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Am J Med. 1981 Jan;70(1):151-68.

Mechanisms of insulin resistance in obesity and noninsulin-dependent (type II) diabetes.

Abstract

Insulin resistance is a characteristic feature of both obesity and noninsulin-dependent diabetes mellitus. In general, the causes of insulin resistance can be placed into three categories: (1) abnormal beta cell secretory products, (2) circulating insulin antagonists, and (3) target tissue defects in insulin action. In obesity and in noninsulin-dependent diabetes mellitus, the cause of the insulin resistance resides at the level of the target tissue. However, the specific mechanisms underlying these insulin-resistant states are heterogeneous. Mechanisms of insulin resistance can be evaluated by constructing in vivo dose-response curves using the euglycemic glucose clamp technique. If dose-response curves are shifted to the right with no impairment in maximal insulin action, then this is termed a decrease in "insulin sensitivity" and is consistent with a pure defect in insulin receptors. If a decrease in maximal insulin action exists, then this is termed a decrease in "insulin responsiveness" and is consistent with a postreceptor defect in insulin action. In obese patients, cellular insulin receptors are decreased and the magnitude of this decrease is inversely related to the degree of hyperinsulinemia. In those patients with only moderate hyperinsulinemia, the insulin resistance is not severe. In these patients, the in vivo dose-response curve between plasma insulin levels and glucose disposal demonstrates a rightward shift with no change in maximal insulin responsiveness. Thus, in this situation, insulin resistance is due to decreased insulin receptors only. In obese patients with more severe insulin resistance, decreased maximal insulin responsiveness is also seen indicating a combined receptor and postreceptor defect. In patients with non-insulin-dependent diabetes mellitus, the same phenomenon is observed; i.e., those patients with mild insulin resistance have decreased insulin sensitivity due to decreased insulin receptors whereas those with severe insulin resistance have decreased insulin sensitivity and decreased insulin responsiveness due to a combined receptor and postreceptor defect. When the spectrum of patients is examined, a continuum of defects exists. In patients with mild insulin resistance, decreased insulin receptors are the only abnormality; in patients with severe insulin resistance, decreased numbers of insulin receptors and the postreceptor defect in insulin action coexist, but the postreceptor defect is the predominant abnormality. Between these extremes the relative roles of receptor defects and postreceptor defects vary, but the general trend is that as insulin resistance worsens, the postreceptor defect becomes more prominant.

PMID:
7006388
[Indexed for MEDLINE]
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