Diabetes Mellitus (DM)

Overview and Treatments

Diabetes Mellitus :
a group of diseases characterized by high levels of blood glucose resulting
from defects in insulin production, insulin action, or both

20.8 million in US ( 7% of population)

estimated 14.6 million diagnosed (only 2/3)
Consists of 3 types:
1) Type 1 diabetes
2) Type 2 diabetes
3) Gestational diabetes

Complications :
- Stroke
- Heart attack
- Kidney disease
- Eye Disease
- Nerve Damage
Diabetes Mellitus
Type 1 Diabetes
- cells that produce insulin are
destroyed
- results in insulin dependence
- commonly detected before 30
Type 2 Diabetes
- blood glucose levels rise due to
1) Lack of insulin
production
2) Insufficient insulin
action (resistant cells)
- commonly detected after 40
- effects > 90%
- eventually leads to -cell failure
(resulting in insulin dependence)
Gestational Diabetes
3-5% of pregnant women in the US
develop gestational diabetes
Sign & Symptoms of DM
Complications of DM
Complications of DM
Complications of DM
Complications of DM
Complications of DM
Testing :
Fasting Plasma Glucose Test Oral Glucose Tolerance Test
(FPG) - (cheap, fast) (OGTT)
*fasting B.G.L. 100-125 mg/dl *tested for 2 hrs after
signals pre-diabetes glucose-
*>126 mg/dl signals diabetes rich drink
*140-199 mg/dl signals pre-
diabetes
*>200 mg/dl signals diabetes

A.K.A.: Glycated Hemoglobin tests

A1C

80 to 90 mg per 100 ml, is the normal fasting blood glucose

concentration in humans and most mammals which is
associated with very low levels of insulin secretion.
 Diabetes - Insulin
Discovered in 1921 by Banting
and Best
Consist of A & B chains linked
by 2 disulfide bonds
(plus additional disulfide in A)
~
A = 21amino acids B = 30 amino acids
Diabetes Insulin
(synthesis, storage, secretion)
Produced within the pancreas by cells islets of Langerhans
insulin mRNA is translated as a single chain precursor called preproinsulin
removal of signal peptide during insertion into the endoplasmic reticulum generates proinsulin
Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the
mature form of insulin

Stored as granules

Zn

This light micrograph of a section

of the human pancreas shows one
of the islets of Langerhans,
center, a group of modified
glandular cells. These cells
secrete insulin, a hormone that
helps the body metabolize
sugars, fats, and starches. The
blue and white lines in the islets
of Langerhans are blood vessels
Diabetes Insulin
(Biochemical Role)
-Tyrosine Kinase
receptors are the locks
in which the insulin
key fits
- Involved in signal
transduction
(insulin hormone being 1st messenger)
In the case of type 1 diabetes, insulin levels
are grossly deficient. Thus type 1 diabetes is
invariably treated with insulin

Type 2 diabetes is frequently associated with

obesity. Serum insulin levels are normal or
elevated, so this is a disease of insulin
resistance. A number of treatment options
may be employed.
 Gestational diabetes
A form of glucose intolerance that is diagnosed in some women
during pregnancy.
Gestational diabetes occurs more frequently among African
Americans, Hispanic/Latino Americans, and American Indians.
It is also more common among obese women and women with a
family history of diabetes.
During pregnancy, gestational diabetes requires treatment to
normalize maternal blood glucose levels to avoid complications
in the infant.
After pregnancy, 5% to 10% of women with gestational diabetes
are found to have type 2 diabetes.
Women who have had gestational diabetes have a 20% to 50%
chance of developing diabetes in the next 5-10 years.
 Secondary DM
Secondary causes of Diabetes mellitus include:
Acromegaly,
Cushing syndrome,
Thyrotoxicosis,
Pheochromocytoma
Chronic pancreatitis,
Cancer
Drug induced hyperglycemia:
Atypical Antipsychotics - Alter receptor binding characteristics, leading to increased insulin
resistance.
Beta-blockers - Inhibit insulin secretion.
Calcium Channel Blockers - Inhibits secretion of insulin by interfering with cytosolic calcium
release.
Corticosteroids - Cause peripheral insulin resistance and gluconeogensis.
Fluoroquinolones - Inhibits insulin secretion by blocking ATP sensitive potassium channels.
Naicin - They cause increased insulin resistance due to increased free fatty acid mobilization.
Phenothiazines - Inhibit insulin secretion.
Protease Inhibitors - Inhibit the conversion of proinsulin to insulin.
Thiazide Diuretics - Inhibit insulin secretion due to hypokalemia. They also cause increased
insulin resistance due to increased free fatty acid mobilization.
 Animation showing overview of diabetes:
http://www.healthscout.com/animation/1/34
/main.html
Animation showing mechanism of action of
insulin:
http://www.vivo.colostate.edu/hbooks/pathp
hys/endocrine/pancreas/insulin_phys.html
 Pancreatic Hormones
The bulk of the pancreas is an exocrine gland
secreting pancreatic fluid into the duodenum
after a meal.
Inside the pancreas are millions of clusters of
cells called islets of Langerhans. The islets are
endocrine tissue containing four types of cells.
In order of abundance, they are:
beta cells, which secrete insulin and amylin;
alpha cells, which secrete glucagon;
delta cells, which secrete somatostatin
gamma cells, which secrete a polypeptide.
Pancreatic Hormones
Insulin
Amylin
Glucagon
Somatostatin
Pancreatic Polypeptide
 Insulin is a small protein consisting of an A
A chain chain of 21 amino acids linked by two disulfide
(SS) bridges to a B chain of 30 amino acids.

Beta cells have channels in their plasma

membrane that serve as glucose
detectors. Beta cells secrete insulin in
response to a rising level of circulating
glucose.
B chain
Insulin affects many organs:
amino acids protein
It stimulates skeletal muscle fibers. uptake synthesis

It stimulates liver cells.

glycogen
glucose
synthesis
It acts on fat cells uptake

It inhibits production of certain fat

enzyme. synthesis

In each case, insulin triggers

enzyme glycogen
these effects by binding to the production breaking
insulin receptor.
 The insulin receptor (IR) is a
transmembrane glycoprotein,
composed of 2 and 2
domains.
.
Its intracellular tyrosine kinase
domain is activated by binding
of insulin, leading to a cascade
of signaling events.
 Management of DM
The major components of the treatment of
diabetes are:
A. Diet
Diet is a basic part of management in every
case. Treatment cannot be effective unless
adequate attention is given to ensuring
appropriate nutrition.

Dietary treatment should aim at:

ensuring weight control
providing nutritional requirements
allowing good glycaemic control with blood glucose
levels as close to normal as possible
correcting any associated blood lipid abnormalities
 A. Diet (cont.)
The following principles are recommended as dietary guidelines for
people with diabetes:

Dietary fat should provide 25-35% of total intake of calories but saturated
fat intake should not exceed 10% of total energy. Cholesterol consumption
should be restricted and limited to 300 mg or less daily.

Protein intake can range between 10-15% total energy (0.8-1 g/kg of
desirable body weight). Requirements increase for children and during
pregnancy. Protein should be derived from both animal and vegetable
sources.

Carbohydrates provide 50-60% of total caloric content of the diet.

Carbohydrates should be complex and high in fibre.

Excessive salt intake is to be avoided. It should be particularly restricted in

people with hypertension and those with nephropathy.
Exercise
Physical activity promotes weight reduction and
improves insulin sensitivity, thus lowering blood
glucose levels.

Together with dietary treatment, a programme of

regular physical activity and exercise should be
considered for each person. Such a programme must
be tailored to the individuals health status and
fitness.

People should, however, be educated about the

potential risk of hypoglycaemia and how to avoid it.
Who need insulin medicine
Type I (insulin dependent) diabetes patients whose body
produces no insulin.
Type 2 diabetes patients that do not always produce enough
insulin.

Treatment

subcutaneous injection
Insulin drug evolution
Stage 1 Insulin was extracted from the glands of
cows and pigs. (1920s)

Stage 2 Convert pig insulin into human insulin by

removing the one amino acid that distinguishes them
and replacing it with the human version.
 Stage 3 Insert the human
insulin gene into E. coli and
culture the recombinant E.coli
to produce insulin (trade name =
Humulin). Yeast is also used
to produce insulin (trade name =
Novolin) (1987).

Recombinant DNA technology has also made it possible to

manufacture slightly-modified forms of human insulin that
work faster (Humalog and NovoLog) or slower
(Lantus) than regular human insulin.
Types of insulin

Regular insulins

Insulin analogs

Pre-mixed insulin

Short peptide mimics

Regular insulins:

Human insulin: Humulin (from E.coli),

Novalin (from yeast)
NPH - neutral protamine Hagedorn (NPH),
protamine mixed.
Lente insulin / Ultralente insullin-
zinc added
Types of insulin

Regular insulins

Insulin analogs

Pre-mixed insulin

Short peptide mimics

Insulin Analogs:

Fatty Acid Acylated insulins

Insulin Lispro (Humalog) (1996)

Insulin Aspart (NovoLog) (2000)

Insulin Glargine (Lantus) (2002)

Insulin Detemir (Levemir) (Jun.,2005)

Insulin Glulisine (Apidra) (Jan., 2006)

 Amino Acid Substitutons
A- B- chain Position
chai
n
Position
Source/ A21 B3 B28 B29 B30 B31
Type And
B32
Human Asn Asn Pro Lys Thr
Aspart Asn Aspartic Lys Thr
acid
Lispro Asn Lys Pro Thr rapid-acting
Glulisin Asn Lys Pro Glu Thr
e
Glargine Gly Pro Lys Thr Arg
Detemir Lys Myristic long-acting
acid
Diabetes Oral Medications
6 Classes :
Sulfonylureas
Biguanides
Sulfonylureas and biguanide combination
drugs
Thiazolidinediones
Alpha-glycosidase inhibitors
Meglitinides
 Sulfonylureas : stimulate cells to produce
more insulin
1st generation
en

2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD)

(1)Orinase (tolbutamide)
o

was used in treatment of typhoid fever in 1940s hypoglycemia

oprt

(3)Tolinase (tolazamide)
Currently > 12,000
n
bdt

(6)Diabinese (chlorpropamide)
i

may become dislodged delayed activity

2nd generation
Rel. Potency

(75)Glucotrol (glipizide)
(150)Glucotrol XL (ex. rel. glipizide)
(150)Micronase, Diabeta (glyburide)
(250)Glynase (micronized glyburide)

3rd generation
(350)Amaryl (glimepiride)
*Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway
*Hydroxylated derivatives have much lower hypoglycemic activity
Mechanism of Action
Sulfonylureas interact with receptors on
pancreatic -cells to block ATP-sensitive
potassium channels
This, in turn, leads to opening of calcium
channels
Which leads to the production of insulin
 Biguanides : improves insulins ability to
move glucose into cells (esp. muscle)
R
R R
N N

R R
N N N
H
N N R R

Metformin H
N N N
- Glucophage, Fortamet, H
H H
Riomet
+ HCl

- mechanism improves insulin sensitivity by increasing peripheral glucose

uptake and utilization.
- Zhou et al (2001) showed that metformin stimulates the hepatic enzyme
AMP-activated protein kinase

- Metformin was first described in the scientific literature in 1957 (Unger et al).
- It was first marketed in France in 1979 but did not receive FDA approval for Type
2 diabetes until 1994.

Metformin is a widely used monotherapy, and also used in combination with the
sulfonylureas in treatment of type 2 diabetes

*only anti-diabetic drug that has been proven to reduce the complications of diabetes, as evidenced in a large study of overweight patients with
diabetes (UKPDS 1998).
 Sulfonylurea & Biguanide
Combo drugs/ Cocktails
Glucovance (Glyburide & Metformine HCl)

NH
& O
NH
S O
O
H
N N

&
N N N
H
H H
O
O NH + HCl

Cl
1-[[ p-[ 2-( 5-chloro-o-anisamido) ethyl] phenyl] sulfonyl]-3-cyclohexylurea
Thiazolidinediones (TZDs) : make
cells more sensitive to insulin (esp. fatty cells)
O

Pioglitazone
N O
S
NH

- Actos, Avandia
O
5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione

- binds to and activates the gamma isoform of the peroxisome proliferator-activated receptor (PPAR).

- PPAR is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue,
cardiac and skeletal muscle, liver and placenta

- upon activation of this nuclear receptor by a ligand such as a TZD,

PPARligand complex binds to a specific region of DNA and thereby
regulates the transcription of many genes involved in glucose and fatty
acid metabolism.

- Marketed in USA in August of 1999

PPAR -
lpha glycosidase inhibitors :
Block enzymes that help digest starches slowing
the rise in B.G.L.
AGIs
- Precose (acarbose),

- Glyset (miglitol)
H H
O
O
O
H N

O O
H H
1-(2-Hydroxy-ethyl)-2-hydroxymethyl-
piperidine-3,4,5-triol
Meglitinides : Stimulate more insulin
production ; dependant upon level of glucose present

Meglitinides
O

- Prandin (repaglinide) N O OH

NH O

2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid

- Starlix (nateglinide)

NH
O
O OH
2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid
 Diabetes Oral Medications
Summary
6 Classes :
Sulfonylureas stimulate cells
Biguanides improves insulins ability to move glucose
Sulfonylureas and biguanide combination
drugs BOTH
Thiazolidinediones cells more sensitive to insulin
Alpha-glycosidase inhibitors Block enzymes that help
digest starches
Meglitinides stimulate cells (dependant upon glucose conc.)
Oral Hypoglycaemic Medications
In Conclusion :
2 major types of diabetes
(3 with Gestational)
Type 1 => insulin dependant (5-10%)
Type 2 => may treat with oral medication
which may alter insulin production &/or
sensitivity ; disease often succumbs to
insulin dependence (>90%)
Self-Care

Patients should be educated to practice self-care. This

allows the patient to assume responsibility and control
of his / her own diabetes management. Self-care
should include:

Blood glucose monitoring

Body weight monitoring
Foot-care
Personal hygiene
Healthy lifestyle/diet or physical activity
Identify targets for control
Stopping smoking
 Mark the RTH value of Glucose

Dr PK
180 mg/dl
 Name the precursor of this hormones

Dr PK
Tyrosine /