Targeting The GLP-1 Receptor As New Chronotherapy Against Nondipping Blood Pressure In Diabetes

摘要 在健康的人中，睡眠期间的血压(BP)比白天水平低10%-20%。 这种昼夜模式的慢性紊乱已被证明是2型糖尿病的独立危险因素。 糖尿病(T2 DM)、动脉粥样硬化、中风、肾病、视网膜病变等。BP下降幅度越小，这些风险就越大， 最严重的表型是反向倾斜-这种模式的特征是在 睡眠时间超过白天水平。血管并发症与2型糖尿病的患病率无一例外 观察到的非降压率高达73%。胰升糖素样肽-1受体激动剂(RAS) 已经成为治疗2型糖尿病的有效降糖疗法，具有不同的半衰期。但 由于GLP-1受体(GLP-1R)广泛存在，GLP-1RA已被证明具有多种有益的 不依赖于它们的降糖特性的效果。抑制食物摄取，消炎， 英国石油公司的减产就是其中之一。我的初步数据显示，BP的节律在 GLP-1RA半衰期短的艾塞那肽在光照开始时给药的糖尿病小鼠模型 在夜幕降临时给药时，相位和节律加剧。与此不谋而合的是， 食物摄入量的昼夜节律恢复或恶化。目前，FDA的指南考虑艾塞那肽的 给药时机只能在降血糖的情况下进行。这项提案的目标是调查是否，以及 血压节律的恢复有助于改善血管的收缩能力和结构。此外， 长半衰期的GLP-1RA将在这些参数上进行探索。此外，一种新的平滑肌-- 将建立特定的GLP-1R基因敲除小鼠模型，以确定GLP-1R在血管顺畅中的作用 肌肉高反应性，2型糖尿病的特征。我假设GLP-1 RAS的定时给药 将纠正血压昼夜节律的紊乱，这将导致糖尿病患者更健康的血管功能 老鼠。在昼夜节律和血管研究方面有着丰富的历史，我的实验室在进行和测试方面具有独特的地位 所有求婚的事。这项计划的资金不仅将为我提供特殊的生物化学培训， 分子、生理和药理学实验，但也潜在地提供了一种新的 改善这些和其他GLP-1RA在治疗T2 DM中的使用的时间治疗方法。

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 type 2 diabetes (T2DM), 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 BP during the sleep period over daytime levels. Vascular complications are invariably associated with T2DM with prevalence rates of 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 timed administration of GLP-1 RAs will correct disruptions in circadian rhythm of BP, which will lead to healthier vascular functioning in diabetic mice. 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.