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

项目总结 2型糖尿病是世界上最流行、最昂贵的慢性病之一。高血压和 非降低血压(BP)是2型糖尿病的常见并存疾病，也是 有害的心血管后果。虽然高达75%的糖尿病患者不是勺子，但没有有效的治疗方法 目标是糖尿病患者的非降压BP。胰升糖素样肽-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-1RAs的使用迅速增加，因为它们 最近认识到的心血管益处，包括降低血压和有效降低HbA1C 和体重。然而，GLP-1RA是否影响糖尿病患者的非降压血压的研究很少。 GLP-1RA降低血压的机制尚不明确。我们的初步数据表明， 首次将短效GLP-1RA，exenatide(Ex)，当注射时。转化为2型糖尿病db/db小鼠 非活动期开始(ZT0，点亮时间)，有效地将非下降压恢复到正常下降压。 相反，当在活动暗阶段开始时(ZT12，亮起时间)给药，Ex恶化 非浸渍BP至反向浸渍(最有害的干扰)。我们的初步数据也首次显示 GLP-1受体(GLP-1R)mRNA随时间变化，受时钟基因BMAL1调控。 有趣的是，我们还发现，在ZT0或ZT12给药的Ex恢复或逆转了小鼠的摄食节律 Db/db小鼠及其对血压的影响。再加上我们最近的出版物，证明了时间- 限制喂养有效防治交感神经系统(SNS)引起的非浸润性BP 糖尿病db/db小鼠和迷走神经将食物摄入与血压调节联系起来的文献证据，我们 假设在ZT0给药GLP-1RA通过GLP-1抑制食物摄取、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 具体目的：1.研究GLP-1RA作为一种新的时辰药物，通过 抑制2型糖尿病患者的食物摄入。目的2.明确GLP-1RA保护BP的机制 2型糖尿病患者的昼夜节律。为了实现这些目标，我们将确定短期普洛斯的效果- 1Ra Ex和长效GLP-1RA利拉鲁肽ZT0或ZT12对大鼠心肌细胞昼夜节律的影响 糖尿病db/db，db/db-Per2Luc，BMal1-Iko，GLP1R-KO， 脑特异性GLP1R-KO和迷走神经特异性GLP1R-KO小鼠。这个 拟议的研究将提供新的临床前证据，表明GLP-1RA是一种新的 以2型糖尿病非降压为靶点的时辰药物，从而改善2型糖尿病的预后和结局 糖尿病患者。此外，拟议的研究结果将为GLP-1受体如何降低提供新的线索 为优化糖尿病患者的GLP-1RA治疗奠定了基础。

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.