Bioinformatics Research Center, North Carolina State University, Raleigh, NC.
Department of Statistics, North Carolina State University, Raleigh, NC.
Diabetes. 2018 Jul;67(7):1428-1440. doi: 10.2337/db17-1164. Epub 2018 Apr 12.
Metformin is the first-line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here, we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA response to metformin treatment and followed up these findings in four replication cohorts. Common variants in and were associated with worse and better metformin response, respectively ( < 5 × 10), and meta-analysis in independent cohorts displayed similar associations with metformin response ( = 1.2 × 10 and = 0.005, respectively). Previous studies have shown that (+/-) knockout mice have increased total body fat ( = 1.78 × 10) and increased fasted circulating glucose ( = 5.73 × 10). Furthermore, rare variants in associated with worse metformin response ( <0.1). STAT3 is a ubiquitously expressed pleiotropic transcriptional activator that participates in the regulation of metabolism and feeding behavior. Here, we provide novel evidence for associations of common and rare variants in and with metformin response that may provide insight into mechanisms important for metformin efficacy in T2D.
二甲双胍是治疗 2 型糖尿病 (T2D) 的一线药物。尽管广泛应用，但二甲双胍的降血糖机制尚未完全阐明。在这里，我们在来自糖尿病心血管风险行动 (ACCORD) 临床试验的一组不同的 T2D 个体中使用全基因组关联方法来识别与二甲双胍治疗 HbA 反应相关的常见和罕见变异体，并在四个复制队列中对这些发现进行了随访。与更好的二甲双胍反应相关的常见变异体位于 和 （ < 5 × 10），在独立队列中的荟萃分析显示出与二甲双胍反应相似的关联（ = 1.2 × 10 和 = 0.005，分别）。先前的研究表明，( +/-) 敲除小鼠具有更高的全身脂肪量（ = 1.78 × 10）和空腹循环葡萄糖量（ = 5.73 × 10）。此外，与二甲双胍反应较差相关的罕见变异体位于 （ <0.1）。STAT3 是一种广泛表达的多功能转录激活因子，参与代谢和摄食行为的调节。在这里，我们提供了位于 和 中的常见和罕见变异体与二甲双胍反应相关的新证据，这可能为理解二甲双胍在 T2D 中的疗效的重要机制提供了新的思路。
