Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naïve patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in discovery and replication cohorts. Greater methylation at these sites associated with a higher risk of not responding to or not tolerating metformin with odds ratios between 1.43 and 3.09 per 1-SD methylation increase. Methylation risk scores (MRSs) of the 11 identified sites differed between glycemic responders and nonresponders with areas under the curve (AUCs) of 0.80 to 0.98. MRSs of the 4 sites associated with future metformin intolerance generated AUCs of 0.85 to 0.93. Some of these blood-based methylation markers mirrored the epigenetic pattern in adipose tissue, a key tissue in diabetes pathogenesis, and genes to which these markers were annotated to had biological functions in hepatocytes that altered metformin-related phenotypes. Overall, we could discriminate between glycemic responders/nonresponders and participants tolerant/intolerant to metformin at diagnosis by measuring blood-based epigenetic markers in drug-naïve patients with T2D. This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy.

二甲双胍是用于治疗2型糖尿病（T2D）的一线药物疗法。但是，许多T2D患者对二甲双胍的反应或耐受性都不佳。当前，没有能够成功预测对二甲双胍的血糖反应或耐受性的表型。我们通过分析未确诊的T2D患者在诊断时的全基因组DNA甲基化，探索基于血液的表观遗传标记是否可以区分二甲双胍反应和耐受性。在发现和复制人群中，血糖反应者/非反应者和二甲双胍耐受/不耐受的患者的11和4个位点的DNA甲基化分别不同。这些位点的甲基化程度较高，与对二甲双胍无反应或不耐受的风险较高，每1-SD甲基化程度的比值比在1.43至3.09之间。血糖反应者和非反应者的11个已鉴定位点的甲基化风险评分（MRS）有所不同，曲线下面积（AUC）为0.80至0.98。与未来二甲双胍不耐受相关的4个位点的MRS产生的AUC为0.85至0.93。这些基于血液的甲基化标记中的一些反映了脂肪组织（糖尿病发病机理中的关键组织）的表观遗传模式，并且这些标记被标注为具有改变二甲双胍相关表型的肝细胞生物学功能的基因。总体而言，我们可以通过在未经药物治疗的T2D患者中测量血基表观遗传标记，从而在诊断时区分血糖反应者/非反应者和参与者对二甲双胍的耐受性/不耐受性。可以进一步开发这种基于表观遗传学的工具，以帮助患有T2D的患者接受最佳治疗。