Pathogenesis of Insulin Resistance in Skeletal Muscle

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.

The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes

“…Insulin resistance of skeletal muscle is a major metabolic feature in obesity and a key factor in the pathogenesis of type 2 diabetes [1]. The underlying molecular mechanisms are complex and still incompletely understood.…”

“…The underlying molecular mechanisms are complex and still incompletely understood. Insulin signalling is impaired at several levels [1,2], but whether these changes are primary or secondary to the metabolic changes remains unclear [2]. Inflammation and cytokine signalling appear to be important, and recent studies have linked insulin resistance with mitochondrial dysfunction.…”

The Prevention and Treatment of Type 2 Diabetes Mellitus with a Plant-Based Diet

“…Skeletal muscle is the major site for disposal of ingested glucose in lean, healthy, normal-glucose-tolerant people [22][23][24][25][26]. Following a meal, approximately one third of ingested glucose is taken up by the liver and the rest by peripheral tissues, primarily skeletal muscle, via an insulin dependent mechanism [22][23][24][25][26].…”

“…Following a meal, approximately one third of ingested glucose is taken up by the liver and the rest by peripheral tissues, primarily skeletal muscle, via an insulin dependent mechanism [22][23][24][25][26]. 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 [22][23][24][25][26]. In insulin resistant states, such as type 2 diabetes and obesity, insulin stimulated glucose disposal in skeletal muscle is markedly impaired [22][23][24][25][26][27][28].…”

Of rodents and men: Species-specific glucose regulation and type 2 diabetes research

“…Skeletal muscle comprises the primary site of glucose clearance in humans, accounting for 50%-90% of glucose uptake, making it the primary insulin-sensitive tissue and the primary site of dysregulation in human peripheral insulin resistance (Shulman et al, 1990;DeFronzo and Tripathy, 2009;Koistinen and Zierath, 2002;Abdul-Ghani and DeFronzo, 2010). By contrast, liver is the primary site of glucose clearance in rodents, with 5 to 10-fold higher glycogen storage in the liver in rodents versus ~10-fold more glycogen storage in muscle than in liver in humans (Ivy, 1999;Kasuga et al, 2003).…”