DM 1

Molecular Aspect of Diabetes
Mellitus and Clinical Implications

Focus on -Cell Dysfunction
IGN Adhiartha
Sub Bagian Endokrinologi dan Metabolisme

FK UNPAD/ Perjan RS Hasan Sadikin
Bandung
PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com
Type 2 DM Definition
T2DM is a heterogeneous disorder
due to prevalent insulin resistance
associated
with
deficient
insulin
secretion or to a prevalent defect of
insulin
secretion
associated
with
impaired
insulin action.
Del Proto et al, Diabetes (suppl.1) 2002.-
The worldwide pandemic of

type 2 diabetes
World wide diabetes
prevalence (millions)
350
300
300
250
221
200
150
150
100
2000
2010
2025
International Diabetes Federation Diabetes Atlas 2000;

Amos et al. Diabet Med 1997;14 (Suppl 5):S1-S85.
% change in age-adjusted
mortality rate since 1980
CVD Mortality Decreases in General Population

and
Diabetes Mortality Increases
50
40
30
Diabetes
20
10
0
-10
-20
Cancer
All-cause
CVD
-30
-40
-50
1980 1982 1984 1986 1988 1990 1992
Sobel et al. Circulation. 2003;107:636-642.
1994 1996 1998
Indonesia
2000 5.6 milions people with DM
2020 8.2 milions people with DM
th
World 5
largest prevalence!!!
(International Diabetes Federation 2003)
Top Ten Countries for estimated number of

adults with diabetes, 1995 and 2025
Country
1995 (millions)
Rank
1
India
2
China
3
U.S.
4
Russian Fed.
5
Japan
6
Brazil
7
Indonesia
8
Pakistan
9
Mexico
10
Ukraine
All other countries
19.4
16.0
13.9
8.9
6.3
4.9
4.5
4.3
3.8
3.6
49.7
Total
135.3
Country
2025 (millions)
India
China
U.S.
Pakistan
Indonesia
Russian Fed.
Mexico
Brazil
Egypt
Japan
57.2
37.6
21.9
14.5
12.4
12.2
11.7
11.6
8.8
8.5
103.6
300.0
Pathogenesis of Type 2
Diabetes
Insulin resistance
?
vs
-cell dysfunction
Pathogenesis of Type 2 Diabetes

Mellitus
Genetics
Genetics
Acquired
Acquired
Insulin
Resistance
Genetics
Hyperinsulinemia
Compensated Insulin
resistance
IGT
Islet Beta
cell Failure
Normal Glucose tolerance
Acquired Glucotoxicity
FFA
Others
Adapted from: DeGroot L,et al,editors.Endocrinology 4 th ed Philadelphia
:WB Saunders Co;2001 p.777
Type 2 DM
Increased Hepatic
Glucose Production
Decreased Insulin
Secretion
Stages of Type 2 Diabetes
Beta Cell
Function
(%)
IGT
-12 10
T2DM phase III
Postprandial T2 DM
Hyperglycemiaphase I
-6
-2 0
T2DM
phase II
Years from Diagnosis

Lebovitz H. Diabetes Review 1999;7:139-53
10
14
450
area density of -cell

area density of amyloid
Diabetes
400
350
300
250
200
150
1
100
50
0
Progression of the syndrome

Area density/pancreatic section %
Fasting plasma insulin (mmol/l)
Insulin secretion and islet changes in

the diabetic syndrome
Insulin Resistance
vTissue resistance to the actions of
insulin
vA state (of a cell, tissue, or organism), in
which a greater than normal amount of
insulin is required to elicite quantitatively
normal response
subunit
s s
Cell Membran
Insulin Receptor
subunit
ras
Tyr-P
SOS
raf
syp
Tyr-P
nck
?
Tyr-P
IRS-1
IRS-2
Tyr-P
Tyr-P
IRS-3 IRS-4
grb
MEKK
PI-3
kinase
?
Insulin
Kinase
and
phosphatase
cascade
Effects
Cellular Mechanisms
of Insulin Action
-cell Insulin S S
130K 130K
S S
95K
Cell membrane
S S
ATP
95K
ADP
P
-Tyr
Glucose
PP
Translocation
Mediators
and/or
Intracellular phosphorylation
1997 PPS
enzymes,
protein, RNA,
DNA synthesis
GLUT4
Kruszynska Y, Olefsky JM. J Invest Med. 1996;44:413-428.
Insulin Resistance:
Causes and Associated Conditions
Aging
Obesity and
inactivity
Medications
Rare
disorders
Genetics
INSULIN
RESISTANCE
Type 2
DM
Hypertension
1998 PPS
PCOS
Atherosclerosis
Dyslipidemia
Etiology of Type 2 Diabetes Mellitus:

Insulin Resistance and Diminished Insulin Secretion
Genes
Insulin Resistance
Lifestyle and
Diet
Normal
Abnormal
Beta Cell Function
Beta Cell Function
Compensatory
Hyperinsulinemia
Normoglycemia
Relative Insulin Deficiency

Hyperglycemia
Type 2 Diabetes Mellitus
Biosynthesis and Insulin Release

Proinsulin - Maturation - Insulin
- C-Peptide - Secretions
Exocitosis
Glucose
Calsium ++
Insulin Resistance at cell membran

Influence glucose influx into cell
Another Secretagoque :
hormones
gut peptide
amino acid
potentation with glucose
Any correlation between insulin sensitivity
and insulin secretion (Curvilinear)
Mechanism of Glucose-Mediated
Insulin Secretion
GLUT-2
Glucose
Glucokinase
Glucokinase
G-6-P
Glucose
G-6-P
Glucose
Metabolism
Metabolism
Signal
Signal (S)
(S)
ATP
ATP
ADP
ADP
Secretory
Secretory
Granules
Granules
K
K++ATP
ATP
++
Ca
Ca++
Depolarization
Ca++
Insulin Secretion
Cellular Mechanisms
of Insulin Action
-cell Insulin S S
130K 130K
S S
95K
Cell membrane
S S
ATP
95K
ADP
P
-Tyr
Glucose
PP
Translocation
Mediators
and/or
Intracellular phosphorylation
1997 PPS
enzymes,
protein, RNA,
DNA synthesis
GLUT4
Kruszynska Y, Olefsky JM. J Invest Med. 1996;44:413-428.
Possible sites and mechanisms of B-cell dysfunction in Type 2 DM

Insulin secretion
Glucose signalling
Glucose
K+
channel
shuts
GLUT-2
Ca2+
channel Ca2+
opens
Insulin
release
Glucose
Glucokinase
Glucose-6-phosphate
K+
Depolarization
Exocytosis
Secretory
granule
transport
ATP
Insulin + C peptide
Cleavage
enzymes
Proinsulin
B cell
Preproinsulin
Insulin synthesis
Glucosa Toxicity
Hyperglycemia
Decrease
Insulin secretion
Insulin effect
Cellular mechanism was not clear
GLUT
Hexoxinase
IAAP
Lactat dehydrogenase
Pathway for The Formation of AGEs

days
hours
Glucose
+
NH2-R
weeks /
months
Schiff
Base
Amadori
Product
..
AGES
Lipoxysdase product
Peroxcid Lipid
Aldehid
ROS
Lipid
Fruktosalisin
Protein
Glucose
Dikarbonil
Oxidation Protein
Glikoxidati Product
Reactive Oxygen Species (ROS) Result Damage
(Adapted Lyons TJ, Jenkins AJ. Diabetes Reviews, 1997;5: 365-91)
The Role of Stress in Tissue Damage

Substrate
stress
Oxidative Carbonyl
stress
stress
Metabolic
[O2 ]
REACTIVE
reactions
Glucose
CARBONYL
Non
Lipid / AA
enzymatic
reactions
Detoxification
Aldose
reductase
( NADPH )
Tissue
Damage
Aldehyde
dehydrogenase
( NAD+ )
Genetics
MODY - Abnormal oscillatory insulin release
Disproportionate amount of Proinsulin
Genetic disorder at DNA Mitochondria
Many others Candidate genes for
Insulin Resistance Gen :
Glucokinase
HNF 4 A, 1 A, 1B
Sulfonilurea receptor
Glut (Glucose Transporter)
Glucagon Receptor
Amyloid Deposits
Islet Amyloid Popypeptide (IAAP)
Produced by -cell, product of IAAP
Secreted with Insulin
Effect : Amyloid deposit formation
-cell mass i
Mechanism ?
Insulin Resistance
With Normal Beta Cells
Climbing the Curve
Insulin
level
Normal curve
Resistant
Insulin sensitivity
1998 PPS
Sensitive
Bergman RN. Diabetes. 1989;38:1512-1527.
Longitudinal findings
500 -
400 -
Non-progressors
NGT
AIR, U/ml
300 -
NGT
NGT
NGT
200 -
IGT
Progressors
100 -
0-
DIA
l
0
l
1
l
2
l
3
l
4
M-Low, mg/kgEMBS/min
l
5
Clinical Implications
Recent study by using hyperbolic load of
glucose tolerance concepts showed that
insulin resistance & cell- dysfunction were
detected much earlier than the appearance
of glucose intolerance
Current data supported the evidence that
primary defect of T2DM pathogenesis was
due to pancreatic -cell dysfunction
Basic pathogenesis for primary
prevention are
a. Improving the insulin secretion
b. Improving insulin sensitivity
T2DM
Prevention of Type 2 Diabetes

Getting Back on the Curve
Insulin
level
Diabetes
Resistant
Normal curve
Insulin sensitivity
1998 PPS
Sensitive
Clinical Implications
Insulin sensitizers have still a potential role
as there are a lot of insulin remained in the
body after the diabetic patients suffer for
long period of time
In the future, the therapy can be directed
towards the ability to sentize pancreatic cell growth (such as
Exendin), gene
therapy,
prevention
againts
cells
destruction due to Amylin deposition
Insulin Resistance:
Causes and Associated Conditions
Aging
Obesity and
inactivity
Medications
Rare
disorders
Genetics
INSULIN
RESISTANCE
Type 2
PCOS
DM
Hypertension
1998 PPS
Atherosclerosis
Dyslipidemia
Site of Action of
Blood Glucose-Lowering Agents
Digestion
- Bedtime
insulin
- Biguanide
Hepatic
Glucose
Production
- Diet
- Acarbose
Extracellular
Glucose Pool
- Sulphonylurea
- Insulin Eksogen
- Benzoic Ac. Der.
- Phenilalanin Der.
Pancreatic B-cell
insulin secretion
Muscle
Glucose
Uptake
- Exercise
- Biguanide
-Thiazolidinedione
GLP-I

DM 1

Încărcat de

Informații document

Titlu original

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

DM 1

Încărcat de

Drepturi de autor:

Formate disponibile

Molecular Aspect of Diabetes

Mellitus and Clinical Implications

Sub Bagian Endokrinologi dan Metabolisme

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

The worldwide pandemic of

International Diabetes Federation Diabetes Atlas 2000;

CVD Mortality Decreases in General Population

Sobel et al. Circulation. 2003;107:636-642.

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

1994 1996 1998

(International Diabetes Federation 2003)

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

Top Ten Countries for estimated number of

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

Pathogenesis of Type 2 Diabetes

Normal Glucose tolerance

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

Stages of Type 2 Diabetes

T2DM phase III

Years from Diagnosis

area density of -cell

Progression of the syndrome

Area density/pancreatic section %

Fasting plasma insulin (mmol/l)

Insulin secretion and islet changes in

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

Etiology of Type 2 Diabetes Mellitus:

Beta Cell Function

Beta Cell Function

Relative Insulin Deficiency

Type 2 Diabetes Mellitus

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

Biosynthesis and Insulin Release

Insulin Resistance at cell membran

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

Possible sites and mechanisms of B-cell dysfunction in Type 2 DM

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

Cellular mechanism was not clear

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

Pathway for The Formation of AGEs

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

The Role of Stress in Tissue Damage

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

Climbing the Curve

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

Bergman RN. Diabetes. 1989;38:1512-1527.

Prevention of Type 2 Diabetes

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

PDF created with FinePrint pdfFactory Pro trial version http://www.fineprint.com

S-ar putea să vă placă și