Targeting GLP-1 receptor as a new chronotherapy against nondipping blood pressure in diabetes

项目摘要 2型糖尿病是世界范围内最普遍和最昂贵的慢性疾病之一。高血压和 非下降型血压（BP）是2型糖尿病的常见合并症， 有害的心血管结果。虽然高达75%的糖尿病患者是非勺型，但没有有效的治疗方法， 针对糖尿病患者的非降压血压。胰高血糖素样肽-1受体激动剂（GLP-1 RA）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-1 RA的使用迅速增加，原因是其 最近认识到的心血管益处，包括降低血压以及有效降低HbA 1C 和体重。然而，几乎没有研究GLP-1 RA是否影响糖尿病患者的非突降血压， GLP-1 RA降低血压的机制仍有待确定。我们的初步数据表明， 当在24小时内将短效GLP-1 RA艾塞那肽（Ex）腹膜内注射到2型糖尿病db/db小鼠中时， 非活动期（ZT 0，光照时间）开始时，有效地将非倾斜BP恢复到正常倾斜BP。 相反，当在活动暗期开始时（ZT 12，熄灯时间）给药时，Ex恶化， 非倾斜BP到反向倾斜（最有害的破坏）。我们的初步数据还首次显示 GLP-1受体（GLP-1 R）mRNA随时间变化，受生物钟基因BMAL 1调控。 有趣的是，我们还发现在ZT 0或ZT 12给予Ex恢复或逆转了大鼠的食物摄入节律。 db/db小鼠血压的影响。再加上我们最近的出版物证明了时间- 限制喂养通过交感神经系统（SNS）有效地预防和治疗非下降型BP， 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ZT 0时给予GLP-1 RA通过GLP-1抑制摄食、迷走神经和SNS 受体及其与生物钟BMAL 1的相互作用，从而保护2型糖尿病患者的血压昼夜节律。两 具体目标是目标1。研究GLP-1 RA作为一种新型时间药物，通过以下途径保护BP昼夜节律 抑制2型糖尿病的食物摄入。目标二。定义GLP-1 RA保护BP的机制 2型糖尿病的治疗方法为了实现这些目标，我们将确定短效GLP的作用- 1 RA Ex和长效GLP-1 RA利拉鲁肽在ZT 0或ZT 12按照以下昼夜节律给药： 糖尿病db/db、db/db-Per 2Luc、Bmal 1-iKO、Glp 1 r-KO、 脑特异性Glp 1 r-KO和迷走神经元特异性Glp 1 r-KO小鼠。的 拟定的研究将提供新的临床前证据，表明GLP-1 RA是一种新的 时间医学针对2型糖尿病中的非下降BP，从而改善糖尿病的并发症和结局。 糖尿病患者此外，拟定研究的结果将揭示GLP-1 RA如何降低 BP，从而为优化GLP-1 RA治疗糖尿病患者奠定基础。

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.