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IR and Hyperinsulinemia

IR and Hyperinsulinemia. Insulin Resistance: A Survival Mechanism, Gone Awry. Part 1. Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa. stschwar@gmail.com. Traditional View: Natural History of Type 2 Diabetes.

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IR and Hyperinsulinemia

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

  2. Traditional View:Natural History of Type 2 Diabetes Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Obesity (visceral) Poor Diet Inactivity IR phenotypeAtherosclerosisobesityhypertensionHDL,TG, HYPERINSULINEMIA Endothelial dysfunctionPCO,ED Disability Insulin Resistance MICVAAmp pp>7.8 DEATH IGT Type II DM  Beta Cell Secretion BlindnessAmputationCRF EyeNerveKidney Risk of Dev. Complications ETOHBPSmoking Disability Microvascular Complications

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

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

  5. Insulin Resistance- Provide Substrate for the Brain • Increased liver production sugar • Decreased peripheral Glucose Uptake • Increased production FFA from Adipose tissue (alternate fuel source) • But potential for Maladaptive Effects of IR on Body if • A. Biologic Clock Dysfunction • B Peripheral IR causes HYPERINSULINEMIA- • increases MAP-kinase pathway- cytokines , • etcinc 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

  6. Insulin Resistance • Increased liver production sugar • Decreased peripheral Glucose Uptake • Increased production FFA from Adipose tissue (alternate fuel source) • But potential for Maladaptive Effects of IR on Body if • A. Biologic Clock Dysfunction • B Peripheral IR causes HYPERINSULINEMIA- • increases MAP-kinase pathway- cytokines , • etcinc 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. Central Insulin Resistance (IR) • Increased liver production sugar • Decreased peripheral Glucose Uptake • Increased production FFA from Liver and Adipose tissue (alternate fuel source) • 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

  8. Day Night

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