Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus.

Abstract

A B S T R A C T We have assessed the mechanisms involved in the pathogenesis of the insulin resistance associated with impaired glucose tolerance and Type II diabetes mellitus by exploring, by means of the euglycemic glucose-clamp technique, the in vivo doseresponse relationship between serum insulin and the overall rate of glucose disposal in 14 control subjects; 8 subjects with impaired glucose tolerance, and 23 subjects with Type II diabetes. Each subject had at least three studies performed on separate days at insulin infusion rates of 40, 120, 240, 1,200, or 1,800 mU/M2 per min. In the subjects with impaired glucose tolerance, the dose-response curve was shifted to the right (half-maximally effective insulin level 240 vs. 135 ,uU/ml for controls), but the maximal rate of glucose disposal remained normal. In patients with Type II diabetes mellitus, the dose-response curve was also shifted to the right, but in addition, there was a marked decrease in the maximal rate of glucose disposal. This pattern was seen both in the 13 nonobese and the 10 obese diabetic subjects. Among these patients, an inverse linear relationship exists (r = -0.72) so that the higher the fasting glucose level, the lower the maximal glucose disposal rate.Basal rates of hepatic glucose output were 74+4, 82±7, 139+24, and 125+16 mg/M2 per min for the control subjects. subjects with impaired glucose tolerance, nonobese Type II diabetic subjects, and obese Type II diabetic subjects, respectively. Higher serum insulin levels were required to suppress hepatic glucose output in the subjects with impaired glucose tolerance and Type II diabetics, compared with controls, but Send reprint requests to Dr. Olefsky,

Insulin degrading enzyme activity and insulin binding of erythrocytes in normal subjects and Type 2 (non-insulin-dependent) diabetic patients

“…However, the results seem to warrant subsequent work to substantiate whether increased insulin degradation by insulin-sensitive tissues in vivo is indeed a common feature of Type 2 diabetes and might be involved in the process of peripheral insulin resistance in such patients. This might be of particular importance in view of the now widely accepted notion of post-receptor defects being the predominant origin of insulin resistance in Type 2 diabetes, and not receptor abnormalities [32][33][34][35][36][37], and that intensive insulin treatment seems to be able to ameliorate considerably post-receptor defects, e.g. in insulin-stimulated glucose disposal [35].…”

“…Type 2 diabetic patients are of particular interest, in whom peripheral insulin resistance due to a combined receptor and post-receptor defect has been implicated in recent years as one pathogenic factor [32][33][34][35][36][37]. Insulin degrading enzyme activity (IDEA) and insulin binding to red blood cells in relation to circulating free insulin concentrations were determined in various groups of Type 2 diabetic patients, including some on sulphonylureas, after short-term insulin treatment, and with severe insulin resistance, and compared with normal subjects and with Type 1 diabetic patients.…”

Effect of long term treatment of aqueous extract of Enicostemma littorale in Type 2 diabetic patients

“…Insulin resistance is a primary defect of Syndrome-X. Insulin resistance is one of the common characteristics in individuals with NIDDM (Defronzo et al, 1985;Kolterman et al, 1981). Insulin, by acting on insulin like growth factors, causes an increase in vascular smooth muscle cell growth in vitro (King and Goodman, 1985).…”

Characterization of an Early Decline in Baseline Plasma Glucose Concentration after Acute Insulin Elevation during Euglycemic Hyperinsulinemic Clamp in Patients with Type 2 Diabetes Mellitus.

“…IT is well established that patients with type 2 diabetes mellitus are resistant to insulin-mediated glucose utilization [1][2][3][4][5][6]. While skeletal muscle is believed to be the major site responsible for insulin resistance [4], the contribution of the liver to wholebody insulin resistance is poorly understood.…”

“…To date, however, hepatic insulin resistance in type 2 diabetes remains controversial; some investigators have found that the insulininduced suppression of hepatic glucose output is impaired [5][6][7][8][9], whereas others have not confirmed these findings [3,10]. In the euglycemic hyperinsulinemic clamp method, skeletal muscle glucose uptake can be assumed to approximate the exogenously infused glucose under a plasma concentration of insulin that allows the complete suppression of hepatic glucose output.…”