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We examined the effect of physiological hyperinsulinemia on insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and phosphatidylinositol (PI) 3-kinase activity in skeletal muscle from six lean-to-moderately obese NIDDM patients and six healthy subjects. A rise in serum insulin levels from ~60 to ~650 pmol/1 increased IRS-1 tyrosine phosphorylation sixfold over basal levels in control muscle (P < 0.01), whereas no significant increase was noted in NIDDM muscle. The reduced IRS-1 phosphorylation in the NIDDM muscle was not related to changes in IRS-1 protein content, since IRS-1 protein expression was similar between control and NIDDM subjects (16.0 ± 1.7 vs. 22.9 ± 4.0 arbitrary units/mg protein for control and NIDDM, respectively; NS). Physiological hyperinsulinemia increased PI 3-kinase activity in control muscle twofold (P < 0.01), whereas no increase in insulin-stimulated PI 3-kinase activity was noted in the NIDDM muscle. Furthermore, in vitro insulin-stimulated (600 pmol/1) 3-0-methylglucose transport was 40% lower in isolated muscle from NIDDM subjects (P < 0.05). The present findings couple both reduced insulin-stimulated IRS-1 tyrosine phosphorylation and PI 3-kinase activity to the impaired insulin-stimulated glucose transport in skeletal muscle from lean-to-moderately obese NIDDM subjects. Diabetes 46:524-527, 1997 I ntense interest has focused on whether the reduced insulin-mediated glucose transport in muscle from NIDDM patients results from alterations in the insulin signal transduction pathway (1-12) or from alterations in the traffic and/or translocation of GLUT4 to the plasma membrane (12-18). Recently, we have shown that an increase in fasting serum insulin levels from -50 to -600 pmol/1 induces a translocation of GLUT4 from an intracellular storage site to the plasma membrane in skeletal muscle from healthy individuals (18,19 increase in insulin levels did not alter the plasma membrane GLUT4 content in muscle biopsies from NIDDM patients (18), providing evidence for a defect in insulin signaling and/or GLUT4 translocation in muscle from NIDDM patients.Evidence from animal studies suggests that insulin signaling defects in muscle are associated with altered whole-body glucose homeostasis (2-5). In morbidly obese humans (6) and obese rodents (2-5), impaired insulin-stimulated glucose transport in skeletal muscle is associated with decreased insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) protein content, decreased IR and IRS-1 phosphorylation, and reduced PI 3-kinase activity. Tumor necrosis factor (TNF)-a has been implicated to play a role in development of insulin resistance in obesity by increasing the serine phosphorylation of IR and IRS-1 (10). In contrast to the obese state, in hyperglycemic-hypoinsulinemic states, such as in the streptozotocin-induced diabetic rat, IR and IRS-1 phosphorylation and PI 3-kinase activity are enhanced in skeletal muscle (2,3), despite reduced insulin-stimulated glucose transport (20).Reduced IR phosphorylation has been observed in skel...