钾通道KCNQ1介导的肥胖母鼠子代β细胞分泌功能下降的机制研究

Maternal obesity (MO) is increasing worldwide and is an important risk factor contributing to type 2 diabetes in offspring, though the mechanisms are not well understood. Recent studies showed that MO offspring islets had a 50% decrease in insulin secretion. KCNQ1 encoded a voltage-gated K+ channel located in pancreatic β cells, which was involved in β cells exocytosis and insulin secretion. Our previous study found that KCNQ1 gene was associated with diabetes and reduced serum insulin levels, which could be modified by birth weight. Furthermore, expression of KCNQ1 could be changed by MO. We therefore hypothesize that expression of KCNQ1 in islets is increased by MO and thereby decreased insulin exocytosis. The glucose tolerance, insulin secretion characteristics, and the expression of KCNQ1 in islets of MO offspring will be evaluated in this study. Blocking KCNQ1 channels with 293B and HMR1556, together with KCNQ1-deficient mice, will be used to confirm the effect of KCNQ1 on β cell dysfunction of MO offspring. From the viewpoint of KCNQ1 channel activity mediated insulin release, and clarify the role of KCNQ1 in β cell dysfunction, this project will provide a novel idea and theory for the prevention and treatment of diabetes.

肥胖母亲（MO）子代β细胞分泌功能显著下降达50%，被视为今后糖尿病爆发的重要危险因素，然机制不明。KCNQ1编码β细胞膜电压门控性钾通道，参与调节胰岛素释放。申请者前期研究及预实验结果显示，MO子代糖代谢异常且胰腺KCNQ1表达上调；而KCNQ1与β细胞分泌功能及糖代谢异常的相关可能受宫内环境（MO）影响。推测KCNQ1参与影响MO子代β细胞分泌功能，并导致糖代谢异常的发生。为验证该假说，本课题拟构建胰腺特异性KCNQ1基因敲除小鼠模型，高脂饮食诱导MO并妊娠，评估MO/对照组不同基因型子鼠糖代谢、β细胞分化发育及功能的差异，明确KCNQ1在MO子代β细胞分泌功能下降及糖代谢异常发生中的作用；全基因组表达谱芯片及生物信息学分析进一步探索其机制。本课题将从MO导致的不良“代谢记忆”这一全新视角，深入探讨KCNQ1介导的β细胞分泌功能下降的机制，为糖尿病早期防治（胎儿期）提供新的理论依据。

KCNQ1（potassium voltage-gated channel, KQT-like subfamily, member 1）基因编码胰岛β细胞膜电压门控性钾通道，参与调节胰岛素释放。国内外多项大型全基因组关联分析研究均提示其与2型糖尿病发生及胰岛素分泌有关。本项目构建KCNQ1胰腺条件性敲除小鼠模型，从DNA、RNA和蛋白水平鉴定基因条件性敲除水平，为研究KCNQ1基因在胰腺中的作用提供了平台。随后，我们通过对小鼠发育、体重、血糖、糖耐量、胰岛面积及细胞增殖等的系统评估，明确了KCNQ1基因在小鼠β细胞分泌胰岛素过程中的关键作用。同时，申请者前期研究及预实验结果显示，肥胖母亲子代糖代谢异常且胰腺KCNQ1表达上调；而KCNQ1与β细胞分泌功能及糖代谢异常的相关可能受宫内环境（母亲肥胖）影响。推测KCNQ1参与影响肥胖母鼠子代β细胞分泌功能，并导致糖代谢异常的发生。为验证该假说，本课题尝试构建高脂饮食诱导肥胖母鼠模型并与KCNQ1基因条件性敲除雄鼠交配妊娠，评估母鼠肥胖对不同基因型子鼠糖代谢、β细胞分化发育及功能的差异。本课题深入探讨KCNQ1介导的β细胞分泌功能下降的机制，为深入理解糖尿病发病机制提供新的理论依据。