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.

项目概要 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 非下降性血压 (BP) 是 2 型糖尿病的常见合并症，也是 2 型糖尿病的重要危险因素 有害的心血管结局。虽然高达 75% 的糖尿病患者为非杓状糖尿病，但尚无有效的治疗方法 针对糖尿病患者的非下降血压。胰高血糖素样肽-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方法 管理糖尿病患者的心血管风险。 GLP-1RA 的使用迅速增加，因为其 最近公认的心血管益处，除了有效降低 HbA1C 之外，还包括降低血压 和体重。然而，GLP-1RA 是否影响糖尿病患者的非下降血压却鲜有研究，并且 GLP-1RA 降低血压的机制仍有待确定。我们的初步数据表明 首次发现短效 GLP-1RA，艾塞那肽 (Ex)，腹腔注射时。 2 型糖尿病 db/db 小鼠 非活动阶段（ZT0，光照时间）的开始，有效地将非浸渍血压恢复到正常浸渍血压。 相反，当在活跃黑暗阶段（ZT12，熄灯时间）开始时给药时，Ex 恶化 非浸渍 BP 至反向浸渍（最有害的破坏）。我们的初步数据也首次显示 GLP-1 受体 (GLP-1R) mRNA 随一天中的时间而变化，并受时钟基因 BMAL1 调节。 有趣的是，我们还发现在 ZT0 或 ZT12 施用 Ex 恢复或逆转了 db/db 小鼠与其对血压的影响平行。连同我们最近的出版物一起展示了时间- 限制进食可通过交感神经系统 (SNS) 有效预防和治疗非低血压 糖尿病 db/db 小鼠和文献证据表明迷走神经将食物摄入与血压调节联系起来，我们 假设在 ZT0 施用 GLP-1RA 通过 GLP-1 抑制食物摄入、迷走神经和 SNS 受体及其与时钟 BMAL1 的串扰，从而保护 2 型糖尿病患者的血压昼夜节律。二 具体目标是目标 1。研究 GLP-1RA 作为一种新型计时药物，通过以下方式保护血压昼夜节律 抑制 2 型糖尿病患者的食物摄入。目标 2. 定义 GLP-1RA 保护 BP 的机制 2 型糖尿病的昼夜节律。为了实现这些目标，我们将确定短效 GLP 的效果- 1RA Ex 和长效 GLP-1RA 利拉鲁肽按昼夜节律在 ZT0 或 ZT12 给药 糖尿病 db/db、db/db-Per2Luc、Bmal1-iKO、Glp1r-KO 中的新陈代谢、食物摄入、时钟基因、SNS 和 BP 不同喂养方案下的脑特异性 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 作为一种新的 计时医学针对 2 型糖尿病的非下降血压，从而改善预后和结果 糖尿病患者。此外，拟议研究的结果将为 GLP-1RA 如何降低 BP，从而为优化糖尿病患者的GLP-1RA治疗奠定了基础。