1. EXERCISE PREVENTION Helmich, S.P. et al. New England J Medicine 325:147-152, 199 Incidence Rates of type 2 (/ 10,000 man-years

2. Regular Walking Decreases Morbidity Rates by 50% in Diabetics Gregg, E.W., Arch Intern Med 163:1440-1447, 2003

3. Boule, N.G. et al JAMA 286:1218-1227, 2001. Exercise Groups Control Groups

4. Boule, N.G. et al JAMA 286:1218-1227, 2001. Exercise GroupsControl Groups

5. INSULIN SENSITIVITY Glucose Uptake (mg/m 2 /min) * Landt, et al, Diabetes Care 8:461-465, 1985 Wallberg-Henriksson et al., Am J Clinical Nutrition 249:C233-C237, 1985 Yki-Jarvinen et al, Diabetes Care 7:520-527, 1984.

9. IRS-1 IRS-2 IRS-3 IRS-4 PI 3 K PIP 3 AKT-1 AKT-2 AKT-3 Glucose Uptake Cell Differentiation ↑Protein Synthesis ↓Gluconeogenesis ↑Glucose Synthesis GLUT4 Glucose

10. IRS-1IRS-2IRS-3IRS-4 PI 3 K PIP 3 AKT-1 AKT-2 AKT-3 Glucose Uptake Cell Differentiation ↑Protein Synthesis ↓Gluconeogenesis ↑Glucose Synthesis GLUT4 Glucose

11. IRS-1IRS-2IRS-3IRS-4 PI 3 K PIP 3 AKT-1 AKT-2 AKT-3 Glucose Uptake Cell Differentiation ↑Protein Synthesis ↓Gluconeogenesis ↑Glucose Synthesis GLUT4 Glucose AMPK

12. Table 1. Summary of clinical trials in diabetes and micro- and macro-vascular disease. VariableDCCTUKPDSSterno-2ADVANCEVADTACCORD Purpose Micro/macrovascular complications:  Retinopathy  neuropathy Micro/macrovascular Complications in newly diagnosed type 2 diabetics Macrovascular complications in microalbuminuric pts.  Retinopathy  Nephropathy  Neuropathy  Ischemic stress tests Vascular outcome in broad range of DM2 Cardiovascular complications Cardiovascular events of DM2 with cardiovascular risk or disease Years Recruit 1983-1989 Follow-up 1993 Recruit 1997-1991 Follow-up 2008 Recruit 1992-1993 Follow-up 1996-7 2001-2003 Recruit 2000-? Follow-up 2008 Recruited 2001 Subject Number1441407516011,1401,791 10,251 Type of DiabetesDM1DM2 Medications Metformin primary med. Added OHA and insulins of goals were not achieved Gliclazine primary med. Added OHA and insulins of goals were not achieved Individualized therapeutic discretion of primary physician Insulin C=Intermediate + rapid (BID) I=Insulin pumps (TID)  “insulins”  Conventional therapy  NPH added to OHAs  Regular + NPH (BID) added to OHAs Rapid @ meals“insulins” added last Insulin only Insulin + 4-5 OHAs OHA  Sulfonylurea +  Metfomin  Metformin (BID)  Gliclazide (BID) added OHAs  Gliclazide  Other OHAs added  Metformin or  Glimiperide  Rosiglitazone added All OHAs in multiples – up to 5 Outcome ↓ 76% risk of retinopathy ↓ 54% progression of retinopathy ↓ 47% development of proliferative or severe non-prolif retinopathy ↓ 39% microalbuminuria ↓ 54% albuminuria ↓ 60% clinical neuropathy ↓ CV events Slows  progression to nephropathy  progression of retinopathy  progression of neuropathy ↓ risk of CV death ↓ 21% nephropathy ↔ retinopathy ↔ CV events Terminated early at 3.5 years because of CV mortality was 257 in I vs. 203 in C. Key: DCCT Diabetes Control and Complication Trial UKPDS UK Prospective Diabetes Study Sterno 2 Type 2 diabetes study at the Sterno Diabetes Center ADVANCE Action in Diabetes and Vascular Disease Preterax and Dlacmioron Modified Release Control Education VADT Veterans Affairs Diabetes Trial ACCORD Action to Control Cardiovascular Risk in Diabetes OHA Oral Hypoglycemic Agent DM1 & DM2 Type 1 & Type 2 Diabetes Mellitus C Control Group I Intervention Group NPH Intermediate Acting Insulin (Neutral Protamine Hagedorn) BID Twice a day TID Three times a day

13. MUSCLE BLOOD FLOW Katz, M. and N. Janjan. Diabetes 27:726-731, 1978 Resistance (mmHg/ml min/100 g Filtration (dl/min mmHg/100 g Capacity (ml/100g)

14. MUSCLE BLOOD FLOW Wallberg-Henriksson et al., Am J Clinical Nutrition 249:C233- C237, 1985 Wallberg-Henriksson, et al, Diabetes 33:851-857, 1984 Capillaries/Fiber

17. SIGNS AND SYMPTOMS OF HYPOGLYCEMIA Apathy SweatingExcessive Hunger DrowsyFainting Convulsions Dizziness FatigueCrying Hand Tremors IrritabilityBlurred Vision Confusion DelusionDouble Vision Headache Slurred SpeechUnsteady Gait Nervousness Poor Coordination Inability to concentrate Loss of Consciousness SIGNS AND SYMPTOMS OF HYPOGLYCEMIA Apathy SweatingExcessive Hunger DrowsyFainting Convulsions Dizziness FatigueCrying Hand Tremors IrritabilityBlurred Vision Confusion DelusionDouble Vision Headache Slurred SpeechUnsteady Gait Nervousness Poor Coordination Inability to concentrate Loss of Consciousness