Insulin resistance differentially affects the PI3-kinase- and MAP kinase-mediated signaling in human muscle

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 compromi sed in insulin resistance and to test the effect of moderate exercise on wh ole-body and cellular insulin action. We conducted euglycemic clamps and mu scle biopsies on type 2 diabetic patients, obese nondiabetics and lean cont rols, with and without a single bout of exercise. Insulin stimulation of th e phosphatidylinositol 3-kinase (PI 3-kinase) pathway, as measured by phosp horylation of the insulin receptor and IRS-1 and by IRS protein association with p85 and with PI 3-kinase, was dramatically reduced in obese nondiabet ics and virtually absent in type 2 diabetic patients. Insulin stimulation o f the MAP kinase pathway was normal in obese and diabetic subjects. Insulin stimulation of glucose-disposal correlated with association of p85 with IR S-1. Exercise 24 hours before the euglycemic clamp increased phosphorylatio n of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI S-kinase association with IRS-1 upon insulin stimulation. Thus, insulin resistance differentially affects the PI 3-kinas e and MAP kinase signaling pathways, and insulin-stimulated IRS-l-associati on with PI 3-kinase defines a key step in insulin resistance.