Role of Glucose Transport in the Postreceptor Defect of Non-insulin-dependent Diabetes Mellitus

Abstract

In an attempt to elucidate the cellular mechanism(s) of the insulin resistance associated with impaired glucose tolerance (IGT) and non-insulin-dependent diabetes (NIDDM), insulin-sensitive glucose transport was studied employing isolated adipocytes obtained from these subjects using the nonmetabolized glucose analogue, 3-O-methyl glucose. In the subjects with IGT, basal and maximal rates of 3-O-methyl glucose uptake were normal while the responses at submaximal insulin concentrations were decreased, i.e., the dose-response curves were shifted rightward, indicative of decreased insulin sensitivity. In contrast, the dose-response curves for insulin-stimulated 3-O-methyl glucose uptake in adipocytes obtained from subjects with NIDDM were right-shifted and, in addition, there was a marked decrease in both the basal and maximally stimulated rates of glucose transport (i.e., decreased insulin responsiveness). Thus, the adipocytes from subjects with IGT show decreased insulin sensitivity consistent with decreased insulin binding, whereas the adipocytes from subjects with NIDDM exhibit both decreased insulin sensitivity and decreased insulin responsiveness consistent with a combined receptor and postreceptor defect in cellular insulin action. In the groups as a whole, the magnitude of the rightward shift in the dose-response curve for insulin-stimulated glucose transport correlated with the reduction in adipocyte insulin binding (r = 0.47, P < 0.02). In these subjects, the level of fasting hyperglycemia was correlated (P < 0.01) to the magnitude of the decrease in maximal glucose transport and a highly significant correlation was found between the maximal insulinstimulated rate of glucose transport and the maximal in vivo rate of insulin-stimulated glucose disposal (r = 0.49, P < 0.01). Therefore, we conclude that the insulin resistance in subjects with IGT is due solely to a decrease in insulin binding, whereas subjects with NIDDM exhibit both decreased insulin binding and decreased maximal rates of insulin-stimulated adipocyte glucose transport due to a postreceptor defect at this site in the insulin action pathway. If adipocytes are reflective of changes in glucose transport in other insulin target tissues, then these findings suggest that the cellular lesion responsible for the postreceptor defect in insulin action, previously demonstrated in vivo in subjects with NIDDM, resides in part at the level of the glucose transport system.