胰岛素抵抗 Defronzo.ppt

INSULIN RESISTANCE AND BETA CELL DYSFUNCTION: A DYNAMIC DUET RESPONSIBLE FOR T2DM
Ralph A. DeFronzo, MD
Professor of Medicine
Chief, Diabetes Division
UTHSC, San Antonio, TX
TREATMENT OF T2DM: A SOUND APPROACH BASED UPON ITS PATHOPHYSIOLOGY
Ralph A. DeFronzo, MD
Professor of Medicine
Chief, Diabetes Division
UTHSC, San Antonio, TX
THE TRIUMVIRATE
Impaired Insulin Secretion
Hyperglycemia
DecreasedGlucose
Uptake
Increased
HGP
DeFronzo RA, Diabetes 37:667-687, 1988
NATURAL HISTORY OF BETA CELL FAILURE IN T2DM
Beta cell failure occurs muchearlier in the natural history of type 2 diabetes and is more severe than previously appreciated
SAN ANTONIO METABOLISM AND VAGES STUDIES
SUBJECTS NUMBER
NGT 318
IGT 259
T2DM 201
Gastaldelli, Ferrannini, Abdul-Ghani, DeFronzo, Diabetologia 47:31-39, 2004;
JCEM 90:493-500, 2005, Diabetes 55:1430-35, 2006
METHODS: OGTT and Insulin Clamp
IGT
<160
<180
<200
<160
<180
<200
IGT
PLASMA GLUCOSE AND INSULIN AUC
0
4
8
12
Glucose AUC
(mmol/L120 min)
0
4
8
12
Insulin AUC
(pmol/L120 min)
CON
CON
T2DM
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
T2DM
IGT
<200
<160
<180
INSULIN SECRETION / INSULIN RESISTANCE
(DISPOSITION) INDEX DURING OGTT
30
20
10
0
40
∆ INS/ ∆ GLU ÷ IR
Lean
NGT
<100
<120
<140
Obese
2-Hour PG(mg/dl)
<240
<280
<360
<320
>400
<400
T2DM
FASTING PLASMA GLUCOSE (FPG) CONCENTRATION AND RELATIVE BETA CELL VOLUME IN OBESE SUBJECTS WITH NGT, IFG, & T2DM
Butler et al, Diabetes 52:102-110,2003
FPG
(mg/dl)
ß-cell Volume (%)
4
3
2
1
0
250
200
150
100
50
NGT
NGT
IFG
IFG
p<
p<
T2DM
T2DM
p<
p<
SUMMARY
Are maximally/near-maximally insulin resistant
Have lost ~80% of their beta cell function (DeFronzo)
Have lost significant beta cell mass (Butler)
Have an incidence of diabetic retinopathy of ~10%
Individuals with IGT:
PREVENTION OF BETA CELL FAILURE IN T2DM
Must intervene early (IGT/IFG)
Interventions should target pathogenic mechanisms k