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,

A B S T R A C T To assess the mechanisms of the insulin resistance in human obesity, we have determined, using a modification of the euglycemic glucose clamp technique, the shape of the in vivo insulinglucose disposal dose-response curves in 7 control and 13 obese human subjects. Each subject had at least three euglycemic studies performed at insulin infusion rates of 15, 40, 120, 240, or 1,200 mU/M2/min. The glucose disposal rate was decreased in all obese subjects compared with controls (101+16 vs. 186+16 mg/M2/min) during the 40 mU/M2/min insulin infusion. The mean dose-response curve for the obese subjects was displaced to the right, i.e., the half-maximally ef: fective instulin concentration was 270+27 ,uU/ml for the obese coompared with 130±10 ,U/ml for controls. In nine of' the obese subjects, the dose-response curves were shifted to the right, and maximal glucose disposal rates (at a maximally effective insulin concentration) were markedly decreased, indicating both a receptor and a postreceptor defect. On the other hand, four obese patients had right-shifted dose-response curves but reached normal maximal glucose disposal rates, consistent with decreased insulin receptors as the only abnormality. When the individual data were analyzed, it was found that the least hyperinsulinemic, least insulin-resistant patients displayed only the receptor defect, whereas those with the greatest hyperinsulinemia exhibited the largest postreceptor defect, suggesting a continuous spectrum of defects as one advances from mild to severe insulin resistance. When insulin's ability to suppress hepatic glucose output was assessed, hyperinsulinemia produced total suppression in all subjects. The doseresponse curve for the obese subjects was shifted to the right, indicating a defect in insulin receptors. InReceived for publication 27 August 1979 and in revised form 30 January 1980. 1272 sulin binding to isolated adipocytes obtained from the obese subjects was decreased, and a highly significanit inverse linear relationship was demonstrated between insulin binding andl the serum instulin concentrationl re(luired f'or halfrmaximnal stimulation of glucose disposal. In conclusioni: (a) decreased cellular insulin receptors contrilbute to the insulin resistance associated with human obesity in all subjects; (b) in the least hyperinsulinemic, insulin-resistant patients, decreased insulin receptors are the sole defect, whereas in the more hyperinsulinemic, insulin-resistant patients, the insulin resistance is the result of a combination of receptor and postreceptor abnormalities; (c) all obese patients were insensitive to insulin's suppressive effects on hepatic glucose output; this was entirely the result of decreased insulin receptors; no postreceptor defect in this insulin effect was demonstrated.

We have studied the acute effects of oral ingestion of dextrose, rice, potato, corn, and bread on postprandial serum glucose, insulin, and glucagon responses in 20 diabetic subjects with nonketotic, noninsulin requiring fasting hyperglycemia. The carbohydrate loads were all calculated to contain 50 g of glucose. The data demonstrate that 1) dextrose and potato elicited similar postprandial serum glucose responses whereas rice and corn elicited lower responses, with bread intermediate; 2) postprandial insulin responses were relatively flat but rice ingestion led to significantly lower insulin responses than did potato; 3) urinary glucose excretion during the 3 h after carbohydrate ingestion was greatest following dextrose and least after rice and corn. In conclusion, there is a range in the magnitude of postprandial hyperglycemia after ingestion of different complex carbohydrates in diabetic patients with fasting hyperglycemia and emphasis on the use of the less hyperglycemic starches could be of therapeutic value in controlling hyperglycemia.

We have studied the short term regulation of insulin receptors by serially measuring insulin binding to erythrocytes during 5 h of infusions of glucose and insulin. Two infusion protocols were employed: (1) Hyperinsulinemic study. Subjects were infused with insulin (80 mU/min) to induce sustained hyperinsulinemia, while euglycemia was approximated by infusion of glucose (8 mg/kg/min). (2) Hyperglycemic study. Subjects were infused with glucose (7 mg/kg/min) and a small amount of insulin (10 mU/min), while endogenous insulin secretion was inhibited with epinephrine and propranolol. Insulin binding to erythrocyte insulin receptors was measured serially during both of these infusion protocols for 5 h. The results demonstrated no change in insulin binding during the first 3 h of either infusion. However, by 5 h of either infusion, a striking 36% decrease in insulin binding, from 6.3 ± 0.5% to 4.0 ± 0.6%, was observed. Scatchard analysis and average affinity analysis of the binding data demonstrated that this decrease in insulin binding was entirely caused by a decrease in receptor affinity. Insulin binding to circulating monocytes was also measured, and comparable effects were observed. When cells were removed from the in vivo environment at 3 h and were incubated in vitro for a subsequent 2 h, decreased insulin binding developed during the incubation. Thus, this short term regulation of insulin receptor affinity occurred in vivo or in vitro, and cells that were programmed during the first 3 h of the infusion study could develop a decrease in insulin receptor affinity in vitro in the absence of plasma factors.

A 14-yr-old woman presented with fasting hyperglycemia (269 mg/dl), fasting hyperinsulinemia (45 microU/ml), acanthosis nigricans, and insulin resistance. The patient's circulating insulin was normal by physical and biological criteria, and insulin receptor antibodies were not detected. Both the patient's in vivo dose-response curve for insulin-stimulated glucose transport in isolated adipocytes were shifted to the right and showed marked decreases in the maximal insulin response. Basal hepatic glucose output was significantly increased, and the in vivo dose-response curve for insulin-mediated suppression of basal hepatic glucose output was shifted to the right. Insulin binding to the patient's erythrocytes, monocytes, and adipocytes was markedly decreased. To confirm that the severe reduction in cellular insulin receptors was a primary rather than an acquired defect, similar studies were conducted using cultured fibroblasts. No detectable binding of insulin to these cells was observed. Further studies showed that the patient's mother and two sisters were hyperinsulinemic and insulin resistant, and had comparable, although less severe, changes in insulin binding. The patient was also demonstrated to have an insulin secretory defect both to both oral and iv glucose challenges. We thus conclude that this family demonstrates a genetic deficiency of insulin receptors, resulting in insulin resistance and, in this patient, severe diabetes mellitus.