Treatment of insulin resistance with peroxisome proliferator–activated receptor γ agonists

Insulin resistance is a characteristic feature of most patients with type 2 diabetes mellitus and is almost a universal finding in type 2 diabetic patients who are overweight (1–3). The presence of insulin resistance leads to increased β-cell insulin secretion with compensatory hyperinsulinemia (1–3). As long as the hyperinsulinemia is adequate to overcome the insulin resistance, glucose tolerance remains normal. In patients destined to develop type 2 diabetes, the β-cell compensatory response declines, and relative, or absolute, insulin insufficiency develops. At this point, insulin secretion cannot keep pace with the underlying insulin resistance, and glucose intolerance and eventually frank type 2 diabetes occur. Based on these observations it is evident that, except for very unusual patients, type 2 diabetes only develops in the context of insulin resistance plus β cell dysfunction. Although there is still some debate as to whether the insulin resistance or the β-cell defect comes first, most epidemiologic studies have indicated that in the early, prediabetic state, insulin resistance is the antecedent abnormality (4, 5).