Insulin resistance differentially affects the PI 3-kinase– and MAP kinase–mediated signaling in human muscle
Kenneth Cusi, … , C. Ronald Kahn, Lawrence J. Mandarino
Kenneth Cusi, … , C. Ronald Kahn, Lawrence J. Mandarino
Published February 1, 2000
Citation Information: J Clin Invest. 2000;105(3):311-320. https://doi.org/10.1172/JCI7535.
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Article

Insulin resistance differentially affects the PI 3-kinase– and MAP kinase–mediated signaling in human muscle

Abstract

The broad nature of insulin resistant glucose metabolism in skeletal muscle of patients with type 2 diabetes suggests a defect in the proximal part of the insulin signaling network. We sought to identify the pathways compromised in insulin resistance and to test the effect of moderate exercise on whole-body and cellular insulin action. We conducted euglycemic clamps and muscle biopsies on type 2 diabetic patients, obese nondiabetics and lean controls, with and without a single bout of exercise. Insulin stimulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, as measured by phosphorylation of the insulin receptor and IRS-1 and by IRS protein association with p85 and with PI 3-kinase, was dramatically reduced in obese nondiabetics and virtually absent in type 2 diabetic patients. Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. Exercise 24 hours before the euglycemic clamp increased phosphorylation of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI 3-kinase association with IRS-1 upon insulin stimulation. Thus, insulin resistance differentially affects the PI 3-kinase and MAP kinase signaling pathways, and insulin-stimulated IRS-1–association with PI 3-kinase defines a key step in insulin resistance.

Authors

Kenneth Cusi, Katsumi Maezono, Abdullah Osman, Merri Pendergrass, Mary Elizabeth Patti, Thongchai Pratipanawatr, Ralph A. DeFronzo, C. Ronald Kahn, Lawrence J. Mandarino

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Effect of exercise on subsequent insulin stimulation of the association ...
Effect of exercise on subsequent insulin stimulation of the association of p85 protein (a) and PI 3-kinase activity (b) with IRS-1. Obese (n = 7) and diabetic (n = 10) subjects underwent euglycemic clamps with muscle biopsies twice: 1 time without prior exercise and again 24 hours after a single 1-hour bout of moderate exercise. Homogenates of muscle biopsy specimens were immunoprecipitated with an antibody directed against IRS-1. Immunoprecipitates were alternatively analyzed for p85 protein by subsequent immunoblot analysis or for PI 3-kinase activity (for details see the text). Basal values are shown as open bars, and insulin-stimulated values are shown as filled bars. Data were expressed relative to IRS-1 content and are given as percent of the mean insulin-stimulated value in the lean control subjects. Data are presented as means ± SEM. *P < 0.05 versus basal values; †P < 0.05 versus lean control values.