RESISTENSI INSULIN

RESISTENSI INSULIN HIPERINSULINEMIA

Toleransi Glukosa Normal

RESISTENSI INSULIN DEFEK SEKRESI INSULIN

TGT

GANGGUAN FUNGSI SEL β

1.Adapted from Diabetes 1996;45:16612.Evans JL. Diabetes 2003

TNF α

Evans JL. Diabetes 2003

Normal glucose metabolism

Impaired glucose metabolism

Type 2 diabetes

30%

70%

100%

50%

150%

100%

Diabetes Obes Metab 1999; 1(1): S1

IGT50% 70-100%

30%

70%

100%

50%

150%

100%

Diabetes Obes Metab 1999; 1(1): S1

50% 70-100%DM-2TGTMGT

go

hypoX-jsk-7-99

IGT Postprandial Hyperglycemia Type 2

DiabetesPhase 1 Type 2

DiabetesPhase 2

Type 2DiabetesPhase 3

- 12 - 10 - 6 - 2 0 2 6 10 14Years from diagnosis

Bet

a ce

ll fu

nctio

n (%

)Stages of type 2 Diabetes in relationship to Stages of type 2 Diabetes in relationship to

--cell functioncell function

25

0

50

75

100

back

GlucoseGlucose G-6-P

Glucokinase

Metabolism

Signal (S)

K+ATP

Depolarization

Ca++

SecretoryGranules

GLUT-2

Insulin Secretion

ATPATP___ADP

800

6am

Insulin secretion profiles in Type 2diabetic patients and healthy people

Insu

lin s

ecr

etio

n (

pmo

l/min

)

Time10am 2pm 6pm 10pm 2am 6am

700

600

500

400

300

200

100

Healthy people

Type 2 diabetic patients

Polonsky KS. Et al., 1988

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

InsulinInsulinSecretionSecretion 11STST

PhasePhase22NDND

PhasePhase

IV Glucose StimulusIV Glucose Stimulus

Non-DiabeticNon-Diabetic

Type 2 Type 2 DiabetesDiabetes

Time (minutes)Time (minutes)-10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90

-10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90

InsulinInsulinSecretionSecretion

GlucoseGlucose G-6-P

Glucokinase

Metabolism

Signal (S)

K+ATP

Depolarization

Ca++

SecretoryGranules

GLUT-2

Insulin Secretion

ATPATP___ADP

back

SIGNAL

Insulin sensitif

Resistensi Insulin

back

glukosa metabolisme

subkutis

viseral

otot

hatijantung

ektopik

CRPTNF α

Adp

Resistensi insulin

TNF α

TNFα-R

autofosforilasi tirosin

Ins-R

IRS

PI3K

Kahn, Atlas of diabetes 2000Evans JL. Diabetes 2003

Insulin sensitif

TNFα-R

TNFα

Kinase serin

Ins-R

IRS

PI3K

Kahn, Atlas of diabetes 2000Evans JL. Diabetes 2003

Resistensi Insulin

back

Khan CR. Atlas of Diabetes 2000

**

**

NORMALRESISTENSI INSULIN

Translokasi

Transkripsi

promoter Coding reg

transcription

mRNA

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

Synthesis GLUT 4

translocation

PPAR

PPRE

Insulinreceptor

Insulin

+ RXR

Glucose

PPAR

promoter Coding reg

+RXR

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

PPRE

Insulin

Insulin resistanceGlucose

mRNA

Synthesis GLUT 4

X

X

transcription

Insulinreceptor

backShepherd and Kahn. NEJM 1999; 341:248-257

INSULIN

GLIKOGEN SINTASE

Produksi Glukosa Hati

GLIKOGEN

GLUKOSA

back

Insulin

Gi

Insulinreceptor

FFA + gliserol

TG

HSL

CatecholaminesCatecholaminesPGEsPGEs

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

+

+

-

-

-

Insulin sensitive (normal)

PPAR+RXR

Fat Cells

Insulin

Gi

Insulinreceptor

TG

HSL

CatecholaminesCatecholaminesPGEsPGEs

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

+

+

-

-

-

-

-

Obesity & Insulin resistance

PPAR+RXR

TNF-α

Fat Cells

FFA + gliserol

A possible mechanism : pioglitazone restores insulinsensitivity through reduction of TNF-α and FFA

Biological activities

PPRE

IRS-1IRS-1

IRTK

Insulin

PI3KPI3K

TNFR

TNF-

SMaseCeramidePKC-

IRS-1-serinephosphorylation

RXR PPARγ

Pioglitazone

“Fatty acid steal ”

Fatty acyl CoAsFFA

FFA

DM tipe-2

Diabetes Care, 1999; 22:562

Insulin Resistance: Associated Conditions

Atherosclerosis

Type 2 diabetesImpaired

glucose tolerance

Polycysticovary disease

Obesity (central)

Dyslipidemia Hypertension

Acanthosisnigricans

Hyperuricemia

Decreasedfibrinolytic activity

InsulinResistance