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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的对于健康人来说，睡眠期间的血压 (BP) 比白天的水平低 10-20%。这种昼夜模式的慢性破坏已被证明是 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、视网膜病变等，血压下降越少，这些风险就会增加。最严重的表型是反向倾斜——一种以血压升高为特征的模式睡眠时间高于白天的水平血管并发症总是与 T2DM 的患病率相关。胰高血糖素样肽 1 (GLP-1) 受体激动剂 (RA) 的非下降率高达 73%。已成为治疗 2 型糖尿病的有效降糖疗法，具有不同的半衰期。由于 GLP-1 受体 (GLP-1R) 广泛存在，GLP-1 RA 已被证明具有多种有益作用其作用与其降糖特性、抑制食物摄入、抗炎特性无关。我的初步数据表明，血压节律明显恢复。糖尿病小鼠模型，在光照开始时给予半衰期短的 GLP-1 RA（艾塞那肽）与此相一致的是，在黑暗开始时进行的阶段及其节奏会加剧。目前，FDA 指南考虑使用艾塞那肽。仅在降血糖的情况下进行给药时间该提案的目的是调查是否和。血压节律的恢复有助于改善血管收缩性和结构。长半衰期的 GLP-1 RA（索马鲁肽）将在这些参数上进行探索。将生成特定的 GLP-1R 敲除小鼠模型，以确定 GLP-1R 在血管平滑肌中的作用肌肉反应过度，这是 2 型糖尿病的特征，我急忙定时服用 GLP-1 RA。将纠正血压昼夜节律的紊乱，从而使糖尿病患者的血管功能更健康我的实验室在昼夜节律和血管研究方面拥有丰富的历史，在开展和测试方面具有独特的优势。该提案的所有资助不仅将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，但也有可能提供一种新颖的方法时间治疗方法可改善这些以及其他 GLP-1 RA 在 T2DM 治疗中的使用。