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

摘要 在健康的个体中，睡眠期间的血压（BP）比白天低10-20%。 这种昼夜模式的慢性中断已被证明是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、肾脏疾病、视网膜病变等。这些风险增加了BP下降的程度， 其中最严重的表型是反向倾斜--一种特征为血压升高的模式， 睡眠时间超过白天水平。血管并发症总是与T2 DM相关，患病率 血压未下降率高达73%。胰高血糖素样肽-1（GLP-1）受体激动剂（RA） 已成为2型糖尿病患者的有效降糖疗法，具有多种半衰期。但 由于GLP-1受体（GLP-1 R）分布广泛，GLP-1 RA已显示出具有多种有益作用， 独立于其降糖特性的作用。抑制食物摄入，抗炎特性， 和血压下降是其中之一。我的初步数据表明，在一个明显的恢复在英国石油公司的节奏， 当在光照开始时给予短半衰期GLP-1 RA艾塞那肽时的糖尿病小鼠模型 当在黑暗开始时施用时，相位和其节律加剧。与此同时， 恢复或恶化食物摄入的昼夜节律。目前，FDA指南认为， 仅在降低葡萄糖的情况下的给药时间。本提案的目的是调查， 如何恢复血压节律有助于改善血管收缩力和结构。另夕h 将根据这些参数探索长半衰期GLP-1 RA（Semaglutide）。此外，一种新的平滑肌- 将产生特定的GLP-1 R敲除小鼠模型，以确定GLP-1 R在血管平滑肌中的作用。 2型糖尿病患者的肌肉高反应性。我假设GLP-1 RA的定时给药 将纠正血压昼夜节律的破坏，这将导致糖尿病患者更健康的血管功能。 小鼠我的实验室在昼夜节律和血管研究方面有着丰富的历史， 所有的提议。这项提案的资助不仅会为我提供生物化学方面的特殊培训， 分子，生理和药理学实验，而且还可能提供一种新的 因此，本发明提供了一种改善这些和其他GLP-1 RA在治疗T2 DM中的用途的方法。

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.