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 3

2. Peripheral Insulin Resistance- Induced Hyperinsulinemia has Adverse Downstream Effects Insulin Metabolic pathway (PI3K) Mitogenic pathway (MAPK) Proliferation, ENDOTHELIAL DYSFUCTION, INFLAMMATION Glucose transport Glykogen synthese Hyperglycemia Hyperinsulinemia Insulin- Resistance

3. INACTIVITY,DIET INFLAMMATION, OXIDATIVE STRESS INCREASED PAI-1,NFKB,MMPS, ROS,AP-1,Egr-1 FFAs

4. Abnormalities seen with IR/ Compensatory Hyperinsulinemia: Risk Factors for ASVD

6. Insulin Resistance a.Increased liver production sugar b.Decreased peripheral Glucose Uptake c.Increased production FFA from Adipose tissue (alternate fuel source) 1.But potential for Maladaptive Effects of IR on Body if A. Biologic Clock Dysfunction B Peripheral IR causes HYPERINSULINEMIA- increases MAP-kinase pathway- cytokines, etc inc ASCVD risk factors C. Visceral Adipose tissue- 1. excessive FFA release, decrease b-cell function= lipotoxicity in genetically susceptible perrson, inc. risk/severity DM 2. adipocytokines increase inflammation, endothelial dysfunction

7. Insulin Resistance Related to Visceral Fat: Normal vs. Type 2 Diabetes NormalType 2 Diabetes Fujimoto, et al. Obes Res. 1994;2:364-371.

8. The Adipocytokine Syndrome: A New Model for Insulin Resistance and ß- Cell Dysfunction Pancreas FFA, TNF  Leptin

10. Flatbush diabetes

11. Insulin Resistance a.Increased liver production sugar b.Decreased peripheral Glucose Uptake c.Increased production FFA from Adipose tissue (alternate fuel source) 1.But potential for Maladaptive Effects of IR on Body if A. Biologic Clock Dysfunction B Peripheral IR causes HYPERINSULINEMIA- increases MAP-kinase pathway- cytokines, etc inc ASCVD risk factors C. Visceral Adipose tissue- 1. excessive FFA release, decrease b-cell function= lipotoxicity in genetically susceptible perrson, inc. risk/severity DM 2. adipocytokines increase inflammation, endothelial dysfunction