Timed Inhibition of Orexin System by Suvorexant Improved Sleep and Glucose Metabolism in Type 2 Diabetic db/db Mice.
Timed Inhibition of Orexin System by Suvorexant Improved Sleep and Glucose Metabolism in Type 2 Diabetic db/db Mice.
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DOI：
10.1210/en.2016-1404
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发表时间：
2016-09
期刊：
影响因子：
4.8
通讯作者：
H. Tsuneki;K. Kon;Hisakatsu Ito;M. Yamazaki;Satoyuki Takahara;N. Toyooka;Y. Ishii;M. Sasahara;T. Wada;M. Yanagisawa;T. Sakurai;T. Sasaoka
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文献类型：
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作者：
H. Tsuneki;K. Kon;Hisakatsu Ito;M. Yamazaki;Satoyuki Takahara;N. Toyooka;Y. Ishii;M. Sasahara;T. Wada;M. Yanagisawa;T. Sakurai;T. Sasaoka
睡眠障碍与2型糖尿病有关;因此，改善睡眠可以改善代谢紊乱。为了研究这种可能性，我们在此研究了苏沃雷生（一种靶向食欲素系统的抗失眠药物）对2型糖尿病小鼠睡眠和葡萄糖代谢的影响。与非糖尿病db/m+对照小鼠相比，糖尿病db/db小鼠在休息期间具有更长的觉醒时间。在开灯时（即，静息期开始时）单次或7天给予苏沃雷生可增加静息期非快速眼动睡眠时间，因此减少清醒时间。苏沃雷生每日静息期给药2-4周可改善db/db小鼠的糖耐量受损，而不影响体重增加、摄食量、全身胰岛素敏感性或血清胰岛素和胰高血糖素水平。脂代谢和炎症指标，如肝脏甘油三酯含量和肝脏及脂肪组织中TNF-α mRNA水平无变化。苏沃雷生对葡萄糖耐量的改善作用与肝脏促凋亡因子的表达水平降低相关，包括静息期肝脏中的磷酸烯醇式丙酮酸羧激酶和过氧化物酶体增殖物激活受体-γ共激活因子-1 α。相比之下，每日清醒期给予苏沃雷生对葡萄糖代谢无有益影响。这些结果表明，苏沃雷生诱导的静息期睡眠时间增加改善了db/db小鼠的肝脏葡萄糖代谢。我们的研究结果为开发针对食欲素操作的睡眠/觉醒调节系统的新型2型糖尿病药物干预提供了见解。
Sleep disturbances are associated with type 2 diabetes; therefore, the amelioration of sleep may improve metabolic disorders. To investigate this possibility, we here examined the effects of suvorexant, an antiinsomnia drug targeting the orexin system, on sleep and glucose metabolism in type 2 diabetic mice. Diabetic db/db mice had a longer wakefulness time during the resting period, as compared with nondiabetic db/m+ control mice. The single or 7-day administration of suvorexant at lights-on (ie, the beginning of the resting phase) increased nonrapid eye movement sleep time during the resting phase and, as a consequence, reduced awake time. The daily resting-phase administration of suvorexant for 2-4 weeks improved impaired glucose tolerance in db/db mice without affecting body weight gain, food intake, systemic insulin sensitivity, or serum insulin, and glucagon levels. No changes were detected in the markers of lipid metabolism and inflammation, such as the hepatic triglyceride content and Tnf-α mRNA levels in liver and adipose tissues. The improving effect of suvorexant on glucose tolerance was associated with a reduction in the expression levels of hepatic gluconeogenic factors, including phosphoenolpyruvate carboxykinase and peroxisome proliferator-activated receptor-γ coactivator-1α in the liver in the resting phase. In contrast, the daily awake-phase administration of suvorexant had no beneficial effect on glucose metabolism. These results suggest that the suvorexant-induced increase of sleep time at the resting phase improved hepatic glucose metabolism in db/db mice. Our results provide insight into the development of novel pharmacological interventions for type 2 diabetes that target the orexin-operated sleep/wake regulatory system.