1. IR and Hyperinsulinemia Insulin Resistance: A Survival Mechanism, Gone Awry Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa. stschwar@gmail.com Part 5

2. Implications for Therapy  Treat Central Mechanisms IR  Treat Peripheral IR- fat, liver, muscle  Treat Inflammation  Treat Biome Thus, Bromocriptine QR Pioglitazone, as only ‘viable’ TZD metformin (liver) (Probiotics) (anti-inflammatory Agents)

3. Focus on Targets Related To Insulin Resistance 1.Brain 2.Peripheral 3.Biome 4.Inflammation

4. Bromocryptine QR: Proposed mechanism of action Morning administration (within 2 hours of waking) of AGENT Corrects Restoration of morning peak in dopaminergic activity (via D2 receptor-mediated activity) Decreased postprandial glucose levels Reduction in insulin resistance Day-long reduction in plasma glucose, TGs and FFAs  Sympathetic tone  HPA axis tone  Hepatic gluconeogenesis  FFA and TG  Insulin resistance  Inflammation/hypercoagulation Low dopaminergic tone in hypothalamus in early morning in diabetes  Sympathetic tone  HPA axis tone  Hepatic gluconeogenesis  FFA and TG  Insulin resistance  Inflammation/hypercoagulation Impaired glucose metabolism, hyperglycemia and insulin resistance Adverse cardiovascular pathology 4 Fonseca. Use of Dopamine agonists in Type-2-Diabetes. Oxford American Pocket Cards. OUP, 2010 Cincotta. Hypothalamic role in Insulin Resistance and insulin Resistance Syndrome. Frontiers in Animal Diabetes Research Series. Taylor and Francis, Eds Hansen, B Shafrir, E London, pp 271-312, 2002

5. β cell-specific effects of (PPAR-γ ) agonists in type 2 diabetes mellitus

8. Potential Immunomodulatory Therapy to Prevent / Treat / Reverse Diabetes- (and not just Type 1D) www.thelancet.com Published online July 26, 2013 http://dx.doi.org/10.1016/SO140-6736(13)60591-7 A promising approach is the use of pharmacological agents, such as orally active chemical chaperones, which can stabilize protein conformation, improve ER folding capacity,and facilitate the trafficking of mutant proteins.110–113 Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2014:7 25–34 CLAUDIA CAVELTI-WEDER, Effects of Gevokizumab on Glycemia and Inflammatory Markers in Type 2 DiabetesDiabetes Care 35:1654–1662, 2012 C. Levitan,,Proposal for generating new beta cells in a muted immune environment for type 1 diabetes [cyclosporin/PPI] Diabetes Metab Res Rev 2013; 29: 604

9. Summary and Central Role for TZD Therapy Peripheral IR Peripheral IR Central IR Central IR Inflam- mation IR Inflam- mation IR Biome IR Biome IR TZD (Pioglitazone) Therapy Metformin Bromocriptine-QR Anti- Inflam. Pro- biotics Weight Reduction: Appetite suppressants