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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.

SUBMITTER: Pagel-Langenickel I

PROVIDER: S-EPMC2852205 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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

Pagel-Langenickel Ines I Bao Jianjun J Pang Liyan L Sack Michael N MN

Endocrine reviews 20091027 1

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 w ...[more]

PMID: 19861693

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Project description:ObjectiveMetabolic derangements, including insulin resistance and hyperlactatemia, are a major complication of major trauma (e.g., burn injury) and affect the prognosis of burn patients. Protein farnesylation, a posttranslational lipid modification of cysteine residues, has been emerging as a potential component of inflammatory response in sepsis. However, farnesylation has not yet been studied in major trauma. To study a role of farnesylation in burn-induced metabolic aberration, we examined the effects of farnesyltransferase (FTase) inhibitor, FTI-277, on burn-induced insulin resistance and metabolic alterations in mouse skeletal muscle.MethodsA full thickness burn (30% total body surface area) was produced under anesthesia in male C57BL/6 mice at 8 weeks of age. After the mice were treated with FTI-277 (5 mg/kg/day, IP) or vehicle for 3 days, muscle insulin signaling, metabolic alterations and inflammatory gene expression were evaluated.ResultsBurn increased FTase expression and farnesylated proteins in mouse muscle compared with sham-burn at 3 days after burn. Simultaneously, insulin-stimulated phosphorylation of insulin receptor (IR), insulin receptor substrate (IRS)-1, Akt and GSK-3β was decreased. Protein expression of PTP-1B (a negative regulator of IR-IRS-1 signaling), PTEN (a negative regulator of Akt-mediated signaling), protein degradation and lactate release by muscle, and plasma lactate levels were increased by burn. Burn-induced impaired insulin signaling and metabolic dysfunction were associated with increased inflammatory gene expression. These burn-induced alterations were reversed or ameliorated by FTI-277.ConclusionsOur data demonstrate that burn increased FTase expression and protein farnesylation along with insulin resistance, metabolic alterations and inflammatory response in mouse skeletal muscle, all of which were prevented by FTI-277 treatment. These results indicate that increased protein farnesylation plays a pivotal role in burn-induced metabolic dysfunction and inflammatory response. Our study identifies FTase as a novel potential molecular target to reverse or ameliorate metabolic derangements in burn patients.

Dataset Information

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

Publications

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

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