title: The role of lipids in the pathogenesis of muscle insulin resistance and beta cell failure in type II diabetes and obesity.
abstract: This review considers evidence for, and putative mechanisms of, lipid-induced 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 rodents. Although causal relations are not as clearcut in chronic human insulin resistant states such as obesity and type 2 diabetes, it is now recognised 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 fatty acids might influence muscle glucose metabolism and insulin action. A key factor is seen to be accumulation of muscle long chain acyl CoAs, which could alter insulin action via several mechanisms including chronic activation of protein kinase C isoforms or ceramide accumulation. These interactions are fundamental to understanding metabolic effects of new insulin "sensitizers", e.g. thiazolidinediones, which alter lipid metabolism and improve muscle insulin sensitivity in insulin resistant states. Recent work has also pointed to a possible role of lipids in beta cell deterioration ("lipotoxicity") associated with type 2 diabetes.
authors.affiliation: Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, Australia. e.Kraegen@garvan.org.au
authors.forename: E W
authors.initials: EW
authors.lastname: Kraegen
authors.forename: G J
authors.initials: GJ
authors.lastname: Cooney
authors.forename: J M
authors.initials: JM
authors.lastname: Ye
authors.forename: A L
authors.initials: AL
authors.lastname: Thompson
authors.forename: S M
authors.initials: SM
authors.lastname: Furler
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D006801:Humans; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000503:physiopathology*; D008055:Lipids / Q000502:physiology*; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009765:Obesity / Q000503:physiopathology*
chemical_list: D008055:Lipids