Advances in diabetes for the millennium: understanding insulin resistance.

Type 2 diabetes is a heterogeneous disorder in which both insulin resistance and impaired insulin secretion play important roles. Studies in monozygotic twins in which one is discordant for type 2 diabetes and studies of first-degree relatives of patients with type 2 diabetes who still have normal glucose tolerance indicate that impaired insulin secretion can be detected before insulin resistance, suggesting that impaired beta-cell function may be the primary genetic defect. The insulin resistance found in most individuals with impaired glucose tolerance and/or type 2 diabetes appears to be largely acquired and can be accounted for by obesity, physical inactivity, and glucose and lipotoxicity. Progressive deterioration in beta-cell function as demonstrated in the United Kingdom Prospective Diabetes Study (UKPDS) and/or worsening of insulin resistance leads to deterioration in glucose tolerance and to secondary failure of oral antidiabetic drugs. Therefore, agents that improve beta-cell function (such as sulfonylureas and meglitinides) and insulin sensitizers (such as metformin and thiazolidinediones) both are useful alone or in combination for treating type 2 diabetes.