Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The "gold standard" glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 nonobese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SI(Clamp)) and minimal model analysis (SI(MM)) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I(0)) and glucose (G(0))] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I(0)) + log(G(0))]) that has substantially better correlation with SI(Clamp) (r = 0.78) than the correlation we observed between SI(MM) and SI(Clamp). Moreover, we observed a comparable overall correlation between QUICKI and SI(Clamp) in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research.

OBJECTIVE -This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses. RESEARCH DESIGN AND METHODS-A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients completed the study. The intent-to-treat population baseline was 53 Ϯ 10 years with BMI of 34.2 Ϯ 5.9 kg/m 2 and HbA 1c of 8.2 Ϯ 1.1%. After 4 weeks of placebo, subjects self-administered 5 g exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 g exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy.RESULTS -At week 30, HbA 1c changes from baseline Ϯ SE for each group were Ϫ0.78 Ϯ 0.10% (10 g), Ϫ0.40 Ϯ 0.11% (5 g), and ϩ0.08 Ϯ 0.10% (placebo; intent to treat; adjusted P Ͻ 0.002). Of evaluable subjects, 46% (10 g), 32% (5 g), and 13% (placebo) achieved HbA 1c Յ7% (P Ͻ 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (Ϫ2.8 Ϯ 0.5 kg [10 g], Ϫ1.6 Ϯ 0.4 kg [5 g]; P Ͻ 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Incidence of mild to moderate hypoglycemia was low and similar across treatment arms, with no severe hypoglycemia.CONCLUSIONS -Exenatide was generally well tolerated and reduced HbA 1c with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.

OBJECTIVE -This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy. RESEARCH DESIGN AND METHODS-This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 Ϯ 11 years, BMI 33 Ϯ 6 kg/m 2 , HbA 1c 8.6 Ϯ 1.2% [ϮSD]) and began 4 weeks at 5 g subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 g b.i.d. exenatide. All subjects continued sulfonylurea therapy.RESULTS -At week 30, HbA 1c changes from baseline were Ϫ0.86 Ϯ 0.11, Ϫ0.46 Ϯ 0.12, and 0.12 Ϯ 0.09% (ϮSE) in the 10-g, 5-g, and placebo arms, respectively (adjusted P Ͻ 0.001). Of evaluable subjects with baseline HbA 1c Ͼ 7% (n ϭ 237), 41% (10 g), 33% (5 g), and 9% (placebo) achieved HbA 1c Յ 7% (P Ͻ 0.001). Fasting plasma glucose concentrations decreased in the 10-g arm compared with placebo (P Ͻ 0.05). Subjects in the exenatide arms had dose-dependent progressive weight loss, with an end-of-study loss in the 10-g exenatide arm of Ϫ1.6 Ϯ 0.3 kg from baseline (P Ͻ 0.05 vs. placebo). The most frequent adverse events were generally mild or moderate and gastrointestinal in nature. No severe hypoglycemia was observed.CONCLUSIONS -Exenatide significantly reduced HbA 1c in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea. Exenatide was generally well tolerated and was associated with weight loss.

To test the hypothesis that obesity/insulin resistance impairs both endothelium-dependent vasodilation and insulinmediated augmentation of endothelium-dependent vasodilation, we studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of methacholine chloride (MCh) or sodium nitroprusside (SNP) during saline infusion and euglycemic hyperinsulinemia in lean insulin-sensitive controls (C), in obese insulin-resistant subjects (OB), and in subjects with non-insulin-dependent diabetes mellitus (NIDDM). MCh induced increments in LBF were ‫ف‬ 40% and 55% lower in OB and NIDDM, respectively, as compared with C ( P Ͻ 0.05).

OBJECTIVE -This study evaluated the effects of exenatide, a novel incretin mimetic, in hyperglycemic patients with type 2 diabetes unable to achieve glycemic control with metforminsulfonylurea combination therapy. RESULTS -Week 30 A1C changes from baseline (ϮSE) were Ϫ0.8 Ϯ 0.1% (10 g), Ϫ0.6 Ϯ 0.1% (5 g), and ϩ0.2 Ϯ 0.1% (placebo; adjusted P Ͻ 0.0001 vs. placebo), yielding placeboadjusted reductions of Ϫ1.0% (10 g) and Ϫ0.8% (5 g). In the evaluable population, exenatide-treated subjects were more likely to achieve A1C Յ7% than placebo-treated subjects (34% [10 g], 27% [5 g], and 9% [placebo]; P Ͻ 0.0001). Both exenatide arms demonstrated significant weight loss (Ϫ1.6 Ϯ 0.2 kg from baseline each exenatide arm, Ϫ0.9 Ϯ 0.2 kg placebo; P Յ 0.01 vs. placebo). Mild or moderate nausea was the most frequent adverse event. The incidence of mild/moderate hypoglycemia was 28% (10 g), 19% (5 g), and 13% (placebo) and appeared lower with MIN than with MAX sulfonylurea treatment. RESEARCH DESIGN AND METHODSCONCLUSIONS -Exenatide significantly reduced A1C in patients with type 2 diabetes unable to achieve adequate glycemic control with maximally effective doses of combined metformin-sulfonylurea therapy. This improvement in glycemic control was associated with no weight gain and was generally well tolerated.