Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues
Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues
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DOI：
10.2337/db16-0512
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发表时间：
2016-12-01
期刊：
影响因子：
7.7
通讯作者：
Wang-Sattler, Rui
中科院分区：
文献类型：
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作者：
Adam, Jonathan;Brandmaier, Stefan;Wang-Sattler, Rui
二甲双胍是提高2型糖尿病（T2D）患者胰岛素敏感性的一线口服药物。我们的目的是利用非靶向代谢组学方法研究二甲双胍的多效性。我们分析了基于人群的人类KORA （Cooperative Health Research in Region of Augsburg）随访调查4队列的空腹血清样本中的353种代谢物。为了比较接受二甲双胍治疗的T2D患者（mt-T2D, n = 74）和未接受抗糖尿病药物治疗的T2D患者（ndt-T2D, n = 115），我们在一项横断面研究中使用了多变量线性回归模型。我们应用了一个广义估计方程来确认683名KORA参与者的纵向样本的初步发现。在转化方法中，我们使用了小鼠血浆、肝脏、骨骼肌和附睾脂肪组织样本，这些样本来自二甲双胍治疗的db/db小鼠，以进一步证实我们在人类研究中的发现。我们发现两种代谢物与二甲双胍治疗显著相关（P < 1.42E-04）。在比较mt-T2D和ndt-T2D时，瓜氨酸在人血清中的相对浓度较低，而未知代谢物X-21365在人血清中的相对浓度较高。在开始二甲双胍治疗的患者中，瓜氨酸在7年随访中被证实显著（P < 2.96E-04）降低。在小鼠实验中，我们证实（P < 4.52E-07），二甲双胍治疗动物的血浆、骨骼肌和脂肪组织中的瓜氨酸值显著降低，但肝脏中没有瓜氨酸值。我们使用非靶向方法观察到瓜氨酸的降低值很可能是由于二甲双胍对联锁尿素和一氧化氮循环的多效性作用。来自多种小鼠组织的转化数据证实并补充了来自人类队列的发现。
Metformin is the first-line oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). Our aim was to investigate the pleiotropic effect of metformin using a nontargeted metabolomics approach. We analyzed 353 metabolites in fasting serum samples of the population-based human KORA (Cooperative Health Research in the Region of Augsburg) follow-up survey 4 cohort. To compare T2D patients treated with metformin (mt-T2D, n = 74) and those without antidiabetes medication (ndt-T2D, n = 115), we used multivariable linear regression models in a cross-sectional study. We applied a generalized estimating equation to confirm the initial findings in longitudinal samples of 683 KORA participants. In a translational approach, we used murine plasma, liver, skeletal muscle, and epididymal adipose tissue samples from metformin-treated db/db mice to further corroborate our findings from the human study. We identified two metabolites significantly (P < 1.42E-04) associated with metformin treatment. Citrulline showed lower relative concentrations and an unknown metabolite X-21365 showed higher relative concentrations in human serum when comparing mt-T2D with ndt-T2D. Citrulline was confirmed to be significantly (P < 2.96E-04) decreased at 7-year follow-up in patients who started metformin treatment. In mice, we validated significantly (P < 4.52E-07) lower citrulline values in plasma, skeletal muscle, and adipose tissue of metformin-treated animals but not in their liver. The lowered values of citrulline we observed by using a nontargeted approach most likely resulted from the pleiotropic effect of metformin on the interlocked urea and nitric oxide cycle. The translational data derived from multiple murine tissues corroborated and complemented the findings from the human cohort.