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Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes

Patients with insulin resistance and type 2 diabetes (T2DM) commonly exhibit elevated plasma free fat acid (FFA) and muscle fat (triglyceride) levels, which may either represent inborn errors of regulation of lipid metabolism, obesity, insulin resistance of adipose tissue or defective insulin secretion with an elevated rate of lipolysis. Alternatively, accumulation of different fat species in the circulation and tissues in T2DM may occur due to an impairment of oxidation of FFAs by the mitochondria (Petersen et al. 2005). Since the ground-breaking studies by Sir Philip Randle documenting the substrate competition between oxidation of fat and glucose, with phosphofructokinase and pyruvate dehydrogenase enzyme activities playing a key role (Randle et al. 1963), the ‘glucose fatty acid cycle’ and elevated FFA levels have been thought to play an important role in insulin resistance. Indeed, inhibition of lipolysis and FFA levels using a nicotinic acid derivative markedly improved in vivo peripheral insulin action including both oxidative and non-oxidative glucose metabolism in T2DM (Vaag et al. 1991). The extent to which increased availability of plasma FFA levels in itself impairs proximal insulin signalling transduction in healthy subjects is controversial (Storgaard et al. 2004). To this end, studies have suggested various additional, parallel or complementary mechanisms by which fatty acids adversely affect muscle insulin action and glucose uptake including degree of saturation and chain length of fatty acids as well as the conversion of fatty acids to the potentially deleterious lipid species ceramide and diaglycerol. Recent data have emerged that mitochondrial overload and limited capacity of the enzyme carnitine palmitoyl-transferase-1 (CPT-1) to transport cytosolic long-chain acyl CoA into the mitochondria may be involved in the development of fat-induced insulin resistance due to the accumulation of incompletely oxidized lipid intermediates (Koves et al. 2008).