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

The insulin resistance associated with NIDDM appears to be caused by decreased insulin binding in conjunction with a significant postreceptor defect in insulin action. In the untreated state, the postreceptor defect appears to be the predominant lesion and the magnitude of this postreceptor defect appears to correlate directly with the degree of fasting hyperglycemia in individual patients. In vitro studies using isolated adipocytes suggest that the postreceptor defect in insulin action resides at the level of the glucose transport system. Insulin treatment ameliorates the postreceptor defect in insulin action which suggests that it is an acquired defect secondary to some aspect of the altered metabolic state. Therapy with the second-generation sulfonylurea compound glyburide enhances overall insulin responsiveness without altering insulin binding. Prevailing insulin levels are increased markedly during glyburide therapy but do not correlate with the clinical response, which suggests that the improvement in target tissue insulin action is the critical determinant in terms of the clinical response to the drug. In vitro studies utilizing cultured human fibroblasts indicate that glyburide increases the number of cell-surface insulin receptors and opposes insulin-mediated down-regulation.