Targeting GLP-1 Receptor as a New Chronotherapy Against Nondipping Blood Pressure in Diabetes

Abstract Type 2 diabetes mellitus (T2DM) is one of the most prevalent and costly chronic diseases worldwide, and cardiovascular diseases are the leading cause of morbidity and mortality in people with T2DM. The use of glucagon-like-peptide-1 receptor agonists (GLP-1RA), the latest drug approved by the FDA for T2DM, has increased rapidly due to their recently recognized cardiovascular benefits, including lowering blood pressure (BP) while effectively control blood glucose. However, the mechanisms via which GLP-1RA lowers BP, and the influence of GLP- 1RA on BP circadian rhythm are poorly understood. This application aims to fill these critical knowledge gaps required for optimizing the increasingly prescribed GLP-1RA therapy. Our preliminary studies demonstrated that GLP-1RA Ex4 lowers BP and potentially modulates BP circadian rhythm depending on the administration time in diabetic db/db mice. Moreover, we found clock Bmal1 binds the promoter of the GLP-1 receptor, and its mRNA expression exhibits time-of-day variation. We and others have demonstrated that food intake plays a critical role in BP circadian rhythm, and GLP-1RA is well recognized to inhibit food intake. Taken together, we hypothesize that GLP-1RA lowers BP and protects BP circadian rhythm in diabetic mice by activating the GLP-1 receptor, inhibits food intake, and modulating intrinsic clocks. Two specific aims are proposed to test the hypothesis: 1) To test the hypothesis that the timing of administration and clock Bmal1 are critical for GLP-1RA to protect BP circadian rhythm and vascular function/structure in db/db and high-fat-fed male and female mice. 2) To determine the mechanisms underlying the hypotensive effect of GLP-1RA. Novel models to be used include inducible global GLP-1R knockout, inducible global Bmal1 knockout, and db/db-per2Luc mice. GLP-1RA effects on BP, food intake, clock expression, metabolism, and vascular function/structure will be monitored.