NRSA Fellowship for Aaron Chacon: Targeting The GLP-1 Receptor As New Chronotherapy Against Nondipping Blood Pressure In Diabetes

ABSTRACT In healthy individuals, blood pressure (BP) is 10-20% lower during the sleep period than daytime levels. Chronic disruption in this day-night pattern has shown to be an independent risk factor for atherosclerosis, stroke, kidney disease, retinopathy, and more. These risks increase the less BP dips, with the most severe phenotype being reverse dipping – a pattern characterized by increased blood pressure during the sleep period over daytime levels. Vascular complications are invariably associated with type 2 diabetes (T2DM) with prevalence rates of hypertension often reported between 75% and 94%, and with nondipping BP observed as high as 73%. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have emerged as effective glucose- lowering therapy, with a diverse range of half-lives, for type 2 diabetics. But because the GLP-1 receptor (GLP- 1R) is widespread, GLP-1 RAs have shown to have a multitude of beneficial effects independent of their glucose-lowering properties. Inhibition of food intake, anti-inflammatory properties, and reduction in BP are among them. My preliminary data demonstrates a clear restoration in BP’s rhythm in a diabetic mouse model when the short half-life GLP-1 RA, exenatide, is administered at the onset of the light phase and its rhythm exacerbated when administered at the onset of the dark. Coinciding with this, is a restoration or worsening in food intake’s diurnal rhythm. Currently, FDA guidelines consider exenatide’s administration timing only in the context of glucose-lowering. The goal of this proposal is to investigate if, and how, restoration of BP rhythm lends to improvement in vascular contractility and structure. Additionally, the long half-life GLP-1 RA, semaglutide, will be explored on these parameters. Moreover, a novel smooth muscle-specific GLP-1R knockout mouse model will be generated to determine the GLP-1R’s role in vascular smooth muscle hyper- reactivity, characteristic in type 2 diabetes. I hypothesize that 1) GLP-1 RA-induced improvements to BP’s rhythm and/or vascular functioning are the result of modulation to food intake, glucose levels, vascular smooth muscle cell signaling, and clock gene oscillation and 2) exenatide offers greater benefit to these observations when administered at the onset of the light phase compared with the dark. With a rich history in circadian and vascular research, my lab is uniquely positioned to carry out and test everything proposed. Funding of this proposal will not only provide me with exceptional training in biochemical, molecular, physiological, and pharmacological experimentation, but also potentially offer a novel chronotherapeutic approach to improve these, and other GLP-1 RA’s, usage in the treatment of T2DM.