Muscle damage impairs insulin stimulation of IRS-1, PI 3-kinase, and Akt-kinase in human skeletal muscle

Luis F. Del Aguila, Raj K. Krishnan, Jan S. Ulbrecht, Peter A. Farrell, Pamela H. Correll, Charles H. Lang, Juleen R. Zierath, John P. Kirwan

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101 Scopus citations

Abstract

Physiological stress associated with muscle damage results in systemic insulin resistance. However, the mechanisms responsible for the insulin resistance are not known; therefore, the present study was conducted to elucidate the molecular mechanisms associated with insulin resistance after muscle damage. Muscle biopsies were obtained before (base) and at 1 h during a hyperinsulinemic-euglycemic clamp (40 mU · kg-1 · min-1) in eight young (age 24 ± 1 yr) healthy sedentary (maximal O2 consumption, 49.7 ± 2.4 ml · kg-1 · min-1) males before and 24 h after eccentric exercise (ECC)-induced muscle damage. To determine the role of cytokines in ECC-induced insulin resistance, venous blood samples were obtained before (control) and 24 h after ECC to evaluate ex vivo endotoxin-induced mononuclear cell secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Glucose disposal was 19% lower after ECC (P < 0.05). Insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation was 45% lower after ECC (P < 0.05). Insulin-stimulated phosphatidylinositol (PI) 3-kinase, Akt (protein kinase B) serine phosphorylation, and Akt activity were reduced 34, 65, and 20%, respectively, after ECC (P < 0.05). TNF-α, but not IL-6 or IL-1β production, increased 2.4-fold 24 h after ECC (P < 0.05). TNF-α production was positively correlated with reduced insulin action on PI 3-kinase (r = 0.77, P = 0.04). In summary, the physiological stress associated with muscle damage impairs insulin stimulation of IRS-1, PI 3-kinase, and Akt-kinase, presumably leading to decreased insulin-mediated glucose uptake. Although more research is needed on the potential role for TNF-α inhibition of insulin action, elevated TNF-α production after muscle damage may impair insulin signal transduction.

Original languageEnglish (US)
Pages (from-to)E206-E212
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume279
Issue number1 42-1
DOIs
StatePublished - Jan 1 2000

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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    Del Aguila, L. F., Krishnan, R. K., Ulbrecht, J. S., Farrell, P. A., Correll, P. H., Lang, C. H., Zierath, J. R., & Kirwan, J. P. (2000). Muscle damage impairs insulin stimulation of IRS-1, PI 3-kinase, and Akt-kinase in human skeletal muscle. American Journal of Physiology - Endocrinology and Metabolism, 279(1 42-1), E206-E212. https://doi.org/10.1152/ajpendo.2000.279.1.e206