Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes.
Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes.
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二甲双胍是治疗 2 型糖尿病最常用的药物。我们对 1024 名苏格兰 2 型糖尿病患者对二甲双胍的血糖反应进行了 GWA 研究。复制是在两个队列中进行的，其中包括 1783 名苏格兰患者和来自英国前瞻性糖尿病研究的 1113 名患者。在荟萃分析 (n=3920) 中，我们观察到包含共济失调毛细血管扩张突变 (ATM) 基因的位点上的 SNP rs11212617 存在关联 (P=2.9 *10−9)，与治疗成功的优势比为 1.35 (95% CI 1.22 至 1.49)。在大鼠肝癌细胞系中，用 KU-55933 抑制 ATM 会减弱二甲双胍对 AMPK 的磷酸化和激活。我们得出结论，ATM 是一种已知参与 DNA 修复和细胞周期控制的基因，在 AMPK 上游二甲双胍的作用中发挥作用，并且该基因的变异会改变对二甲双胍的血糖反应。
Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We carried out a GWA study on glycaemic response to metformin in 1024 Scottish patients with type 2 diabetes. Replication was in two cohorts consisting of 1783 Scottish patients and 1113 patients from the UK Prospective Diabetes Study. In a meta-analysis (n=3920) we observed an association (P=2.9 *10−9) for a SNP rs11212617 at a locus containing the ataxia telangiectasia mutated (ATM) gene with an odds ratio of 1.35 (95% CI 1.22 to 1.49) for treatment success. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMPK in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMPK, and variation in this gene alters glycaemic response to metformin.