Content area
Full Text
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/l 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/l) 3-Omethylglucose 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
Intense 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/l induces a translocation of GLUT4 from an intracellular storage site to the plasma membrane in skeletal muscle from healthy individuals (18,19). Conversely, a similar 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...