BackgroundGlucagon like peptide-1 (GLP-1) receptor agonist treatment may improve endothelial function via direct and indirect mechanisms. We compared the acute and chronic effects of the GLP-1 receptor agonist exenatide vs. metformin on endothelial function in patients with obesity and pre-diabetes.MethodsWe performed a randomized, open-label, clinical trial in 50 non-diabetic individuals (mean age 58.5 ± 10.0; 38 females) with abdominal obesity and either impaired fasting glucose, elevated HbA1c, or impaired glucose tolerance (IGT) who were randomized to receive 3-months of exenatide or metformin. Microvascular endothelial function, assessed by digital reactive hyperemia (reactive hyperemic index: RHI), C-reactive protein (CRP), circulating oxidized LDL (oxLDL), and vascular cell adhesion molecule-1 (VCAM-1) were measured at baseline and 3-months. Seven subjects with IGT participated in a sub-study comparing the effects of pre-administration of exenatide and metformin on postprandial endothelial function.ResultsThere were no differences for the change in RHI (Δ exenatide: 0.01 ± 0.68 vs. Δ metformin: -0.17 ± 0.72, P = 0.348), CRP, oxLDL, or VCAM-1 between exenatide and metformin treatment. Triglycerides were reduced more with exenatide compared to metformin (Δ exenatide: -25.5 ± 45.7 mg/dL vs. Δ metformin: -2.9 ± 22.8 mg/dL, P = 0.032). In the sub-study, there was no difference in postprandial RHI between exenatide and metformin.ConclusionsThree months of exenatide therapy had similar effects on microvascular endothelial function, markers of inflammation, oxidative stress, and vascular activation, as metformin, in patients with obesity and pre-diabetes.Clinical trials registrationThis study is registered on http://www.clinicaltrials.gov/: NCT00546728

Despite systemic delivery of insulin, pancreas-kidney transplantation in patients with diabetes results in carbohydrate metabolism similar to that in nondiabetic subjects receiving the same immunosuppressive agents after kidney transplantation.

The isotope dilution technique has been extensively used to assess insulin action in humans. To determine if nonsteady state (NSS) has led to erroneous estimates of hepatic and extrahepatic insulin sensitivity, we measured glucose turnover in healthy subjects during infusion of insulin at rates of 0.25, 0.6, and 2.0 mU.kg-1.min-1. Turnover was calculated using Steele's traditional NSS equations [fixed-effective volume (pV) method] as well as with methods [radioactive infused glucose (hot-GINF) or variable pV] designed to minimize NSS error. In contrast to the fixed-pV method, both the hot-GINF and variable-pV methods indicated that several hours were required for suppression of hepatic glucose release at all insulin concentrations and that small increases in plasma insulin (approximately 100 pmol/l) had comparable effects on glucose disappearance and hepatic glucose release. Nevertheless, despite these differences, when turnover during the final hour of the insulin infusions was plotted vs. the prevailing insulin concentration, all three methods yielded similar insulin dose-response curves for suppression of hepatic glucose release. Thus despite previous errors in measurement of glucose turnover, the widely accepted belief that the human liver is exquisitely sensitive to small changes in insulin is correct.

The authors hypothesized that carvedilol controlled‐release plus lisinopril combination therapy (C+L) would increase endothelial function and decrease oxidative stress to a greater extent than hydrochlorothiazide plus lisinopril combination therapy (H+L) in obese patients with hypertension. Twenty‐five abdominally obese patients (aged 54.4±7.3 years; 14 women) with hypertension/prehypertension were enrolled in a 7‐month (two 3‐month treatment periods separated by a 1‐month washout), randomized, double‐blind, controlled, crossover clinical trial comparing C+L vs H+L. Endothelial function, measured by digital reactive hyperemic index (RHI), circulating oxidized low‐density lipoprotein (oxLDL), 8‐isoprostane, and asymmetric dimethylarginine (ADMA) were obtained at baseline, post‐period 1, post‐washout, and post‐period 2. Analyses were adjusted for baseline measurements by analysis of covariance, with robust variance estimation for confidence intervals and P values. C+L treatment compared to H+L treatment significantly improved RHI (0.74, 95% confidence interval, 0.31–1.19, P =.001). This difference persisted after adjustment for the change in systolic blood pressure. No significant treatment differences were observed for oxLDL, 8‐isoprostane, or ADMA. These data provide evidence that independent of blood pressure–lowering, C+L therapy improves endothelial function to a greater extent than H+L therapy. Levels of oxidative stress were not significantly different between treatments, suggesting that other mechanisms may be responsible for the improvement in endothelial function.

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