The role of lipids in the pathogenesis of muscle insulin resistance and beta cell failure in type II diabetes and obesity

This review considers evidence for, and putative mechanisms of, lipid-induc ed muscle insulin resistance. Acute free fatty acid elevation causes muscle insulin resistance in a few hours, with similar muscle lipid accumulation as accompanies more prolonged high fat diet-induced insulin resistance in r odents. Although causal relations are not as clearcut in chronic human insu lin resistant states such as obesity and type 2 diabetes, it is now recogni sed that muscle lipids also accumulate in these states. The classic Randle glucose-fatty acid cycle is only one of a number of mechanisms by which fat ty acids might influence muscle glucose metabolism and insulin action. A ke y factor is seen to be accumulation of muscle long chain acyl CoAs, which c ould alter insulin action via several mechanisms including chronic activati on of protein kinase C isoforms or ceramide accumulation. These interaction s are fundamental to understanding metabolic effects of new insulin "sensit izers", eg thiazolidinediones, which alter lipid metabolism and improve mus cle insulin sensitivity in insulin resistant states. Recent work has also p ointed to a possible role of lipids in beta cell deterioration ("lipotoxici ty") associated with type 2 diabetes.