1. Genetic Predisposition Environmental Factors Obesity TYPE 2 DIABETES
Normal -cells
Defective -cells
Insulin Resistance
Hyperinsulinemia with
Normal Glucose Tolerance
Impaired Glucose Tolerance
≥ 65% -cell defect
TYPE 2 DIABETES
Figure A1.

2. Insulin sensitivity (SI)
Minimal Model
Glucose
levels
Insulin sensitivity (SI)
Β-cell response
Insulin
levels
Insulin injection
Glucose injection
Figure A2.

3. Figure A3.

4. Week 0 Week 2 Week 4 Secretion Week 6 Insulin Sensitivity 2500 2000
1500
Week 6
Secretion
1000
500 1 2 3 4 5 6 7 8
Insulin Sensitivity
Figure A4.

5. Cause of Hyperinsulinemia? Conventional wisdom:
Insulin Resistance
Figure A4
Figure A5
Cause of Hyperinsulinemia?
Conventional wisdom:
Increased fasting glycemia
and/or impaired glucose tolerance
Hyperinsulinemia
(Increased secretion,
Reduced clearance)
Figure A5.

6. Insulin GLP-1 Glucose GH FFA Cortisol
BASELINE
6 WKS FAT FEEDING
300
9.0 * *
Insulin *
200
6.0 pM pM
100 * *
3.0 *
GLP-1 *
0.0
125
4.0
Glucose
mg/dL
ng/mL
100 *
2.0 GH 75
0.0
8.0
1.0 *
FFA * * * * * * * * * *
0.8
6.0
Cortisol * *
0.6 *
μg/mL mM
4.0 *
0.4
2.0
0.2
0.0
0.0
6am 9
12pm 3
6pm 9
12am 3
6am
6am 9
12pm 3
6pm 9
12am 3
6am
Figure A6.

7. AND INTERSTITIAL FLUID
INSULIN IN PLASMA
AND INTERSTITIAL FLUID
Hand-in-glove relationship between interstitial insulin and glucose disposal
Plasma
Lymph
Insulin Levels
Glucose Uptake 2 4 6 10 60
240
360
Time (minutes)
120
180
300 8
Lymph Insulin (uU/ml) 20 30 50 40 Rd
Glucose disposal
Figure A7.

8. Plasma Interstitial fluid Glucose uptake into cells
Insulin injection
INSULIN
[μU/ml]
Plasma
INSULIN
[μU/ml]
Interstitial fluid
Glucose uptake
into cells
GLUCOSE DISPOSAL
[mg/kg per min]
Figure A8.

9. Glucose Flux (mg/min per kg) Glucose Flux (mg/min per kg)4 8 12 16
UPTAKE 30 60 90
120
150
180
INSULIN
3.33 mU/min per kg
Glucose Flux (mg/min per kg)
Time (minutes) 30 60 90
120
150
180 -1 1 2 3 4
Glucose Flux (mg/min per kg)
Time (minutes)
LIVER OUTPUT
INSULIN
3.33 mU/min per kg
HGO
NHGO Rd
Figure A9.

10. Figure A10.

11. Transendothelial transport barrier
Insulin
FFA
adipocytes
GLUCOSE PRODUCTION
Figure A11.

12. Week 0 Week 6 Dog 1 Dog 2 Dog 3 Dog 435
Week 0
Week 6 * * * * * * 30
Dog 1
Body Weight (kg) 25
Dog 2 20 -2 2 4 6
Weeks on diet
1000 *
Dog 3
750
+110%
Body Fat (cm3) *
500
Omental
250
+115%
Dog 4
SubQ
Figure A12.
Week 0
Week 6

13. FFA Visceral Fat Resistant Liver PEPCK G6Pase SREBP1 FABP TNF- IL-6
Leptin
Adiponectin
PPAR
SREBP-1
HSL
LPL
Slide 45 Changes in gene expression
Figure A13.

14. β3-blockade Free Fatty Acids Figure A14. 0.4 0.3 0.2 0.1 0.4 0.3 0.2

15. FFA “Pulsatile Lipolysis” “Constitutive Lipolysis” GH TSH, PTH ANP
Glucocorticoids
“intrinsic”
Figure A15.