Targeting GLP-1 receptor as a 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时间疗法

• 批准号: 10642845
• 负责人: MING C GONG
• 金额: $ 69.52万
• 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: 2022-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642845
• 关键词: ARNTL gene; Agonist; Animals; Antidiabetic Drugs; Bilateral; Blood Pressure; Body Weight; Brain; Cardiovascular system; Chronic Disease; Chronotherapy; Circadian Rhythms; Clinical Trials; Darkness; Data; Diabetes Mellitus; Diabetic mouse; Duodenum; Eating; FDA approved; Fatty acid glycerol esters; Female; Foundations; Future; GLP-I receptor; Genes; Glycosylated hemoglobin A; Goals; High Fat Diet; Hippocampus; Hypertension; Hypothalamic structure; Knock-out; Knockout Mice; Knowledge; Light; Link; Literature; Mediating; Messenger RNA; Metabolism; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Phase; Prognosis; Publications; Regimen; Rest; Risk Factors; Role; Scheme; Sympathetic Nervous System; Time; Time-restricted feeding; Type 2 diabetic; Vagotomy; Vagus nerve structure; blood pressure reduction; cardiovascular risk factor; comorbidity; cost; db/db mouse; diabetic; diabetic patient; effective therapy; exenatide; feeding; gut-brain axis; improved; liraglutide; male; novel; pre-clinical; prevent; protective effect; sex; sexual dimorphism; targeted treatment

PROJECT SUMMARY Type 2 diabetes is one of the most prevalent and costly chronic diseases worldwide. Hypertension and nondipping blood pressure (BP) are prevalent comorbidities of type 2 diabetes and significant risk factors for detrimental cardiovascular outcomes. While up to 75% of diabetic patients are nondippers, no effective therapy targets nondipping BP in diabetes. Glucagon-like-peptide-1 receptor agonists (GLP-1RA) are a class of recently FDA-approved anti-diabetic drugs that provide exciting new means for the critical but challenging task of managing cardiovascular risk in diabetic patients. The use of GLP-1RAs increased rapidly due to their recently recognized cardiovascular benefits, including lowering BP in addition to effectively reducing HbA1C and body weight. However, whether GLP-1RA influences nondipping BP in diabetes is scarcely studied, and the mechanisms via which GLP-1RA lowers BP remain to be defined. Our preliminary data demonstrate for the first time that a short-acting GLP-1RA, exenatide (Ex), when injected i.p. into type 2 diabetic db/db mice at the beginning of the inactive phase (ZT0, light on time), effectively restored nondipping BP to normal dipping BP. In contrast, when administered at the beginning of the active dark phase (ZT12, light off time), Ex worsened nondipping BP to reversed dipping (most harmful disruption). Our preliminary data also show for the first time that GLP-1 receptor (GLP-1R) mRNA varies with the time of day and is regulated by clock gene BMAL1. Interestingly, we also found that Ex administrated at ZT0 or ZT12 restored or inverted food intake rhythm in db/db mice in parallel with its effects on BP. Together with our recent publication that demonstrated time- restricted feeding effectively prevents and treats nondipping BP via the sympathetic nervous system (SNS) in diabetic db/db mice and literature evidence that the vagus nerve links food intake to modulation of BP, we hypothesize that GLP-1RA administered at ZT0 inhibits food intake, vagus nerve, and SNS via the GLP-1 receptor and its cross-talk with clock BMAL1, thus protecting BP circadian rhythm in type 2 diabetes. Two specific aims are Aim 1. Investigate GLP-1RA as a novel chronomedicine to protect BP circadian rhythm via inhibiting food intake in type 2 diabetes. Aim 2. Define the mechanism by which GLP-1RA protects BP circadian rhythm in type 2 diabetes. To achieve these goals, we will determine the effects of short-acting GLP- 1RA Ex and long-acting GLP-1RA liraglutide administered at ZT0 or ZT12 on the circadian rhythms of metabolism, food intake, clock genes, SNS, and BP in diabetic db/db, db/db-Per2Luc, Bmal1-iKO, Glp1r-KO, brain-specific Glp1r-KO, and vagal neuron-specific Glp1r-KO mice under various feeding regimens. The proposed studies will provide novel pre-clinical evidence suggesting GLP-1RA serves as a novel chronomedicine targeting the nondipping BP in type 2 diabetes, thus improving prognoses and outcomes of diabetic patients. Furthermore, results from the proposed studies will shed new light on how GLP-1RAs lower BP, thus laying a foundation for optimizing GLP-1RA therapy for diabetic patients.

项目摘要 2型糖尿病是全球最普遍，最昂贵的慢性疾病之一。高血压和 非血压（BP）是2型糖尿病的普遍合并症，以及重大危险因素 有害的心血管结局。虽然多达75％的糖尿病患者是无效的治疗 靶向非糖尿病的BP。胰高血糖素肽-1受体激动剂（GLP-1RA）是一类 最近，FDA批准的抗糖尿病药物为关键但具有挑战性的任务提供了令人兴奋的新手段 糖尿病患者的心血管风险。由于GLP-1RA的使用迅速增加 最近认可的心血管益处，包括有效降低HBA1C之外降低BP 和体重。但是，GLP-1RA是否影响糖尿病中的非BP，几乎没有研究，并且 GLP-1RA降低BP的通过机制仍有待定义。我们的初步数据证明了 第一次注射腹腔注射时，首次是短效GLP-1RA（EX）（EX）。进入2型糖尿病DB/DB小鼠 非活性相的开始（ZT0，按时亮）有效地恢复了非BP的BP。 相反，当在活动暗阶段开始时（ZT12，点亮时间）进行管理时，Ex会恶化 非bp倾斜浸入（最有害的破坏）。我们的初步数据也首次显示 该GLP-1受体（GLP-1R）mRNA随着一天的时间而变化，并由时钟基因BMAL1调节。 有趣的是，我们还发现，在ZT0或ZT12进行的EX恢复或倒置的食物摄入节奏 DB/DB小鼠与其对BP的影响并联。加上我们最近的出版物表现出时间 - 限制喂养可以有效防止和治疗通过交感神经系统（SNS）在 糖尿病DB/DB小鼠和文献证据表明，迷走神经将食物摄入与BP的调节联系起来，我们 假设在ZT0处施用的GLP-1RA可以通过GLP-1抑制食物摄入，迷走神经和SN 受体及其与时钟BMAL1的串扰，从而保护2型糖尿病中的BP昼夜节律。二 具体目的是目标1。将GLP-1RA作为一种新型的媒介素研究，以保护BP昼夜节律通过 抑制2型糖尿病中的食物摄入量。目标2。定义GLP-1RA保护BP的机制 2型糖尿病中的昼夜节律。为了实现这些目标，我们将确定简短作用GLP的影响 1RA EX和长效GLP-1RA liraglutide在ZT0或ZT12上施用的昼夜节律 糖尿病DB/dB中的代谢，食物摄入，时钟基因，SNS和BP，db/db-per2luc，bmal1-iko，glp1r-ko，glp1r-ko， 在各种喂养方案下，大脑特异性GLP1R-KO和迷走神经元特异性GLP1R-KO小鼠。这 拟议的研究将提供新的临床前证据，表明GLP-1RA是一种新颖的证据 靶向2型糖尿病中非dondipping bp的媒介氨酸，从而改善了预后和预后 糖尿病患者。此外，拟议的研究的结果将为GLP-1RA降低如何降低新的启示 BP，从而为糖尿病患者优化GLP-1RA治疗奠定了基础。