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

TLDR

Insulin‑resistant glucose metabolism in skeletal muscle of type 2 diabetes patients indicates a proximal defect in insulin signaling. The study aimed to identify insulin‑resistance–compromised pathways and assess moderate exercise effects on whole‑body and cellular insulin action. Euglycemic clamps and muscle biopsies were performed in type 2 diabetics, obese nondiabetics, and lean controls, with and without a single exercise bout. Insulin stimulation of the PI 3‑kinase pathway was markedly impaired in obese nondiabetics and absent in type 2 diabetics, whereas MAP kinase signaling remained normal; glucose disposal correlated with IRS‑1–p85 association, and a single exercise bout increased insulin‑receptor and IRS‑1 phosphorylation but did not restore PI 3‑kinase activity or glucose uptake, highlighting that IRS‑1–PI 3‑kinase association is a key step in insulin resistance.

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.