Targeting timing of food intake as a novel strategy against disruption of blood pressure circadian rhythm in diabetes

正常的血压昼夜节律对人体健康至关重要，如早晨血压 浪涌与危及生命的心血管事件的发生率增加有关。此外，中断 高达75%的糖尿病患者出现BP昼夜节律，这正在成为未来的一个指标 靶器官损伤和不良心血管结局。然而，BP昼夜节律的机制 糖尿病患者的血压节律紊乱在很大程度上是未知的， 糖尿病的昼夜节律尚未确定。我们的初步研究发现，通过限制 活动期食物可利用时间（ATRF）对糖尿病db/db小鼠具有显著的保护作用 血压昼夜节律的严重紊乱此外，BMAL 1，一个强制性的时钟基因，是必需的 胰高血糖素样肽-1（GLP-1）受体激活通过以下方式模拟BP昼夜节律的保护作用： ATRF。这些有趣的发现表明，ATRF可以作为一种新的策略，以促进正常的血压 昼夜节律，从而显著改善糖尿病患者的心血管预后。的 目前的建议将通过测试特定的假设，即活跃时间- 限制进食（ATRF）或GLP-1激活可恢复正常平滑肌和肾脏BMAL 1， 因此交感神经振荡保护糖尿病小鼠免受血压昼夜节律的破坏。 三个具体目标是：（1）。确定BMAL 1在糖尿病中失调的机制， 由ATRF恢复。2）。检验ATRF通过平滑肌保护血压昼夜节律的假设， 糖尿病患者的肾脏BMAL 1。3）。将ATRF定义为一种新型的时间营养疗法，将GLP-1作为靶点， 保护糖尿病患者血压昼夜节律的新药物治疗。我们会监控他们的昼夜节律 血压节律，食物摄入，BMAL 1调节，血管平滑肌功能和信号传导，肾 功能，以及在随意和ATRF喂养方案下的交感神经调节。各种鼠标 将使用的模型是糖尿病db/db小鼠、db/db-per 2Luc小鼠、高脂肪饮食喂养的小鼠、平滑肌和 肾BMAL 1敲除小鼠。

The normal blood pressure (BP) circadian rhythm is essential to human health, as morning BP surge is associated with increased incidence of life-threatening cardiovascular events. Moreover, disruption of BP circadian rhythm, which occurs in up to 75% of diabetic patients, is emerging as an index for future target organ injury and poor cardiovascular outcomes. However, the mechanism by which BP circadian rhythm is disrupted in diabetes is largely unknown, and an effective strategy to restore the disrupted BP circadian rhythm in diabetes has not yet been identified. Our preliminary studies found that by limiting the time of food available to the active period (ATRF) provided striking protection of the diabetic db/db mice from the severe disruption of BP circadian rhythm. Moreover, BMAL1, an obligatory clock gene, is required for and glucagon-like peptide-1 (GLP-1) receptor activation mimics the protection of BP circadian rhythm by ATRF. These intriguing findings suggest that ATRF can serve as a novel strategy to promote normal BP circadian rhythms, thus significantly improving the cardiovascular prognosis of diabetic patients. The current proposal will examine this new exciting possibility by testing the specific hypothesis that active time- restricted feeding (ATRF) or GLP-1 activation restores normal smooth muscle and renal BMAL1 and sympathetic oscillations thus protects diabetic mice from disruptions of blood pressure circadian rhythm. The three specific aims are 1). Determine the mechanism by which BMAL1 is dysregulated in diabetes and restored by ATRF. 2). Test the hypothesis that ATRF protects BP circadian rhythm via smooth muscle and renal BMAL1 in diabetes. 3). Define ATRF as a novel chrononutritional therapy and targeting GLP-1 as a new pharmacological therapy to protect BP circadian rhythm in diabetes. We will monitor the circadian rhythms of BP, food intake, BMAL1 regulation, vascular smooth muscle function and signaling, renal function, and sympathetic regulation under ad libitum and ATRF feeding regimens. The various mouse models will be used are diabetic db/db mice, db/db-per2Luc mice, high-fat diet fed mice, smooth muscle and renal BMAL1 knockout mice.