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Am J Physiol Endocrinol Metab 279: E206-E212, 2000;
0193-1849/00 $5.00
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Vol. 279, Issue 1, E206-E212, July 2000

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

Luis F. Del Aguila1, Raj K. Krishnan1, Jan S. Ulbrecht2, Peter A. Farrell1, Pamela H. Correll3, Charles H. Lang4, Juleen R. Zierath5, and John P. Kirwan1

1 Noll Physiological Research Center and Departments of 2 Biobehavioral Health and Clinical Medicine, 3 Veterinary Science, and 4 Molecular and Cellular Physiology, The Pennsylvania State University, University Park, Pennsylvania 16802; and 5 Department of Clinical Physiology, Karolinska Hospital, Karolinska Institute, SE 171-76, Stockholm, Sweden

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)-alpha , interleukin (IL)-6, and IL-1beta . 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-alpha , but not IL-6 or IL-1beta production, increased 2.4-fold 24 h after ECC (P < 0.05). TNF-alpha 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-alpha inhibition of insulin action, elevated TNF-alpha production after muscle damage may impair insulin signal transduction.

tumor necrosis factor-alpha ; cytokines; signal transduction; stress diabetes; glucose uptake


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