Pathogenesis of insulin resistance in skeletal muscle

Muhammad A Abdul-Ghani, Ralph A DeFronzo, Muhammad A Abdul-Ghani, Ralph A DeFronzo

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.

Figures

Figure 1
Figure 1
Dose-response curve relating the plasma insulin concentration to the rate of insulin mediated wgole body glucose uptake in controls and type 2 diabetic subjects. *P < .01 (from [21]).
Figure 2
Figure 2
Insulin-stimulated whole body glucose uptake measured with the euglycemic clamp in lean healthy and type 2 diabetic subjects (left) and time course of change in leg glucose uptake in type 2 diabetic and control subjects (right) (from [5]).
Figure 3
Figure 3
Insulin-stimulated glucose disposal (40 mU/m2·min euglycemic insulin clamp) in lean healthy control (CON) subjects, lean drug naïve type 2 diabetic subjects (T2DM), lean normal-glucose-tolerant (NGT) hypertensive subjects (HTN), NGT hypertriglyceridemic subjects, and nondiabetic subjects with coronary artery disease (CAD). The open portion of the bar represents nonoxidative glucose disposal (glycogen synthesis) and the solid portion represents glucose oxidation. See DeFronzo and Ferrannini [80], DeFronzo [81].
Figure 4
Figure 4
Insulin signal transduction system in normal glucose tolerant subjects (see text for a detailed discussion).
Figure 5
Figure 5
In insulin resistant individuals insulin signaling is impaired at the level of IRS-1 leading to decreased glucose transport/phosphorylation/metabolism and impaired nitric oxide synthase activation/endothelial function. Increased intramycellar fat and fatty acid meyabolite content and mitochondrial dysfunction also exist in skeletal muscle in insulin resistant individuals (see text for a detailed discussion).

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