Despite the advent of new treatments, glucose control in the type 2 diabetes population is unsatisfactory. AC2993 (synthetic exendin-4; exenatide), a novel glucose-dependent insulinotropic agent, exhibited notable antidiabetic potential in two clinical studies in patients with type 2 diabetes. In study A, 24 subjects received sc injections of study medication (0.1 micro g/kg AC2993 or placebo) twice daily with meals for 5 d. Statistically significant reductions in mean postprandial circulating concentrations of glucose, insulin, and glucagon occurred following treatment with AC2993. In study B, 13 subjects receiving a single dose of study medication (0.05, 0.1, or 0.2 micro g/kg AC2993 or placebo) following an overnight fast had reduced fasting plasma glucose concentrations during the subsequent 8-h period. The relative glucose and insulin concentration profiles were consistent with glucose-dependent insulinotropism. AC2993 was well tolerated. Mild transient headache, nausea, and vomiting were the main adverse events. In conclusion, AC2993 acutely and markedly reduces fasting and postprandial glucose concentrations in patients with type 2 diabetes. During fasting, glucose-dependent enhancement of insulin secretion and suppression of glucagon secretion are the predominant mechanisms, and postprandially, slowing of gastric emptying is additionally operative. This robust antidiabetic effect warrants further evaluation of AC2993.

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 We have studied 17 elderly and 27 nonelderly, nonobese subjects (mean age 69±1 and 37±2 yr, respectively) to assess the mechanisms responsible for the abnormal carbohydrate tolerance associated with aging. Serum glucose and insulin levels were significantly elevated in the elderly subjects compared with the nonelderly subjects during a 75-g oral glucose tolerance test, suggesting an insulin resistant state. Peripheral insulin sensitivity was assessed in both groups using the euglycemic glucose clamp technique during an insulin infusion rate of 40

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.

OBJECTIVE -Mealtime amylin replacement with the human amylin analog pramlintide, as an adjunct to mealtime insulin replacement, reduces postprandial glucose excursions in patients with type 2 diabetes. The aim of the present study was to assess the long-term efficacy and safety of pramlintide in this patient population.RESEARCH DESIGN AND METHODS -In a 52-week, double-blind, placebocontrolled, parallel-group, multicenter study, 656 patients with type 2 diabetes (age 57 Ϯ 10 years, diabetes duration 12 Ϯ 7 years, BMI 34.0 Ϯ 7.0 kg/m 2 , HbA 1c 9.1 Ϯ 1.2%, mean Ϯ SD) treated with insulin (alone or in combination with sulfonylureas and/or metformin) were randomized to receive additional preprandial subcutaneous injections of either placebo or pramlintide (60 g TID, 90 g BID, or 120 g BID).RESULTS -Treatment with pramlintide 120 g BID led to a sustained reduction from baseline in HbA 1c (Ϫ0.68 and Ϫ0.62% at weeks 26 and 52, respectively), which was significantly greater than that seen with placebo (P Ͻ 0.05). The proportion of patients achieving an HbA 1c Ͻ8% was approximately twofold greater with pramlintide (120 g BID) than with placebo (46 vs. 28%, P Ͻ 0.05). The glycemic improvement with pramlintide 120 g BID was accompanied by a mean weight loss (Ϫ1.4 kg vs. ϩ0.7 kg with placebo at week 52, P Ͻ 0.05) and occurred without an overall increase in the severe hypoglycemia event rate. The most common adverse event associated with pramlintide use was transient, mild-to-moderate nausea.CONCLUSIONS -Mealtime amylin replacement with pramlintide 120 g BID, as an adjunct to insulin therapy, improves long-term glycemic and weight control in patients with type 2 diabetes. Diabetes Care 26:784 -790, 2003