Patent 7,462,150 December 9, 2008
Appl. No.: 11/450,937 June 9, 2006
Techniques are described for use by a
pacemaker or implantable cardioverter/
defibrillator (ICD) or other implantable
medical device. The techniques are provided
for evaluating the likelihood that the patient, in
which the device is implanted, has impaired
glucose tolerance (IGT) or diabetes mellitus.
Briefly, a value representative of sleep quality
of the patient is detected and then the
likelihood that the patient has IGT or diabetes
mellitus is determined based on the sleep
quality value. In this regard, it has been found
that a decrease in overall sleep quality is
associated with an increased likelihood of IGT
or diabetes mellitus, which is in turn
associated with an increased risk of mortality.
Hence, sleep quality may be used as a proxy
for evaluating the likelihood that the patient
Current R&D Highlights, Jan.-Mar. 2009

Patents
has IGT or diabetes mellitus and for assessing
associated mortality risk.
Treatment of diabetes with copper
binding compounds
Baker; John Richard et al.
US Patent 7,459,446 December 2, 2008
Appl. No 11/023,827 December 28, 2004
Novel methods of treating a patient for
diseases, disorders, and conditions including
diabetes mellitus, comprising administering,
for example, copper binding compounds.
Substituted carboxylic acid derivatives
for the treatment of diabetes and lipid
disorders, their preparation and use
Choi; Yong Moon et al
SK Holding Co., Ltd., Seoul, Korea
US Patent 7,456,293 November 25, 2008
Appl. No 11/391,031 March 28, 2006
The invention is concerned with racemic
or enantiomerically enriched substituted
carboxylic
acids
and
derivatives
or
pharmaceutically acceptable salts thereof. The
present invention also includes pharmaceutical
compositions comprising an effective amount
of a compound of Formula 1 in admixture with
a pharmaceutically acceptable carrier or
excipient. The compositions may include
additional therapeutic agents for combination
therapy. The present invention provides a new
class of pharmaceutically active compounds,
which are useful in the treatment and control
of diabetes and its related metabolic diseases.
Cyclohexylglycine
derivatives
as
dipeptidyl peptidase inhibitors for the
treatment or prevention of diabetes.
Edmondson; Scott D. et al
Merck & Co., Inc.,Rahway, New Jersy,
US
US Patent 7,456,204 November 25, 2008
Appl. No 10/560,771 June 10, 2004
The present invention is directed to novel
cyclohexylglycine derivatives which are
inhibitors of the dipeptidyl peptidase-IV
enzyme ("DP-IV inhibitors") and which are
useful in the treatment or prevention of
Current R&D Highlights, Jan.-Mar. 2009

diseases in which the dipeptidyl peptidase-IV


enzyme is involved, such as diabetes and
particularly type 2 diabetes. The invention is
also directed to pharmaceutical compositions
comprising these compounds and the use of
these compounds and compositions in the
prevention or treatment of such diseases in
which the dipeptidyl peptidase-IV enzyme is
involved.
Treatment of gestational diabetes
Hiles; Richard A. et al
Amylin Pharmaceuticals, Inc., San Diego,
California,US
US Patent 7,452,858 November 18, 2008
Methods for treating gestational diabetes
which comprise administration of an effective
amount of an exendin or an exendin agonist,
alone or in conjunction with other compounds
or compositions that lower blood glucose
levels.
Chroman carboxylic acid derivatives
for the treatment of diabetes and lipid
disorders.
Choi; Yong Moon et al.
SK Holdings Co, Ltd., Seoul, Korea
US Patent 7,446,127 November 4, 2008
Appl. No.: 10/926,615 August 26, 2004
There are disclosed derivatives of 3chromancarboxylic
acid
and
their
pharmaceutically acceptable salts thereof and
prodrugs thereof which are useful for treatment
and control of non-insulin dependent diabetes
mellitus (type II diabetes) and its related
vascular disease as well as obesity and lipid
disorders.
Herbal compositions for the treatment
of diabetes and/or conditions associated
therewith.
Fogel, Dov; et al.
Ascarit Ltd; Illinois,US
WO/2009/001362
Application
No.:
PCT/Il2008/000880
Publication
Date:
31.12.2008, Filing Date:26.06.2008
The present invention discloses herbal
compositions comprising at least one Urtica
125

Patents
species or an extract thereof, at least one
Artemisia species or an extract thereof, and an
extract of at least one Morus species, wherein
this extract is prepared of morus leaves and
comprises morus latex further are disclosed
methods for the preparation of these
compositions, uses thereof in treating and /or
preventing diabetes, related conditions and
hypertriglyceridemia, as well as methods of
treating subjects suffering from these
conditions.
Biomarkers
for
pre-diabetes,
cardiovascular
diseases,
and
other
metabolic-syndrome related disorders and
methods using the same.
Hu, Yun, Fu;
Metabolon, Inc.; Capitola, Durham, North
Carolina, US
WO/2009/014639 Application No.PCT/
US2008/008756 Publication Date:29.01.2009
Filing Date:17.07.2008
Biomarkers relating to insulin resistance,
pre-diabetes, type-2 diabetes, metabolic
syndrome,
atherosclerosis,
and
cardiomyopathy are provided, as well as
methods for using such biomarkers as
biomarkers for insulin resistance, pre-diabetes,
type-2
diabetes,
metabolic
syndrome,
atherosclerosis, and cardiomyopathy. in
addition, methods for modulating the
respective disorders or conditions of a subject
are also provided also provided are suites of
small molecule entities as biomarkers for
insulin resistance, pre-diabetes, type-2
diabetes, metabolic syndrome, atherosclerosis,
and cardiomyopathy.
Herbal formulations for controlling
blood glucose levels in patients with
diabetes.
ATP Marketing & Promotion AG Niederumen, Switzerland
WO/2009/024175 Application No.: PCT/
EP2007/007426 Publication Date:26.02.2009
Filing Date:21.08.2007
The present invention relates to herbal
formulations for controlling blood glucose
126

levels in a patient with diabetes and the use


thereof for treating diabetes the formulations
according to the present invention are
particularly useful for treating patients with
diabetes type 2. for this, the present invention
provides a herbal formulation comprising
cinnamon and gymnema sylvestre extract.
Non-invasive in vivo imaging and
methods for treating type I diabetes.
Biocrine AB, Stockholm Sweden.
WO/2009/027106 Application No.: PCT/
EP2008/007130 Publication Date:05.03.2009
filing date:01.09.2008
The invention provides novel drug
discovery platforms and methods for treating
type I diabetes.
Molecules and methods for treatment
and detection of diabetes.
University of Washington Seattle,
Washington, US
WO/2009/033121 Application No.:PCT/
US2008/075524 Publication Date:12.03.2009
Filing Date:06.09.2008
Described are antibodies that specifically
recognize and bind the epitope of glutamate
decarboxylase (gad65) that is bound by
antibody b96 11, and anti-idiotypic antibodies
that are capable of competing with gad65 for
binding with b96.11 and competitively inhibit
such binding these antibodies can be provided
in the form of a pharmaceutical composition
and can be used in methods for delaying the
onset of type 1 diabetes and for inhibiting
insulitis and other diabetic symptoms also
provided are methods for detecting a
susceptibility to type 1 diabetes in a subject
and for detecting the presence of anti-idiotypic
antibodies to gad65 the method comprises
contacting a specimen with an antibody of the
invention the method further comprises
detecting binding of the molecule to the
specimen the absence (or relative absence) of
binding is indicative of susceptibility to type 1
diabetes and of the absence of anti-idiotypic
antibodies.
Current R&D Highlights, Jan.-Mar. 2009

Patents
A method for treating diabetes.
Mclane, Michael et al.
Genaera Corporation, Campus Drive,
Plymouth Meeting, Pennsylvania, US
WO/2009/032321 Application No.:PCT/
US2008/010455 Publication Date:12.03.2009
Filing Date:08.09.2008
This application is directed to the use of
steroid compounds for the selective inhibition
of the enzyme ptp1b in a mammal for the
treatment of diabetes.
Therapeutic agent for type-2 diabetes.
Ishii, Shinichi et al.
Mitsubishi Tanabe Pharma Corporation
Osaka, Japan.
WO/2009/011420 Application No.: PCT/
JP2008/063008 Publication Date:22.01.2009
Filing Date:18.07.2008
Disclosed is a medicinal agent comprising
ursodeoxycholic acid or a pharmacologically
acceptable salt thereof as an active ingredient,
which can be act as a therapeutic agent for
type-2 diabetes accompanied by fatty liver or
liver dysfunction.
The use of compounds such as
pyridoxal derivatives for the treatment of
diabetes or diseases associated with the
metabolic syndrome.
Erlinge, David et al.
Strom and Gulliksson AB, Malmo,
Sweden
WO/2009/005469 Application No.: PCT/
SE2008/050831 Publication Date:08.01.2009
Filing date:03.07.2008
The invention relates to compounds
having the general formula (i), (ii) or (iii), and
which are useful for the treatment or
prevention of diabetes or diseases associated
with the metabolic syndrome.
Biomarkers for diabetes, obesity,
and/or hypertension.
Hancock, William, S et al.
Northeastern
University,
Boston,
Massachusetts, US
WO/2009/006568 Application No.:PCT/
Current R&D Highlights, Jan.-Mar. 2009

US2008/069145 Publication Date:08.01.2009


Filing Date:03.07.2008
Methods of identifying subjects having, or
at risk of developing, diabetes, obesity, and/or
hypertension are disclosed, as well as methods
of identifying biomarkers for diabetes, obesity,
and/or hypertension, and biomarkers identified
by such methods.
Novel AS160-like protein, test systems,
methods and uses involving it for the
identification of diabetes type 2 therapeutics.
Tennagels, Norbert; (DE).
Sanofi-Aventis [FR/FR]; 174, Avenue De
France, F-75013 Paris (FR) (All Except US).
WO/2009/015808 Application No.:PCT/
EP2008/006024 Publication Date:05.02.2009
Filing Date:23.07.2008
The present invention relates to novel
AKT substrate 160kDa-like protein (AS160like protein), to a method of identifying a
substance altering glucose uptake and/or
GLUT4 translocation to the plasma membrane
cell comprising contacting a test system
comprising AKT substrate 160kDa-like protein
(AS160-like protein) with a test substance, and
identifying a test substance as a substance
altering glucose uptake of a cell by detecting a
signal indicative for altered glucose uptake of
a cell; a test system comprising a gene coding
for the AKT substrate 160 kDa-like protein
(AS160-like protein) and an inducible
promoter providing for controllable expression
of the gene; the use of the test system for the
identification of a substance improving
glucose uptake and/or GLUT4 translocation to
the plasma membrane of a cell; and the use of
AS160-like protein in a model for type 2
diabetes.
Method,
system
and
computer
simulation environment for
testing of
monitoring and control strategies in
diabetes.
Kovatchev, Boris, P et al.
University of Virginia, Virginia, US
WO/2008/157781 Application No.: PCT/
127

Patents
US2008/067725 Publication Date:24.12.2008
Filing Date:20.06.2008
A simulation environment for in silico
testing of monitoring methods, open-loop and
closed-loop treatment strategies in type 1
diabetes
some
exemplary
principal
components of the simulation environment
comprise, but not limited thereto, the
following: 1) a 'population' of in silico
'subjects' with type 1 diabetes in three age
groups; 2) a simulator of cgm sensor errors; 3)
a simulator of insulin pumps and discrete
insulin delivery; 4) an interface allowing the
input of user-specified treatment scenarios;
and 5) a set of standardized outcome measures
and graphs evaluating the quality of the tested
treatment strategies these components can be
used separately or in combination for the
preclinical evaluation of open-loop or closedloop control treatments of diabetes.
Method for monitoring diabetes insulin
therapy.
Chuvashov, Vladimir Dmitryevitch et al.
Petersburg, Russia
WO/2009/031943 Application No.:PCT/
RU2008/000577 Publication Date:12.03.2009
Filing Date:25.08.2008
The invention relates to medicine, in
particular to endocrinology, more specifically
to the monitoring of insulin therapy of patients
suffering from diabetes. the method for
monitoring diabetes insulin therapy is based on
the measurement of a glucose concentration in

128

the blood or in the hypodermic medium by


means of an optical and/or electrochemical
method, and consists in periodically injecting
test doses of (ultra) short insulin into a
measuring point, thereby generating a shortterm local deterioration of a glucose level and
obtaining a difference in measurement results
for determining a current glucose level during
a given measuring interval the inventive
method makes it possible to increase the
accuracy of measurement of a current
glycemia level, also when using a non-invasive
method of measurement, since the result
depends only on two parameters, i.e. the
insulin test dose and the current glucose level
in the organism.
N-azacyclic
substituted
pyrrole,
pyrazole, imidazole, triazole and tetrazole
derivatives as agonists of the RUP3 or
GPR119 receptor for the treatment of
diabetes and metabolic disorders.
Metabolex, Inc., Hayward, California, US
WO/2009/014910 Application No.: PCT/
US2008/069714 Publication Date:29.01.2009
Filing Date:10.07.2008
Compounds and methods are provided for
the treatment of, inter alia, type ii diabetes and
other diseases associated with poor glycemic
control.

Current R&D Highlights, Jan.-Mar. 2009

CDRI Publications

Papers Published on Diabetes by

Central Drug Research Institute, Lucknow


During the period from 1952 to 2008.
1. Ahamad R, Srivastava SP, Maurya R, Rajendran SM, Arya KR and Srivastava A - Mild
antihyperglycaemic activity in Eclipta alba, Berberis aristata, Betula utilis, Cedrus deodara, Myristica
fragrans, Terminalia chebula (2008) - Ind. J. Sci. & Technology 1,1-6
2. Maurya, R., Akanksha, Jayendra, Singh, A.B., Srivastava, A.K., 2008; Bioorganic & Medicinal
Chemistry Letters; 18; 65346537.
3. Dixit A and Saxena AK - QSAR analysis of PPAR-? agonists as anti-diabetic agents (2008) - Eur. J.
Med. Chem. 43, 73-80
4. Khan MM, Saxena R, Puri Anju, Chander R, Khanna AK, Saxena AK and Saxena JK - Regulation of
glycogen metabolism by antidyslipidemic action of gemfibrozil and cholestyramine in dyslipidemic
diabetic hamster model (2008) - Med Chem Research 17, 245-257
5. Singh AB, Chaturvedi JP, Narender T and Srivastava AK - Preliminary studies on the hypoglycemic
effect of Peganum harmala seeds ethanol extract on normal and streptozotocin induced diabetic rats
(2008) - Indian Journal of Clinical Biochemistry 23, 391-393
6. Tamrakar AK, Tiwari P, Ahmad R, Kumar R, Lakshmi V, Srivastava MN and Srivastava AK Antihyperglycaemic activity of Sinularia firma and Sinularia erecta in streptozotocin induced diabetic
rats (2008) - Med Chem Research 17, 62-73
7. Tiwari P, Tamarkar AK, Ahmad R, Kumar R, Lakshmi V. and Srivastava AK - Antihyperglycemic
activity of ceriops tagal in normoglycemic and streptozotocin-induced diabetic rats (2008) - Med
Chem Research 17, 74-84
8. Suryawanshi,

Satyendra;

Mehrotra,

Nitin;

Asthana,

K;

Gupta,

Ram

Liquid

chromatography/tandem mass spectrometric study and analysis of xanthone and secoiridoid glycoside
composition of Swertia chirata, a potent antidiabetic (2006) - Rapid Communications In Mass
Spectrometry: RCM, 20, 3761-3768
9. Gupta, Asheesh ; Raghubir, Ram, - Energy metabolism in the granulation tissue of diabetic rats during
cutaneous wound healing, (2005) - Molecular And Cellular Biochemistry, Volume 270, Issue 1-2,
71-77.

Current R&D Highlights, Jan.-Mar. 2009

129

CDRI Publications
10. Prathipati, P , Pandey, G , Saxena, A.K. - CoMFA and docking studies on glycogen phosphorylase a
inhibitors as antidiabetic agents. (2005) - J Chem Inf Model. 2005 Jan-Feb;45(1):136-45.
11. Gupta, A. & Raghubir, R. - Energy metabolism in granulation tissues of normal and diabetic rats
during cutaneous wound healing. (2004) - Mol. Cell. Biochem., 260, 1-7.
12. Verma, S.S., Mishra, C., Tamrakar, A.K., Tripathi, B.K., Srivastava, A.K. & Tripathi, R.P. - Reductive
amination of glycosyl aldoses: Synthesis of N-glycosylated beta-glycosyl amino alcohols and their
antidiabetic potential. (2004) - J. Carbohydrate Chem., 23, 493-511.
13. Rizvi, F., Puri, A., Bhatia, G., Khanna, A.K., Wulff, E.M., Rastogi, A.K. & Chander, R. Antidyslipidemic action of fenofibrate in dyslipidemic-diabetic hamster model. (2003) - Biochem.
Biophys. Res. Commn., 305, 215-22.
14. Saxena, A.M., Murthy, P.S.R. & Mukherjee, S.K. - Mode of action of three structurally different
hypoglycaemic agents: A comparative study. (1996) - Indian J. Expt. Biol., 34, 351-55.
15. Singh, S., Gupta, J. & Agarwal, C.G. - Conjugated dienes in lipids of apolipoprotein containing
lipoproteins of normal and type-2 (non-insulin dependent) diabetic patients. (1992) - Indian J.
Biochem., Biophys., 29, 282-86.
16. Ahmad, Faiyaz, Khan, M.M., Rastogi, A.K. & Kidwai, J.R. - Insulin and glucagon releasing activity in
coleonol, its effect on blood glucose level in normal and aloxan diabetic rats. (1991) - Acta Diabetol,
Lat., 28, 71-7.
17. Bajpai, Madhubala, Asthana, R.K., Sharma, N.K., Chatterjee, S.K. & Mukherjee, S.K. Hypoglycaemic effect of swerchirin form the hexane fraction of Swertia chirayita. (1991) - Planta
Med., 57, 99-202.
18. Sethi, P.P.S., Mitra, M.K., Sircar, A.R., Shanker, Kripa, Gaur, S.P.S. & Rastogi, A.K. - The effect of
antiplatelet drug on micorproteineuria in different stages of diabetic nephropathy. (1991) - Indian J.
Neph., 1, 144.
19. Agarwal, V.R., Rastogi, A.K. & Sagar, P. - In vitro insulin action on erythrocyte glucose metabolism
in normal and diabetic rats. (1988) - Diabetologia, 31, 51-53.
20. Agarwal, V., Rastogi, A.K., Sahib, M.K. & P. Sagar. - Insulin binding parameters in erythrocytes of
alloxan induced diabetic rat. (1987) - Indian J. Expt. Biol., 25, 43-44.
21. Kumari, K., Bansal, V., Jagmohan, Agarwal, C.G., Rastogi, A.K. & Sahib, M.K. - Retrospective
glycemic status of diabetic patients: Glycosylation of blood proteins in diabetes and chronic renal
failure. (1987) - Acta Diabet. Latina, 24, 91.
22. Mukjherjee, B., Bhatia, G.S., Chatterjee, A.K. & Mukherjee, S.K. - Impairment of insulin mechanism
of islets of Langerhans in rats made diabetic by alloxan and streptozotocin. (1986) - Indian J. Physiol.
Allied., Sci., 39, 108.

130

Current R&D Highlights, Jan.-Mar. 2009

CDRI Publications
23. Agarwal, V.R., Rastogi, A.K., Sahib, M.K. & Sagar, P. - In vitro effect on acetylcholinesterase of
erythrocyte membranes of normal and diabetic rats. (1985) - Acta diabet. Latina, 22, 359.
24. Agarwal, V.R., Rastogi, A.K., Sahib, M.K. & Sagar, P. - In vitro insulin action on different AT Pases
of erythrocyte membranes in normal and diabetic rats. (1985) - Acta diabet. Latina, 22, 111.
25. Gitika, S.B. & Mukherjee, S.K. - Changes in blood lactic and pyruvic acid level in phenyl ethylbiguanides treated diabetic rhesus monkeys and albino rats. (1981) - Ind. J. Physiol. And Allied Sci.,
35, 102-103.
26. Mathur, K.B. & Kishore, V. - Synthesis and hypoglycaemic activity of arginine peptides. (1980) Indian J. Biochem. Biophys., 17, 303-05.
27. Mukerjee, S.S., Sethi, N., Roy, A.K., Srivastava, G.N. & Mukherjee, S. K. - Chronic toxicity studies of
a hypoglycaemic compound, Centpiperalone, in rats and rhesus monkeys. (1979) - Indian J. Exp.
Biol., 17, 1346-49.
28. Mukerjee, S.S. & Mukherjee, S.K. - Activators of serum lipoprotein lipase in alloxan diabetic rats.
(1978) - Experientia, 34, 1429-30.
29. Asthana, T.C. & Jain, P.C. - b-Phenoxy-b-phenylpropionic acid,a-benzyloxy-, a-thiobenzyloxy-&aanilino-a-phenylacetic acids & their derivatives as potential hypoglycaemic agents. (1977) - Indian J.
Chem., 15B, 383-85.
30. Mukherjee, S.K. - A novel hypoglycaemic compound. (1973) - Biochem. Pharmacol., 22, 1529.
31. Gupta, C.M., Bhaduri, A.P., Khanna, N.M. & Mukherjee, S.K. - A novel class of hypoglycaemic
agents

Syntheses

&

SAR

in

2-substituted-4

(3H)-quinazolones,

2-substituted-4-

hydroxypolymethylene [5,6] pyrimidines & 3-substituted-4-oxo-pyrido[1,2-a] pyrimidines. (1971) Indian J. Chem., 9, 201-06.
32. Asthana, T.C., Gupta, S.K., Khosla, M.C. & Anand, N. - a-Phenoxy and thiophenoxyphenylacetic acid
derivatives as hypoglycaemic agents. (1970) - Indian J. Chem., 8, 1086-95.
33. Asthana, T.C., Gupta, S.K., Khosla, M.C. & Anand, N. - a-Phenoxy & thiophenoxyphenylacetic acid
derivatives as hypoglycaemic agents. (1969) - Indian J. Chem., 8, 1086-95.
34. Shoeb, A., Popli, S.P., Mukherjee, S.K. & Dhar, M.L. - Studies in possible oral hypoglycaemic agents
: Part V - Synthesis of carbamoylindoles, carbamoylisoindolines, 3-indolylethyl urea (or thiourea) & 2isoindolinylpropyl urea (or thiourea) derivatives & their biological activity. (1967) - Indian J. Chem.,
5, 142-44.
35. Shoeb, A., Popli, S.P., Mukherjee, S.K. & Dhar, M.L. - Studies in possible oral hypoglycaemic agents
: Part VI - Synthesis of some 2- & 4-pyridylethyl ureas & thioureas & some barbiturates & their
biological activity. (1967) - Indian J. Chem., 5, 145-46.

Current R&D Highlights, Jan.-Mar. 2009

131

CDRI Publications
36. Shoeb, A., Mukerjee, S.K., Anand, N. & Dhar, M.L. - Oral hypoglycaemic agents. Part IV - Synthesis
of 1-aryl sulphonyl 3-substituted-2-imidazolidinones & 1,1,3-trisubstituted ureas. (1965) - Indian J.
Chem., 3, 507-509.
37. Acharya, B.P., De, U.N. & Mukherjee, S.K. - Effect of synthetic antidiabetic compounds & insulin on
the alcohol induced gastric acidity in rabbits. (1961) - Indian J. Med. Res., 49, 62-67.
38. Dhar, D.N., Popli, S.P. & Dhar, M.L. - Studies in possible oral hypoglycaemic agents: Part IISynthesis of hydantoins & hydantoic esters by alternate methods. (1961) - J. Sci. Industr. Res., 20C,
145-147.
39. Mukherjee, S.K., De, U.N. & Mukerji, B. - Comparative study of the hypoglycaemic action of
sulphonylureas & their nature of action. (1960) - J. Sci. Industr. Res., 19C, 268-274.
40. Roy, A.K., Zaidi, S.H. & Popli, S.P. - Hypoglycaemic activity of some hydantoins, hydantoic ester &
related compounds in rats. (1960) - J. Sci. Industr. Res., 19C, 75-77.
41. Mukherjee, S.K. & De, U.N. - Studies on D 860-Another new oral hypoglycaemic sulfonamide. (1958)
- Indian J. Med. Res., 46, 223-233.
42. Mukherjee, S.K., De, U.N. & Mukerji, B. - Clinical experience with a new oral hypoglycaemic drug.
(1957) - J. Indian Med. Ass., 28, 466-468.
43. Mukherjee, S.K., De, U.N. & Mukerji, B. - Studies in experimental diabetes: Part IV - Tissue
phosphatase activity in protected & in alloxan diabetic rats. (1956) - Indian J. Med. Res., 44, 415420.
44. Raja Rama Rao, M.R. & De, N.N. - An antidiabetic principle from Rivea cuneata (Wight). (1952) Curr. Sci., 21, 69.
(Based on the information available in Annual reports of C.D.R.I.
Occurance of any error or omission may kindly be ignored.
Compiled by: Wamiq F. Rahman)

132

Current R&D Highlights, Jan.-Mar. 2009