Exenatide Protects Against Glucose- and Lipid-Induced Endothelial Dysfunction: Evidence for Direct Vasodilation Effect of GLP-1 Receptor Agonists in Humans

Abstract

GLP-1 receptor (GLP-1R) agonists may improve endothelial function (EF) via metabolic improvement and direct vascular action. The current study determined the effect of GLP-1R agonist exenatide on postprandial EF in type 2 diabetes and the mechanisms underlying GLP-1R agonist–mediated vasodilation. Two crossover studies were conducted: 36 participants with type 2 diabetes received subcutaneous exenatide or placebo for 11 days and EF, and glucose and lipid responses to breakfast and lunch were determined; and 32 participants with impaired glucose tolerance (IGT) or diet-controlled type 2 diabetes had EF measured before and after intravenous exenatide, with or without the GLP-1R antagonist exendin-9. Mechanisms of GLP-1R agonist action were studied ex vivo on human subcutaneous adipose tissue arterioles and endothelial cells. Subcutaneous exenatide increased postprandial EF independent of reductions in plasma glucose and triglycerides. Intravenous exenatide increased fasting EF, and exendin-9 abolished this effect. Exenatide elicited eNOS activation and NO production in endothelial cells, and induced dose-dependent vasorelaxation and reduced high-glucose or lipid-induced endothelial dysfunction in arterioles ex vivo. These effects were reduced with AMPK inhibition. In conclusion, exenatide augmented postprandial EF in subjects with diabetes and prevented high-glucose and lipid-induced endothelial dysfunction in human arterioles. These effects were largely direct, via GLP-1R and AMPK activation.

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

“…Interestingly, infusion of exenatide increased power in the endothelial domain of vasomotion. This corresponds with the observation that a single subcutaneous dose of exenatide prevents postprandial endothelial dysfunction in subjects with prediabetes or diabetes mellitus, 39,40 when measured by reactive hyperemia applanation tonometry. However, because we observed no exenatide changes in capillary perfusion or total vasomotion in current trial, it is unclear whether the improvement in endothelial power has physiological relevance.…”

GLP-1R Agonists and Endothelial Dysfunction: More Than Just Glucose Lowering?

“…Nevertheless, these carefully performed studies by Koska and colleagues (16,17) support a direct role for exenatide on the endothelial function in humans and are consistent with prior studies for GLP-1(7-36) but are in contrast to many studies using GLP-1R agonists and DPP-4 inhibitors. How, then, do we interpret these differences, and how can we reconcile whether or not GLP-1R agonists directly modify endothelial function?…”

“…The study by Koska et al (17) demonstrates that exenatide exerts a protective endothelial function effect in the postprandial period following short-term therapy in patients with T2D (diabetes duration .5 years). A potential limitation of this study was the lack of an active comparator to control for changes in glycemia, lipids, insulin, and adiposity, which are factors known to influence endothelial function.…”

“…The studies by Koska and colleagues (16,17) are important as they have better defined how GLP-1R agonists impact endothelial function in humans. Moreover, novel physiological insights derived from these elegant experiments supporting the presence of direct vascular effects with GLP-1R agonists may ultimately help to better interpret the pending results of large cardiovascular and microvascular outcome studies using these agents.…”

Effects of iron overload and exenatide on erythrocyte deformability in a rat model

“…Studies showed an improvement in endothelial dysfunction with GLP-1 agonists (19,20). Antioxidative properties of these molecules are also demonstrated in several trials (21,22).…”