Cited by 154Mitochondrial Function and PathologyMetabolism, Diabetes, and CancerAdipose Tissue and Metabolism

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The Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance

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Pagel-Langenickel, Ines, Bao, Jianjun, Pang, Liyan, Sack, Michael N.·2010·Endocrine Reviews

DOI 10.1210/er.2009-0003PMC PMC2852205

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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.

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Authors: Pagel-Langenickel, I., Bao, J., Pang, L., & Sack, M. N.
Affiliations: Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1454
National Institutes of Health (US)
ORCID: Sack, Michael N.
Venue: Endocrine Reviews
Publisher: The Endocrine Society
Published: 2009-10-27
Volume: 31
Issue: 1
Pages: 25-51
ISSN: 0163-769X (ISSN-L)
1945-7189
DOI: 10.1210/er.2009-0003
PMC: PMC2852205
OpenAlex: W2161339546
Cited by: 154
References: 333
Citations by year: 2026: 6 · 2025: 5 · 2024: 6 · 2023: 6 · 2022: 5 · 2021: 3 · 2020: 13 · 2019: 7 · 2018: 8 · 2017: 8 · 2016: 11 · 2015: 7 · 2014: 15 · 2013: 17 · 2012: 11
FWCI: 0.94
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Endocrine Reviews (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Keywords: skeletal muscle insulin resistance, mitochondrial dysfunction, type 2 diabetes, peripheral insulin resistance, mitochondrial DNA variants, mitochondrial-targeted therapy, insulin sensitivity, skeletal muscle metabolism
MeSH terms: Animals, Diabetes Mellitus, Type 2, Humans, Insulin Resistance, Mitochondria, Muscle, Organ Specificity, Prediabetic State, Muscle, Skeletal, Metabolic Syndrome, Mitochondrial Diseases

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The Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance

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