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.

Diabetes is increasing rapidly worldwide and frequently results in severe vascular complications. A target glycated hemoglobin of less than 7% has commonly been recommended in hopes of preventing both macrovascular and microvascular complications. Although results from trials of intensive glycemic control have generally supported the notion that lower glycated hemoglobin values reduce microvascular disease, the evidence for similar benefits for macrovascular disease has been less clear. As macrovascular disease is the major cause of morbidity and mortality in type 2 diabetes, this remains one of the more important unresolved clinical questions. Recent results from the ACCORD, ADVANCE, and VADT studies have challenged the conventional believe that lower glycated hemoglobin values should be pursued in all diabetic patients. Factors that may influence whether intensive glucose management is advisable include duration of diabetes, pre-existing macrovascular disease, hypoglycemic unawareness, and significant comorbidities. Glycated hemoglobin goals should account for these factors and be individualized for each patient.