Chacon Aaron N, Su Wen, Hou Tianfei, Guo Zhenheng, Gong Ming C
bioRxiv. 2024 Jul 4:2024.07.02.601700. doi: 10.1101/2024.07.02.601700.
Type 2 diabetics have an increased prevalence of hypertension and nondipping blood pressure (BP), which worsen cardiovascular outcomes. Exenatide, a short acting glucagon-like peptide-1 receptor agonist (GLP-1RA) used to treat type 2 diabetes, also demonstrates blood pressure (BP)-lowering effects. However, the mechanisms behind this and the impact of administration timing on BP dipping remain unclear. We investigated the effects of exenatide intraperitoneal injected at light onset (ZT0) or dark onset (ZT12) in diabetic (db/db) mice and nondiabetic controls. Using radio-telemetry and BioDAQ cages, we continuously monitored BP and food intake. Db/db mice exhibited non-dipping BP and increased food intake. ZT0 exenatide administration restored BP dipping by specifically lowering light-phase BP, while ZT12 exenatide reversed dipping by lowering dark-phase BP. These effects correlated with altered food intake patterns, and importantly, were abolished when food access was removed. Additionally, urinary norepinephrine excretion, measured by HPLC, was significantly reduced 6 hours post-exenatide at both ZT0 and ZT12, suggesting sympathetic nervous system involvement. Notably, combining exenatide with either ganglionic blocker mecamylamine or α-blocker prazosin did not enhance BP reduction beyond the individual effects of each blocker. These findings reveal that exenatide, when administered at light onset, restores BP dipping in db/db mice by suppressing light-phase food intake and sympathetic activity. Importantly, the efficacy of exenatide is dependent on food availability and its timing relative to circadian rhythms, highlighting the potential for chronotherapy in optimizing GLP-1RA- based treatments for type 2 diabetes and hypertension.
Maintaining a normal blood pressure (BP) circadian rhythm is vital for cardiovascular health, but diabetes often disrupts this rhythm. The effect of exenatide, a GLP-1 receptor agonist (GLP-1RA), on BP rhythm in diabetes is uncertain.This study investigates the impact of exenatide administration timing on BP patterns in diabetic db/db mice.Findings indicate that exenatide given at the onset of rest restores normal BP dipping, while at the start of the active phase worsens BP rhythm by modulating food intake and sympathetic activity.Timing GLP-1 RA administration may optimize BP control and provide cardiovascular benefits for type 2 diabetes patients.
2型糖尿病患者高血压和血压非勺型变化（BP）的患病率增加，这会使心血管疾病预后恶化。艾塞那肽是一种用于治疗2型糖尿病的短效胰高血糖素样肽-1受体激动剂（GLP-1RA），也具有降压作用。然而，其背后的机制以及给药时间对血压勺型变化的影响仍不清楚。我们研究了在光照开始时（ZT0）或黑暗开始时（ZT12）腹腔注射艾塞那肽对糖尿病（db/db）小鼠和非糖尿病对照小鼠的影响。使用无线电遥测和BioDAQ笼，我们持续监测血压和食物摄入量。db/db小鼠表现出血压非勺型变化且食物摄入量增加。ZT0给予艾塞那肽通过特异性降低光照期血压恢复了血压勺型变化，而ZT12给予艾塞那肽通过降低黑暗期血压逆转了勺型变化。这些作用与食物摄入模式的改变相关，重要的是，当去除食物供应时这些作用消失。此外，通过高效液相色谱法测量，在ZT0和ZT12给予艾塞那肽后6小时尿去甲肾上腺素排泄均显著减少，提示交感神经系统参与其中。值得注意的是，将艾塞那肽与神经节阻滞剂美加明或α受体阻滞剂哌唑嗪联合使用，并不会在每种阻滞剂单独作用的基础上增强血压降低效果。这些发现表明，在光照开始时给予艾塞那肽，通过抑制光照期食物摄入和交感神经活动，可恢复db/db小鼠的血压勺型变化。重要的是，艾塞那肽的疗效取决于食物供应情况及其相对于昼夜节律的时间，这突出了时间疗法在优化基于GLP-1RA的2型糖尿病和高血压治疗中的潜力。
维持正常的血压昼夜节律对心血管健康至关重要，但糖尿病常常会扰乱这种节律。GLP-1受体激动剂（GLP-1RA）艾塞那肽对糖尿病患者血压节律的影响尚不确定。本研究调查了艾塞那肽给药时间对糖尿病db/db小鼠血压模式的影响。研究结果表明，在休息开始时给予艾塞那肽可恢复正常的血压勺型变化，而在活动期开始时给予则会通过调节食物摄入和交感神经活动使血压节律恶化。安排GLP-1RA给药时间可能会优化血压控制，并为2型糖尿病患者带来心血管益处。
