Pathogenesis of insulin resistance in skeletal muscle.

Muhammad A Abdul-Ghani,Ralph A Defronzo

doi:10.1155/2010/476279

Abstract

Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Recent studies have reported a mitochondrial defect in oxidative phosphorylation in skeletal muscle in variety of insulin resistant states. In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle.

Highlights

Skeletal muscle is the major site for disposal of ingested glucose in lean healthy normal glucose tolerance (NGT) individuals [1,2,3,4]
The recent studies have reported the existence of a defect in mitochondrial oxidative phosphorylation in skeletal muscle in insulin resistance states [16,17,18,19,20] and suggest that this mitochondrial defect contributes to the increased intramyocellar fat content
A defect in the insulin signaling cascade at the level of insulinreceptor substrate (IRS)-1 is likely the primady defect that leads to insulin resistance in skeletal muscle

Summary

Introduction

Skeletal muscle is the major site for disposal of ingested glucose in lean healthy normal glucose tolerance (NGT) individuals [1,2,3,4]. The postprandial hyperglycemia stimulates insulin secretion from the pancreas and the rise in plasma insulin concentration stimulates glucose uptake in skeletal muscle leading to the disposal of ingested glucose [1,2,3,4]. In insulin resistance states, such as T2DM and obesity, insulin-stimulated glucose disposal in skeletal muscle is markedly impaired [1,2,3,4,5,6]. The recent studies have reported the existence of a defect in mitochondrial oxidative phosphorylation in skeletal muscle in insulin resistance states [16,17,18,19,20] and suggest that this mitochondrial defect contributes to the increased intramyocellar fat content. In this paper we will summarize the evidence that supports the existence of insulin resistance in skeletal muscle, the cellular mechanism(s) that lead to the development of insulin resistance, and the clinical consequences of insulin resistance in skeletal muscle

Normal Skeletal Muscle Metabolism

Insulin Resistance in Skeletal Muscle

Mitochondrial Defect in Insulin Resistance

Cellular Mechanism of Insulin Resistance

Findings

Summary