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 2

2. Insulin Resistance a.Increased liver production sugar b.Decreased peripheral Glucose Uptake c.Increased production FFA from Adipose tissue (alternate fuel source) 1.Normal Response to Hibernation, Migration, Periods of Food lack!! BUT ALSO, Normal DIURNAL VARIATION IN INSULIN SENSITIVITY 2. Centrally Induced IR Exacerbated by: obesity, high fat diets, high CHO diets, abnormal sleep cycle, decreased exercise, 3. Also Associated with Abnormal Gut Microbiome

3. And OCCURS DIURNALLY as well Adaptive Mala-adaptive Exacerbated by: obesity, high fat diets, high CHO diets, abnormal sleep cycle, decreased exercise

4. ADAPTIVE IR MAL-ADAPTIVE IR

5. Poor Diet/ Inactivity--Walking the dog Courtesy Jim Sowers

7. HI FAT, Hi CHO Diet Suppress dopamine surge in SCN AM Obesity, Dec. Exer, abn. Sleep cycles

8. Implications for Therapy  Treat Central Mechanisms IR  Treat Peripheral IR- fat, liver, muscle  Treat Inflammation  Treat Biome

9. 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

10. Insulin Roles Based on Nature of Insulin Receptors Signaling Pathways