The role of mitochondria in the pathophysiology of skeletal muscle insulin resistance

Abstract

Multiple organs contribute to the development of peripheral insulin resistance, with the major contributors being skeletal muscle, liver, and adipose tissue. Because insulin resistance usually precedes the development of type 2 diabetes mellitus (T2DM) by many years, understanding the pathophysiology of insulin resistance should enable development of therapeutic strategies to prevent disease progression. Some subjects with mitochondrial genomic variants/defects and a subset of lean individuals with hereditary predisposition to T2DM exhibit skeletal muscle mitochondrial dysfunction early in the course of insulin resistance. In contrast, in the majority of subjects with T2DM the plurality of evidence implicates skeletal muscle mitochondrial dysfunction as a consequence of perturbations associated with T2DM, and these mitochondrial deficits then contribute to subsequent disease progression. We review the affirmative and contrarian data regarding skeletal muscle mitochondrial biology in the pathogenesis of insulin resistance and explore potential therapeutic options to intrinsically modulate mitochondria as a strategy to combat insulin resistance. Furthermore, an overview of restricted molecular manipulations of skeletal muscle metabolic and mitochondrial biology offers insight into the mitochondrial role in metabolic substrate partitioning and in promoting innate adaptive and maladaptive responses that collectively regulate peripheral insulin sensitivity. We conclude that skeletal muscle mitochondrial dysfunction is not generally a major initiator of the pathophysiology of insulin resistance, although its dysfunction is integral to this pathophysiology and it remains an intriguing target to reverse/delay the progressive perturbations synonymous with T2DM.

Figure 1

Mitochondrial role in the development of insulin resistance and T2DM. This schematic shows primary mitochondrial defects to the left of the hatched line in the center of the cell and the development of mitochondrial deficits in response to environmental cues and aging to the right of the hatched line. In primary disruption in the mitochondrial metabolic capacity, FAO is diminished, fat intermediates accumulate and DAG, which appears to be the primary intermediate that then activates protein kinase C isoforms. These in turn phosphorylate and inactivate numerous kinase substrates in the insulin signaling pathway. The reduced insulin sensitivity exacerbates the metabolic perturbations by reducing glucose uptake and possibly by further down-regulation of the mitochondrial biogenesis program. The etiologies of primary mitochondrial defects are labeled 1–3. The etiologies of secondary disruption of mitochondrial dysfunction are labeled 4–7. High-fat diet can promote mitochondrial biogenesis; alternatively nutrient overload, which may include both glucose and fats, enhances both lipid intermediates that facilitate oxidative damage and impair insulin signaling. Furthermore, the nutrient overload presents excess reducing equivalents to the ETC that can result in increased ROS generation. The oxidative damage, in turn, disrupts the mitochondrial oxidative capacity, which then recapitulates the phenotype of primary mitochondrial deficits promoting insulin resistance. Ox PHOS, Mitochondrial oxidative phosphorylation.

Figure 2

Adaptive and maladaptive consequences of the molecular modulation of skeletal muscle mitochondrial biology determine overall insulin resistance. A, Skeletal muscle-restricted knockdown of mitochondrial regulatory proteins that exhibit adaptive augmentation of glycolysis, glucose oxidation, and possibly uncoupled respiration resulting in the overall improvement in insulin sensitivity and resilience to fat-induced lipid accumulation. B, Skeletal muscle-restricted overexpression of mitochondrial regulatory proteins and the skeletal muscle-restricted knockdown of a fatty acid transporter that result in the exacerbation of insulin resistance. C, Induction of various regulatory and functional mitochondrial proteins that improve insulin sensitivity. The myokines secreted by skeletal muscle are in response to the skeletal muscle-restricted deletion of PGC-1α and inducible Akt1, respectively. The myokines then moderate additional peripheral metabolic tissues to enhance insulin sensitivity. TFAM, Transcription factor A of mitochondria; FGF, fibroblast growth factor; FFA, free fatty acid; FA, fatty acid; Ox PHOS, mitochondrial oxidative phosphorylation.