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

Amanda R Martins,William T Festuccia,Rafael H Lambertucci,Leonardo R Silveira,Sandro M Hirabara,Rui Curi,Renato T Nachbar,Maria F Cury-Boaventura,Renata Gorjao,Marco A Vinolo

doi:10.1186/1476-511x-11-30

Abstract

Insulin resistance condition is associated to the development of several syndromes, such as obesity, type 2 diabetes mellitus and metabolic syndrome. Although the factors linking insulin resistance to these syndromes are not precisely defined yet, evidence suggests that the elevated plasma free fatty acid (FFA) level plays an important role in the development of skeletal muscle insulin resistance. Accordantly, in vivo and in vitro exposure of skeletal muscle and myocytes to physiological concentrations of saturated fatty acids is associated with insulin resistance condition. Several mechanisms have been postulated to account for fatty acids-induced muscle insulin resistance, including Randle cycle, oxidative stress, inflammation and mitochondrial dysfunction. Here we reviewed experimental evidence supporting the involvement of each of these propositions in the development of skeletal muscle insulin resistance induced by saturated fatty acids and propose an integrative model placing mitochondrial dysfunction as an important and common factor to the other mechanisms.

Highlights

Insulin resistance is broadly defined as the reduction in insulin ability to stimulate glucose uptake from body peripheral tissues
Mechanisms underlying the insulin resistance induced by saturated fatty acids Competition between fatty acids and glucose: the randle cycle The first mechanistic explanation for the inverse relationship between fatty acids availability and glucose utilization was proposed by Randle et al [13]
Mitochondrial dysfunction plays a central role in the fatty acid-induced insulin resistance As discussed above, several mechanisms have been proposed to explain the insulin resistance induced by saturated fatty acids. All these mechanisms operate in coordinated, integrated manner linking fatty acids availability to skeletal muscle insulin resistance. To account for this multifactorial characteristic of saturated fatty acid actions, we propose an integrative model centered on mitochondrial dysfunction as an important factor in the genesis of insulin resistance induced by fatty acids (Figure 1)

Summary

Introduction

Insulin resistance is broadly defined as the reduction in insulin ability to stimulate glucose uptake from body peripheral tissues. Evidence points for an important role of fatty acids in the genesis of the mitochondrial dysfunction associated with obesity and type 2 diabetes mellitus In this sense, lipid infusion or administration of high-fat diet to health human and rodents were associated with impaired mitochondrial function characterized by a reduction in ATP synthesis, oxygen consumption and oxidative phosphorylation [16,75,138,139]. Lipid infusion or administration of high-fat diet to health human and rodents were associated with impaired mitochondrial function characterized by a reduction in ATP synthesis, oxygen consumption and oxidative phosphorylation [16,75,138,139] These findings were corroborated by in vitro studies in which treatment of cultured skeletal muscle cells with palmitic acid increased ROS production, impaired fatty acid oxidation and decreased PGC-1 expression [103,104,140,141]. We proposed a unifying hypothesis that places the importance of mitochondria in the establishment of FFA-induced insulin resistance

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