Tissue-specific regulation of early steps in insulin action in septic rats

Sepsis is known to induce insulin resistance, but the exact molecular mecha nism involved is unknown. In the present study we have examined the levels and phosphorylation state of the insulin receptor and of insulin receptor s ubstrate 1 (IRS-1), as well as the association between IRS-1 and phosphatid ylinositol 3-kinase (PI 3-kinase) in the liver and muscle of septic rats by immunoprecipitation and immunoblotting with anti-insulin receptor, anti-IR S-1, anti-PI 3-kinase and anti-phosphotyrosine antibodies. There were no ch anges in the insulin receptor concentration and phosphorylation levels in t he liver and muscle of septic rats. IRS-1 protein levels were decreased by 40 +/- 3% (p < 0.01) in muscle but not in liver of septic rats. In samples previously immunoprecipitated with anti-IRS-1 antibody and blotted with ant iphosphotyrosine antibody, the insulin-stimulated IRS-1 phosphorylation lev els in the muscle of septic rats decreased by 38 +/- 5% (p < 0.01) and insu lin-stimulated IRS-I association with PI 3-kinase decreased by 44 +/- 7% in muscle (p < 0.01) but no changes were seen in liver. These data suggest th at there is a tissue-specific regulation of early steps of insulin signal t ransduction in septic rats, and the changes observed in muscle may have a r ole in the insulin resistance of these animals. (C) 2001 Elsevier Science I nc. All rights reserved.