Cellular mechanisms of insulin resistance in humans

Abstract

Carbon nuclear magnetic resonance ( 13C NMR) spectroscopy and phosphorus ( 31P) NMR spectroscopy have been used to help define the contribution of insulin-stimulated muscle glycogen synthesis to whole-body insulin-stimulated glucose metabolism in normal individuals and the extent to which this process is defective in patients with type 2 (non–insulin-dependent) diabetes. Assessments of the response to hyperglycemic–hyperinsulinemic clamping have shown that abnormalities of muscle glycogen synthesis, apparently mediated by a defect in GLUT-4 transport and/or hexokinase activity, play a major role in causing insulin resistance in type 2 diabetes. Studies of the mechanisms by which free fatty acids (FFA) cause insulin resistance in humans indicate that increased FFA levels inhibit glucose transport, which may be a consequence of decreased insulin receptor substrate (IRS-1)–associated phosphatidylinositol 3-kinase activity. 13C NMR spectroscopy studies have documented that liver glycogen concentrations are reduced and the rate of hepatic gluconeogenesis is increased in subjects with type 2 diabetes; thus, the higher rate of glucose production in type 2 diabetes can be attributed entirely to increased rates of hepatic gluconeogenesis. These cellular mechanisms of insulin resistance can be addressed through combination therapy with agents that reverse the principal pathophysiologic defects of type 2 diabetes. The biguanide metformin appears to lower glucose by suppressing hepatic glucose production, whereas the thiazolidinedione troglitazone appears to increase glucose clearance by peripheral tissues. The two agents together have been shown to provide better glucose control than either drug alone, without stimulating insulin secretion.