Agonist: the case for insulin resistance as a necessary and sufficient cause of type II diabetes mellitus.
The results of many cross-sectional studies have indicated that insulin resistance is a consistent, abnormal metabolic characteristic of people with NIDDM. Recently many investigators studying different populations have reported that insulin resistance is a prediabetic abnormality and is a major risk factor for the disease. Although deficient insulin secretion is also characteristic of people with NIDDM, there are no data to indicate that it precedes the onset of the disease, except in rare instances of families with glucokinase mutations. Therefore, in most cases, it appears that deficient insulin secretion occurs secondarily to insulin resistance, and there is experimental evidence indicating the mechanism of this effect. The clearest examples of this pathophysiologic mechanism are persons with insulin receptor mutations and severe insulin resistance in whom NIDDM develops despite normal insulin secretion. In addition, prospective studies have indicated that NIDDM rarely develops in the most insulin-sensitive subjects, and the relatively lower insulin concentrations in patients with a known beta-cell defect--that is a glucokinase mutation--are compatible with normal glucose tolerance if ideal whole body insulin sensitivity is maintained. These data indicate beyond a reasonable doubt that insulin resistance is a sufficient cause of NIDDM and in most instances is necessary for its development.
Bogardus
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Clinical Diabetes and Nutrition Section, NIH, NIDDK, Phoenix, AZ 85016, USA.
D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000209:etiology*; D006801:Humans; D007333:Insulin Resistance; D012307:Risk Factors