艾塞那肽降糖疗效存在明显的个体差异，但遗传因素在艾塞那肽降糖疗效中的作用及机制尚未完全阐明。文献报道KCNQ1基因多态性与降糖药物疗效密切相关。前期临床研究发现KCNQ1 rs2237892位点是影响艾塞那肽疗效的关键因素；预实验提示rs2237892位点通过调控LncRNA KCNQ1OT1水平影响KCNQ1表达；KCNQ1钾通道在艾塞那肽调控胰岛素分泌中起重要作用。据此，我们提出：KCNQ1 rs2237892影响LncRNA KCNQ1OT1水平，进而调控KCNQ1钾通道表达，进一步调节KCNQ1钾通道Iks及K+流动方向，影响艾塞那肽调控胰岛素分泌，最终引起艾塞那肽降糖疗效差异。本项目拟在临床、动物、组织及细胞水平研究KCNQ1钾通道在艾塞那肽调控胰岛β细胞功能中的作用及机制；在此基础上进一步验证rs2237892对艾塞那肽降糖疗效的预测作用，为艾塞那肽的精准个体化治疗提供新思路。

Therapeutic responses to exenatide vary considerably among patients with type 2 diabetes mellitus; however, the role and mechanism of action of genetic factors in these therapeutic responses remain elusive. It is reported that a gene polymorphism in KCNQ1 is closely associated with the therapeutic response to antidiabetic drugs. In our previous clinical study, KCNQ1 rs2237892 was found to be a key factor affecting therapeutic response to exenatide. Moreover, based on our preliminary results, rs2237892 could influence KCNQ1 expression by regulating the level of the long noncoding RNA KCNQ1OT1. The KCNQ1 potassium channel plays an important role in insulin secretion, which is regulated by exenatide. Thus, we propose that KCNQ1 mediates KCNQ1OT1 to regulate KCNQ1 expression, further regulating the IKs current and K+ flow direction, and influencing the effect of exenatide on insulin secretion, ultimately contributing to the therapeutic effects of exenatide. In the present study, we examined the role of the KCNQ1 potassium channel in beta cell function regulated by exenatide, as well as the underlying mechanism using clinical samples, animal models, tissues, and cells. Based on our findings, we further verified the predictive role of rs2237892 in the therapeutic response to exenatide in clinical research, and provide novel insights into precise and individualized treatment with exenatide.