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

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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    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 wholebody 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.

    Original languageEnglish (US)
    Pages (from-to)311-320
    Number of pages10
    JournalJournal of Clinical Investigation
    Volume105
    Issue number3
    DOIs
    StatePublished - Feb 2000

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    ASJC Scopus subject areas

    • Medicine(all)

    Cite this

    Cusi, K., Maezono, K., Osman, A., Pendergrass, M., Patti, M. E., Pratipanawatr, T., DeFronzo, R. A., Kahn, C. R., & Mandarino, L. J. (2000). Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. Journal of Clinical Investigation, 105(3), 311-320. https://doi.org/10.1172/JCI7535