胰岛素分泌的双开关:KCNH6的促胰岛素分泌作用

Double switch of insulin secretion:the effect of KCNH6 on insulin secretion

以往认为,使用60年的经典降糖老药磺脲类药物作用于体内的胰岛素"开关",即胰岛β细胞去极化钾通道KATP,从而促进胰岛素分泌。我们的研究发现,体内胰岛素分泌还受胰岛β细胞复极化钾通道KCNH6的调节。本项目从一个大型四代糖尿病家系入手,发现该家系同时存在新生儿低血糖与成年糖尿病。该家系KCNH6钾通道基因突变与新生儿低血糖与成年糖尿病共分离。有趣的是,KCNH6基因敲除(KO)或点突变人源化敲入(KI)小鼠的糖尿病表型特征与该家系糖尿病人一致。经过近10年的研究,揭示了KCNH6对胰岛素分泌至关重要,提出了胰岛素分泌"双开关"控制理论。研究成果发表在2018年末的Cell子刊Cell Reports上。

It was believed that sulfonylureas,a 60-year-old classical antidiabetic drug,acted on the insulin secretion"switch",i.e.KATP,the depolarized potassium channel of isletβ-cells in vivo,thus promoting insulin secretion.Our study found that insulin secretion is also regulated by KCNH6,the repolarization potassium channel of isletβ-cells in vivo.This study was starting from finding a large family with four generation diabetes.We found that there were neonatal hypoglycemia and adult diabetes in this family.KCNH6 potassium channel gene mutation was co-separated from neonatal hypoglycemia and adult diabetes.Interestingly,mice with KCNH6 knockout(KO)or humanized point mutation knockin(KI)have the same diabetic phenotypic characteristics as those of the diabetic family.After nearly 10 years of research,it was revealed that KCNH6 is very important for insulin secretion,and the"double switch"control theory of insulin secretion was put forward.The results were published in the journal Cell Reports at the end of 2018.