The Liver Circadian Clock Modulates Biochemical and Physiological Responses to Metformin.

Metformin is widely used in the treatment of type 2 diabetes to lower blood glucose. Though it is a relatively safe and effective drug, clinical efficacy is variable and under certain circumstances it may contribute to life-threatening lactic acidosis. Thus, additional understanding of metformin pharmacokinetics and pharmacodynamics could provide important information regarding therapeutic usage of this widely prescribed drug. Here we report a significant effect of time of day on acute blood glucose reduction in response to metformin administration and on blood lactate levels in healthy mice. Furthermore, we demonstrate that while metformin transport into hepatocytes is unaltered by time of day, the kinetics of metformin-induced activation of AMP-activated protein kinase (AMPK) in the liver are remarkably altered with circadian time. Liver-specific ablation of Bmal1 expression alters metformin induction of AMPK and blood glucose response but does not completely abolish time of day differences. Together, these data demonstrate that circadian rhythms impact the biological responses to metformin in a complex manner.

二甲双胍广泛用于2型糖尿病的治疗以降低血糖。尽管它是一种相对安全有效的药物，但临床疗效存在差异，在某些情况下可能导致危及生命的乳酸酸中毒。因此，进一步了解二甲双胍的药代动力学和药效学可为这种广泛使用的药物的治疗应用提供重要信息。在此我们报道了在健康小鼠中，一天中的不同时间对二甲双胍给药后的急性血糖降低以及血乳酸水平有显著影响。此外，我们证明虽然二甲双胍进入肝细胞的转运不受一天中时间的影响，但肝脏中二甲双胍诱导的腺苷酸活化蛋白激酶（AMPK）激活的动力学随昼夜时间有显著变化。肝脏特异性敲除Bmal1基因表达会改变二甲双胍对AMPK的诱导以及血糖反应，但不会完全消除一天中不同时间的差异。总之，这些数据表明昼夜节律以复杂的方式影响对二甲双胍的生物学反应。