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

靶向 GLP-1 受体作为对抗糖尿病非下降血压的新计时疗法

• 批准号: 10672174
• 负责人: Aaron Chacon
• 金额: $ 3.64万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-02 至 2024-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10672174
• 关键词: Agonist; Anti-Inflammatory Agents; Atherosclerosis; Biochemical; Blood Glucose; Blood Pressure; Blood Vessels; Characteristics; Chronic; Chronotherapy; Circadian Rhythms; Clinical Trials; Darkness; Data; Diabetes Mellitus; Diabetic mouse; Disease; Diurnal Rhythm; Eating; Food; Functional disorder; Funding; Future; GLP-I receptor; Genes; Glucose; Glycosylated hemoglobin A; Goals; Guidelines; Half-Life; Health; Hour; Impairment; In Situ; Individual; Ingestion; Insulin; Kidney Diseases; Knockout Mice; Light; Measurement; Measures; Metabolic; Metabolism; Molecular; Monitor; Mus; Muscle Contraction; Non-Insulin-Dependent Diabetes Mellitus; Organ; Outcome; Pancreas; Pattern; Phase; Phenotype; Physiological; Positioning Attribute; Prevalence; Property; Proteins; Recording of previous events; Reporting; Research; Resistance; Rest; Retinal Diseases; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Role; Satiation; Series; Signal Pathway; Signal Transduction; Sleep; Smooth Muscle; Stroke; Structure; Testing; Time; Training; Type 2 diabetic; Vascular Diseases; Vascular Smooth Muscle; Western Blotting; blood glucose regulation; blood pressure elevation; blood pressure reduction; blood pressure regulation; carbohydrate metabolism; cardioprotection; circadian; db/db mouse; design; diabetic; diabetic patient; exenatide; experimental study; glucagon-like peptide 1; improved; in vivo; indexing; mortality; mouse Cre recombinase; mouse model; novel; pharmacologic; pleiotropism; response; restoration

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.

抽象的 在健康的个体中，血压（BP）在睡眠期间比白天水平低10-20％。 在这种昼夜模式中的慢性破坏已显示为2型糖尿病的独立危险因素 （T2DM），动脉粥样硬化，中风，肾脏疾病，视网膜病等。这些风险增加了BP下降， 最严重的表型是反向浸入 - 这种模式为以BP的增加为特征 白天水平的睡眠期。血管并发症总是与T2DM与患病率相关 非bp的速率高达73％。胰高血糖素样肽-1（GLP-1）受体激动剂（RAS） 对于2型糖尿病患者而言，出现了有效的降糖疗法，具有一半的潜水员范围。但 由于GLP-1受体（GLP-1R）广泛，因此GLP-1 RAS已证明具有多种有益的 与降低葡萄糖的特性无关的影响。抑制食物摄入，抗炎特性， 其中包括BP。我的初步数据表明，在BP的节奏中有明确的恢复 糖尿病小鼠模型在光线发作时施用短的半衰期GLP-1 RA（艾烯肽） 当在黑暗的开始时给药时，相位及其节奏加剧。与此相吻合的是 恢复或担心食物摄入的昼夜节奏。目前，FDA指南考虑了Actenatide的 仅在降糖的背景下进行给药时间。该提议的目的是调查是否以及 BP节奏的恢复如何改善血管收缩和结构。另外， 将在这些参数上探索长半衰期GLP-1 RA，Semaglutide。而且，一种新颖的平滑肌 - 将生成特定的GLP-1R敲除鼠标模型，以确定GLP-1R在血管平滑中的作用 肌肉过度反应性，在2型糖尿病中具有特征。我假设GLP-1 RAS的定时给药 将纠正BP昼夜节律的干扰，这将导致糖尿病的更健康的血管功能 老鼠。在昼夜节律和血管研究中有悠久的历史，我的实验室在执行和测试方面具有独特的位置 一切都提出了。该建议的资金不仅会为我提供生化的特殊培训， 分子，物理和药物实验，但也有可能提供新颖的 用于改进这些和其他GLP-1 RA的时间治疗方法，用于治疗T2DM。