IR and Hyperinsulinemia

Insulin Resistance: Insulin Resistance:

A Survival Mechanism, Gone AwryA Survival Mechanism, Gone Awry

Stan Schwartz MD,FACPAffiliate, Main Line Health System

Emeritus, Clinical Associate Professor of Medicine, U of Pa.

stschwar@gmail.com

Part 3

Peripheral Insulin Resistance- Induced Hyperinsulinemia

has Adverse Downstream Effects

Insulin

Met

abol

ic p

athw

ay

(PI3

K)M

itogenic pathway

(MAPK)

Proliferation, ENDOTHELIAL DYSFUCTION, INFLAMMATION

Glucose transportGlykogen syntheseHyperglycemia

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 Resistancea.Increased liver production sugarb.Decreased peripheral Glucose Uptakec.Increased production FFA from Adipose tissue (alternate fuel source)

1. But potential for Maladaptive Effects of IR on Body ifA. Biologic Clock DysfunctionB 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= lipotoxicityin genetically susceptible perrson, inc. risk/severity DM2. adipocytokines increase inflammation, endothelial dysfunction

Insulin Resistance Related to Visceral Fat:Normal vs. Type 2 Diabetes

Normal Type 2 Diabetes

Fujimoto, et al. Obes Res. 1994;2:364-371.

The Adipocytokine Syndrome: A New Model for Insulin Resistance and ß-

Cell Dysfunction

Pancreas

FFA, TNF Leptin

Flatbush diabetes

Insulin Resistancea.Increased liver production sugarb.Decreased peripheral Glucose Uptakec.Increased production FFA from Adipose tissue (alternate fuel source)

1. But potential for Maladaptive Effects of IR on Body ifA. Biologic Clock DysfunctionB 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= lipotoxicityin genetically susceptible perrson, inc. risk/severity DM2. adipocytokines increase inflammation, endothelial dysfunction