Safai N, Suvitaival T, Ali A, Spégel P, Al-Majdoub M, Carstensen B, Vestergaard H, Ridderstråle M
Steno Diabetes Center Copenhagen, Gentofte, Denmark.
Unit of Molecular Metabolism, Department of Clinical Sciences Malmö, Lund University, Malmö.
Diabet Med. 2018 Jul;35(7):944-953. doi: 10.1111/dme.13636. Epub 2018 May 2.
Metformin is the first-line treatment for Type 2 diabetes. However, not all people benefit from this drug. Our aim was to investigate the effects of metformin on the plasma metabolome and whether the pretreatment metabolite profile can predict HbA outcome.
Post hoc analysis of the Copenhagen Insulin and Metformin Therapy (CIMT) trial, a multicentre study from May 2008 to December 2012, was carried out. We used a non-target method to analyse 87 plasma metabolites in participants with Type 2 diabetes (n = 370) who were randomized in a 1 : 1 ratio to 18 months of metformin or placebo treatment. Metabolites were measured by liquid chromatography-mass spectrometry at baseline and at 18-month follow-up and the data were analysed using a linear mixed-effect model.
At baseline, participants who were on metformin before the trial (n = 312) had higher levels of leucine/isoleucine and five lysophosphatidylethanolamines (LPEs), and lower levels of carnitine and valine compared with metformin-naïve participants (n = 58). At follow-up, participants randomized to metformin (n = 188) had elevated levels of leucine/isoleucine and reduced carnitine, tyrosine and valine compared with placebo (n = 182). At baseline, participants on metformin treatment with the highest levels of carnitine C10:1 and leucine/isoleucine had the lowest HbA (P-interaction = 0.02 and 0.03, respectively). This association was not significant with HbA at follow-up.
Metformin treatment is associated with decreased levels of valine, tyrosine and carnitine, and increased levels of leucine/isoleucine. None of the identified metabolites can predict the HbA -lowering effect of metformin. Further studies of the association between metformin, carnitine and leucine/isoleucine are warranted.
二甲双胍是2型糖尿病的一线治疗药物。然而，并非所有人都能从这种药物中获益。我们的目的是研究二甲双胍对血浆代谢组的影响，以及治疗前的代谢物谱是否能预测糖化血红蛋白（HbA）的结果。
对哥本哈根胰岛素与二甲双胍治疗（CIMT）试验进行事后分析，该试验是一项从2008年5月至2012年12月的多中心研究。我们采用非靶向方法分析了2型糖尿病患者（n = 370）的87种血浆代谢物，这些患者以1∶1的比例随机分配接受为期18个月的二甲双胍或安慰剂治疗。在基线和18个月随访时通过液相色谱 - 质谱法测量代谢物，并使用线性混合效应模型分析数据。
在基线时，试验前服用二甲双胍的参与者（n = 312）与未服用二甲双胍的参与者（n = 58）相比，亮氨酸/异亮氨酸和五种溶血磷脂酰乙醇胺（LPE）水平较高，肉碱和缬氨酸水平较低。在随访时，随机分配接受二甲双胍治疗的参与者（n = 188）与接受安慰剂治疗的参与者（n = 182）相比，亮氨酸/异亮氨酸水平升高，肉碱、酪氨酸和缬氨酸水平降低。在基线时，肉碱C10:1和亮氨酸/异亮氨酸水平最高的二甲双胍治疗参与者的糖化血红蛋白水平最低（P交互作用分别为0.02和0.03）。这种关联在随访时与糖化血红蛋白无显著相关性。
二甲双胍治疗与缬氨酸、酪氨酸和肉碱水平降低以及亮氨酸/异亮氨酸水平升高有关。所鉴定的代谢物均不能预测二甲双胍的糖化血红蛋白降低效果。有必要进一步研究二甲双胍、肉碱和亮氨酸/异亮氨酸之间的关联。
