Insulin resistance in noninsulin-dependent diabetes mellitus: Impact of sulfonylurea agents in vivo and in vitro

Abstract

Insulin resistance is a characteristic feature of noninsulin-dependent diabetes mellitus (NIDDM). Although abnormal beta-cell secretory products and circulating insulin antagonists can cause insulin resistance, the available evidence indicates that patients with NIDDM are insulin-resistant secondary to defects in target tissue insulin action. Abnormalities of cellular insulin action can be divided into two general categories; that is, receptor defects and postreceptor defects. The relative contributions of these various defects to the overall in vivo insulin-resistant state can be assessed by examining the contour of the dose-response curve for in vivo insulin action in conjunction with an assessment of cellular insulin binding. If the dose-response curve is shifted to the right without a decrease in the maximal insulin effect, this is consistent with an isolated receptor defect and is termed “decreased sensitivity.” A decrease in maximal insulin effect indicates the presence of a postreceptor defect in insulin action and is termed “decreased responsiveness.” Patients with impaired glucose tolerance and NIDDM exhibit decreased insulin binding and are insulin-resistant with the severity of the insulin resistance paralleling the degree of carbohydrate intolerance. Examination of the dose-response relationship for in vivo insulin action in these patients reveals that the patients with impaired glucose tolerance manifest only decreased sensitivity with a rightward shift of their dose-response curve and no alteration in their maximal response. This finding is consistent with their insulin resistance resulting solely from the observed decrease in insulin binding (receptor defect). The patients with NIDDM display both a rightward shift in their dose-response curve and a decrease in the maximal response; that is, these patients exhibit both decreased sensitivity and decreased responsiveness consistent with a combined receptor and postreceptor defect. A direct relationship exists between the degree of fasting hyperglycemia and the magnitude of the postreceptor defect. Thus, the insulin resistance associated with abnormal carbohydrate tolerance comprises a spectrum with the least insulin-resistant patients having an isolated receptor defect, while the more insulin-resistant patients exhibit a combined receptor and postreceptor defect with the postreceptor defect representing the predominant lesion in the most insulin-resistant patients. Additional in vivo studies indicate that the postreceptor defect in insulin action is in some way secondary to the relative insulin deficiency in the untreated state since it is ameliorated by a brief course of intense insulin therapy. Preliminary results indicate that a three-month period of therapy with the second-generation sulfonylurea glyburide led to improved glycemic control and improvement of the postreceptor defect in insulin action independent of the drug's effects upon endogenous insulin secretion. In vitro studies demonstrate that cultured human fibroblasts possess specific cell-surface insulin receptors with characteristics similar to those of other cell types studied previously in terms of internalization of bound insulin, insulin-mediated down-regulation, and receptor regeneration. The characteristics of insulin binding are similar in fibroblasts obtained from control subjects and NIDDM patients indicating that the decreased insulin binding seen in NIDDM patients when using freshly isolated tissues is most likely due to the altered metabolic milieu rather than genetic factors. The presence of the second-generation sulfonylurea glyburide in the incubation media leads to an increase in the number of cell-surface receptors which appears to be the result of inhibition of the process of insulin-induced receptor down-regulation.