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
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