Insulin resistance, diabetes, and the adipocyte.

Abstract

The etiology, natural history, and relationship of insulin resistance to type 2 diabetes mellitus and the effects of insulin-sensitizing agents are described. Insulin resistance results from a combination of genetic and environmental factors and contributes to type 2 diabetes mellitus, dyslipidemia, hypertension, central (abdominal) obesity, and cardiovascular disease. Insulin resistance does not necessarily progress to impaired glucose tolerance or diabetes because insulin secretion by normal pancreatic beta cells can increase to compensate for reduced physiological activity. Diabetes may develop in insulin-resistant persons with inherited secretory and glucose-sensing defects in beta cells. The pathogenesis of diabetes appears to involve a progressive decrease in beta-cell mass, potentially triggered by abnormalities in adipocytokine release from intraabdominal fat cells. Metformin and the thiazolidinediones are used to treat insulin resistance, but their actions differ. Metformin reduces free-fatty-acid efflux from fat cells, thereby suppressing hepatic glucose production, and indirectly improves peripheral insulin sensitivity and endothelial function. Thiazolidinediones improve peripheral insulin sensitivity by reducing circulating free fatty acids but also by suppressing adipocytokines, which increase insulin resistance. Thiazolidinediones also improve endothelial function and may prevent or delay the onset of diabetes. Insulin is intrinsically antiatherogenic but may mediate arterial inflammation in insulin-resistant patients. Unlike metformin, the thiazolidinediones suppress this inflammatory pathway and may indirectly help preserve beta-cell function. Insulin resistance, resulting from a combination of genetic and environmental factors, plays a central role in type 2 diabetes mellitus. Diabetes may develop in insulin-resistant persons with inherited secretory and glucose-sensing defects in beta cells. Metformin and thiazolidinediones are insulin-sensitizing agents with different mechanisms of action and effects in patients with type 2 diabetes mellitus.