IR and Hyperinsulinemia Insulin Resistance: A Survival Mechanism, Gone Awry Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical.

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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. Part 3

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

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

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

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

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

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

Flatbush diabetes

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