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 1

2. Traditional View: Natural History of Type 2 Diabetes IR phenotype Atherosclerosis obesity hypertension  HDL,  TG, HYPERINSULINEMIA Endothelial dysfunction PCO,ED Envir.+ Other Disease Obesity (visceral) Poor Diet Inactivity Insulin Resistance Risk of Dev. Complications ETOH BP Smoking Eye Nerve Kidney  Beta Cell Secretion Genes Blindness Amputation CRF Disability MI CVA Amp Age 0-1515-40+15-50+25-70+ Macrovascular Complications IGT Type II DM Microvascular Complications DEATH pp>7.8

4. EPIGENITICSEPIGENITICS Pathogenic, β-Cell-Centric Construct for All Diabetes Implications for Classification, Diagnosis, Prevention, Therapy, Research Inflammatory; Abnormal Immune Modulation β-Cell secretion/mass Polygenic- other Monogenic (HLA) Polygenic Monogenic - MODY − Mitochondrial Resistance (obesity) inflammatory adipokines Resistance-(obesity)- FFA Poor diet, inactivity Non Inflammatory Environmental Inflam. Triggers eg: viral,endocrine disruptors, food AGE’s, biome Gene EPIGENITICSEPIGENITICS endocrine disruptors, food AGE’s,biome Environmental Triggers PHENOTYPE

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

6. Insulin Resistance- Provide Substrate for the Brain 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. D. adipocytokines increase inflammation, endothelial dysfunction

7. 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. D. adipocytokines increase inflammation, endothelial dysfunction

8. Central Insulin Resistance (IR) a.Increased liver production sugar b.Decreased peripheral Glucose Uptake c.Increased production FFA from Liver and 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: translates to IR all day long

12. Day Night