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DM

INSULIN

SINDROMA

HIPERGLIKEMIA KRONIS KH LEMAK


DEFINISI

PROTEIN

Ref. : Peter H. Bennett; Definition, Diagnosis, and Classification of Diabetes Mellitus and Impaired Glucose Tolerance; Joslins Diabetes Mellitus; 13th ed.; 1994; hal. 193

Diagnosis DM
140
200

M G T

TGT
100
126

D M

Klasifikasi
DM DM DM DM tipe-1 tipe-2 tipe Gestasional tipe lain

Natural History of Type 2 Diabetes


Obesity 350 300 250 Glucose 200 (mg/dL) 150 100 50 250 200 Relative 150 Function 100 (%) 50 0 -10 -5 IGT Diabetes Uncontrolled hyperglycemia

Postprandial Glucose
Fasting Glucose

Insulin Resistance Insulin Level


Beta-cell failure

10

15

20

25

30

Years of Diabetes

Adapted from International Diabetes Center (IDC Minneapolis, Minnesota

Postprandial glucose in normal, pre-diabetic and diabetic subjects


220

Plasma glucose (mg/dl)

200 180 Diabetes

160
140 120 100 Normoglycemia IGT

3
Harris MI Diabetes Care 1993; 16:

Time following meal (hrs)

Natural History of Type 2 Diabetes GD


N > 126 100-125 PP > 200 140-199

Insulin secretion
DM-2 TGT MGT Normal 50% 70-100% 150% 100%

< 100
< 100

< 140
< 140

Diabetes Obes Metab 1999; 1(1): S1

Natural History of Type 2 Diabetes


Insulin sensitivity
30% 50% 70% 100% DM-2 TGT MGT Normal

Insulin secretion
50% 70-100% 150% 100%

Diabetes Obes Metab 1999; 1(1): S1

Stages of type 2 Diabetes in relationship to 100 -cell function

75
Beta cell function (%)

50

IGT
25

Postprandial Hyperglycemia

Type 2 Diabetes Phase 1

Type 2 Diabetes Phase 2


2 6 10

Type 2 Diabetes Phase 3

0
- 12 - 10 -6 -2 0 14

Years from diagnosis hypoX-jsk-7-99

RESISTENSI INSULIN

SEKRESI INSULIN

GLUKOSA DARAH

Topik
FISIOLOGI TRANSPORT GLUKOSA* TRANSPORT GLUKOSA PD DM-2* FISIOLOGI SEKRESI INSULIN* SEKRESI INSULIN PADA DM-2* RESISTENSI INSULIN*

FISIOLOGI TRANSPORT GLUKOSA

Distribution of oral glucose to tissues of the body

Cherrington, A.D. Diabetes 1999; 48:1198-

ekstra sel

intra sel

glukosa

hidrofilik

membran sel lipofilik

ekstra sel

intra sel

glukosa

hidrofilik
GLUCOSE TRANSPORTER (GLUT) 1 - 7

membran sel lipofilik

pankreas/hepar

GLUT-2
Insulin dependent
Insulin independent
GLUCOSE TRANSPORTER (GLUT) 1 - 7

otot & lemak GLUT-4

ekstra sel

intra sel reseptor insulin

insulin

GLUT-4

membran sel lipofilik

Translokasi GLUT 4 dari penyimpanan intrasel ke permukaan sel


Reseptor Insulin Insulin Membran plasma Sinyal Intraselular Penyimpanan intraselular

Glukosa

Vesikel GLUT 4

Bergabung dengan Membran plasma

ekstra sel

intra sel reseptor insulin

insulin

GLUT-4

membran sel lipofilik

Insulin

Glucose

Insulin receptor

Synthesis GLUT 4 PPARg


+ RXR

mRNA

PPRE

transcription

promoter

Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

intra sel
ekstra sel insulin

reseptor insulin

insulin

insulin

GLUT-4

insulin membran sel lipofilik

FISIOLOGI

intra sel
ekstra sel insulin

reseptor insulin

insulin

insulin

GLUT-4

insulin membran sel lipofilik

DM-2

Translokasi GLUT 4 dari penyimpanan intrasel ke permukaan sel


Reseptor Insulin Insulin Membran plasma Sinyal Intraselular Penyimpanan intraselular

Glukosa

Vesikel GLUT 4

Bergabung dengan Membran plasma

FISIOLOGI SEKRESI INSULIN


Sel pankreas
Glucose
GLUT-2
Glucokinase

Glucose

G-6-P K+ATP

Metabolism
Signal (S) Secretory Granules ATP ADP

Depolarization

Ca++

Insulin Secretion

Rorsman,Renstrom 2003

Patterns of Insulin Response to IV Glucose: Non-Diabetic and Diabetic Individuals


IV Glucose Stimulus
Insulin Secretion
-10 -5 0 5

Phase
10 15 20 25 30 35

1ST

Phase
40 45 50 55 60 65 70 75 80

2ND

Non-Diabetic

85 9

Insulin Secretion

Type 2 Diabetes

-10 -5

10

15 20 25 30 35 40 45 50 55 60

65 70 75 80 85 9

Time

Insulin secretion profiles in Type 2 diabetic patients and healthy people


800

Insulin secretion (pmol/min)

700 600 500 400 300 200

Healthy people Type 2 diabetic patients

100
6am
Polonsky KS. Et al., 1988

10am

2pm

6pm

10pm

2am

6am

Time

Insulin sensitif

Resistensi Insulin

Natural History of Type 2 Diabetes


Insulin sensitivity
30% 50% 70% 100%

Insulin secretion DM-2 TGT


MGT Normal 50% 70-100% 150% 100%

Diabetes Obes Metab 1999; 1(1): S1

TNF
3

*
GO

Hak, Lemieux ATVB 1999

Insulin sensitive (normal)


Insulin

FFA + gliserol
HSL

Insulin receptor

+ -

TG

PPARg +RXR

Gi
+

Fat Cells
Catecholamines PGEs Adenosine

Modified from Diabetes, Obesity and Metabolism, 3 (Supp.1), 2001, S11-S19.

Obesity & Insulin resistance


Insulin

FFA + gliserol
HSL

Insulin receptor

+ -

TNF-
PPARg +RXR

TG

Gi
+

Fat Cells
Catecholamines PGEs Adenosine

Modified from Diabetes, Obesity and Metabolism, 3 (Supp.1), 2001, S11-S19.

back
Evans JL. Diabetes 2003

TNF IL-6
TG* Glukoneogenesis*
Hak, Lemieux ATVB 1999

TNF
LPL

HSL

IL-6
TG

FFA
back
Hak, Lemieux ATVB 1999

INSULIN
GLIKOGEN
GLIKOGEN SINTASE

back back

Produksi Glukosa Hati

TNF

TNF-R

Ins-R

Kinase serin

IRS

PI3K
Kahn, Atlas of diabetes 2000
Evans JL. Diabetes 2003

FFA

Translokasi

Transkripsi

Insulin resistance
Insulin

Glucose

Insulin receptor

X Synthesis GLUT 4
PPARg +RXR mRNA

PPRE

transcription

promoter

Coding reg

back
Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

INSULIN
GLIKOGEN
GLIKOGEN SINTASE

GLUT-4

HGP

INSULIN
GLIKOGEN
GLIKOGEN SINTASE

GLUT-4

HGP

Development of Type 2 Diabetes


INSULIN RESISTANCE

Impaired Beta-Cell Function

Insulin Resistance Hyperinsulinemia Normal Glucose Tolerance Insulin Resistance Declining Insulin Levels Impaired Glucose Tolerance

Type 2 Diabetes
Adapted from Diabetes 1996;45:1661

Evans JL. Diabetes 2003

PPARg agonist Regulation of FFA release from TG in Fat Cells


Insulin

FFA + gliserol
HSL

Insulin receptor

+ -

TNF-
PPARg +RXR
Pio

TG

Gi
+

Fat Cells
Catecholamines PGEs Adenosine

Modified from Diabetes, Obesity and Metabolism, 3 (Supp.1), 2001, S11-S19.

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