Muscle damage impairs insulin stimulation of IRS-1, PI 3-kinase, and Aktkinase in human skeletal muscle. Am J Physiol Endocrinol Metab 279: E206-E212, 2000.-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

more »

... (base) and at 1 h during a hyperinsulinemic-euglycemic clamp (40 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ) in eight young (age 24 Ϯ 1 yr) healthy sedentary (maximal O 2 consumption, 49.7 Ϯ 2.4 ml ⅐ kg Ϫ1 ⅐ min Ϫ1 ) 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)-␣, interleukin (IL)-6, and IL-1␤. Glucose disposal was 19% lower after ECC (P Ͻ 0.05). Insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation was 45% lower after ECC (P Ͻ 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 Ͻ 0.05). TNF-␣, but not IL-6 or IL-1␤ production, increased 2.4-fold 24 h after ECC (P Ͻ 0.05). TNF-␣ production was positively correlated with reduced insulin action on PI 3-kinase (r ϭ 0.77, P ϭ 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-␣ inhibition of insulin action, elevated TNF-␣ production after muscle damage may impair insulin signal transduction.