Mitochondrial Dysfunction, Insulin Resistance, and Potential Genetic Implications

Abstract

Insulin resistance (IR) is fundamental to the development of type 2 diabetes (T2D) and is present in most prediabetic (preDM) individuals. Insulin resistance has both heritable and environmental determinants centered on energy storage and metabolism. Recent insights from human genetic studies, coupled with comprehensive in vivo and ex vivo metabolic studies in humans and rodents, have highlighted the critical role of reduced mitochondrial function as a predisposing condition for ectopic lipid deposition and IR. These studies support the hypothesis that reduced mitochondrial function, particularly in insulin-responsive tissues such as skeletal muscle, white adipose tissue, and the liver, is inextricably linked to tissue and whole body IR through the effects on cellular energy balance. Here we discuss these findings as well as address potential mechanisms that serve as the nexus between mitochondrial malfunction and IR.

Keywords: insulin resistance; lipid accumulation; mitochondrial dysfunction; prediabetes; type 2 diabetes.

Figure 1.

Mechanism of sn-1,2 DAG-PKCθ/PKCε-mediated skeletal muscle IR. Increase in sn-1,2 DAGs caused by reduced mitochondrial function and fatty acid oversupply activates PKCθ and PKCε, leading to serine phosphorylation of IRS-1 and increased threonine phosphorylation of the insulin receptor on threonine 1160. Both of these in turn result in inhibition of insulin-induced PI3K/Akt2 activity. As a consequence, insulin-induced translocation of GLUT4 to the plasma membrane, glucose uptake, and glycogen synthesis are decreased. Abbreviations: DAG, diacylglycerol; GLUT4, glucose transporter type 4; GS, glycogen synthase; IRS, insulin receptor substrate; PCK, protein kinase C; PI3K, phosphoinositide-3-kinase; NAT2, N-acetyltransferase 2.

Figure 2.

Mechanism of sn-1,2 DAG-PKCε-mediated hepatic IR. Accumulation of sn-1,2 DAGs promote a translocation of PKCε to the plasma membrane, and PKCε phosphorylates insulin receptor at Threonine 1160, inhibiting insulin receptor kinase activity. Lowered insulin-stimulated PI3K/Akt activity leads to decreased insulin-stimulated glycogen synthesis through a reduction of GSK3/GS activity, and decreased insulin inhibition of gluconeogenesis through a reduction of FOXO1 phosphorylation. Increased FOXO1 nuclear translocation promotes transcription of gluconeogenic enzymes such as PEP-CK and G6P. Thus, DAG inhibits a direct effect of insulin on suppressing hepatic glucose production by inhibiting insulin-stimulated hepatic glycogen synthesis and increasing insulin-mediated transcription of gluconeogenic enzymes. Insulin action on WAT also indirectly regulates hepatic glucose production. In insulin resistant WAT, insulin inhibition of lipolysis is decreased, resulting in increased lipolysis and fatty acid and glycerol fluxes. Increased delivery of fatty acids to the liver leads to an increase in hepatic acetyl-CoA content and PC activity, promoting hepatic gluconeogenesis. Increased glycerol flux to the liver fosters a conversion of glycerol to glucose. Abbreviations: DAG, diacylglycerol; FOXO1, transcription factor forkhead box O1; G6P, glucose-6-phosphatase; GS, glycogen synthase; GSK3, glycogen synthase kinase 3; IRS, insulin receptor substrate; NAT2, N-acetyltransferase 2; PC, pyruvate carboxylase; PCK, protein kinase C; PEP-CK, Phosphoenolpyruvate carboxykinase; PI3K, phosphoinositide-3-kinase; WAT, white adipose tissue.