Grants and Contracts Details
Description
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.
Status | Finished |
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Effective start/end date | 1/2/22 → 1/1/24 |
Funding
- National Heart Lung and Blood Institute: $71,930.00
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