Evidence for a Primary Roie of Insulin Resistance in the Pathogenesis of Type 2 Diabetes

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Abstract
Although the primary defect(s) responsible for the development of type 2 diabetes still is unknown, several recent cross-sectional and longitudinal studies have clarified the sequence of events leading to type 2 diabetes. Relatives of type 2 diabetic patients, who have normal glucose tolerance, are characterized by hyperinsulinemia and insulin resistance compared to relatives with no family history of diabetes. In individuals with impaired glucose tolerance, insulin resistance is more severe than in those with normal glucose tolerance. The acute insulin response is lower in subjects with impaired glucose tolerance than in those with normal glucose tolerance but the decrease in the acute insulin response is similarly related to increases in plasma glucose as in normal subjects. A high postprandial insulin concentration, as well as the degree of insulin resistance, predicts the transition of glucose tolerance from impaired to diabetic. These data suggest that hyperinsulinemia and insulin resistance rather than insulin deficiency predict the subsequent development of type 2 diabetes in individuals genetically susceptible to the disease. As insulin resistance can be ameliorated with therapeutic measures such as weight loss and exercise, apparently healthy individuals with high insulin concentrations and a family history of type 2 diabetes might be regarded as a high-risk group which will require intensive attention from health care professionals.