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.

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

Figure A3.

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.

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.

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.

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.

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.

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.

Figure A10.

Transendothelial transport barrier Insulin FFA adipocytes GLUCOSE PRODUCTION Figure A11.

Week 0 Week 6 Dog 1 Dog 2 Dog 3 Dog 4 35 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

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.

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

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