Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function

Insulin resistance is broadly defined as the reduction in insulin ability to stimulate glucose uptake from body peripheral tissues. At physiological conditions, insulin activates glucose uptake by stimulating the canonical IRS-PI3K-Akt pathway and by phosphorylating and inactivating Akt substrate 160 (AS160), a protein that, when activated, prevents glucose transporter (GLUT) 4 translocation to the membrane. Thus, by inhibiting AS160, insulin promotes the GLUT4 translocation from inner vesicules, promoting fusion to the plasma membrane and consequently glucose uptake [1].Although insulin resistance is a key component of several chronic syndromes associated with obesity such as type 2 diabetes mellitus and metabolic syndrome, the involved factors and their underlying mechanisms linking excessive adiposity to insulin resistance were not completely elucidated yet [2-5]. Evidence suggests that fatty acids, whose circulating levels are markedly increased in obesity and associated-diseases, might play a role in the development of skeletal muscle insulin resistance [6,7]. In this sense, prolonged exposure of skeletal muscle and myocytes to high levels of fatty acids leads to severe insulin resistance [8,9]. Among the different types of fatty acids, saturated long-chain fatty acids such as palmitic and stearic acids were demonstrated to be potent inducers of insulin resistance [5,10]. Several mechanisms have been suggested by us [2,5,11,12] and others [6,8,13-16] to explain how saturated fatty acids impair insulin actions such as the Randle cycle, accumulation of intracellular lipid derivatives (diacylglycerol and ceramides), oxidative stress, modulation of gene transcription, inflammation and mitochondrial dysfunction. In the present review, we discuss evidence supporting the involvement of these mechanisms in the regulation of insulin sensitivity by saturated fatty acids and propose the mitochondrial dysfunction found in conditions of elevated fatty acid levels has a cent