From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion.-猫眼课题宝

DOI：

10.1016/j.celrep.2018.12.005

发表时间：

2018-12

期刊：

Cell reports

影响因子：

8.8

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

Jinkui Yang;Jing-Kai Lu;S. Yuan;Asan;Xi Cao;Hai-Yan Qiu;Tingting Shi;Fang-Yuan Yang;Qian Li;Cui-Ping Liu;Qiang-ju Wu;Yu-hui Wang;Haixia Huang;Abudurexiti Kayoumu;Jian-Ping Feng;Rongrong Xie;Xiao-rong Zhu;Chang Liu;Guang-Ran Yang;Ming-Rong Zhang;Chun-Lan Xie;Chen Chen-Chen;Bo Zhang;George Liu;Xiu-Qing Zhang;A. Xu

葡萄糖刺激的胰岛β细胞的胰岛素分泌是由KATP通道介导的。然而，非KATPK+通道在胰岛素分泌中的作用在很大程度上是未知的。在这里，我们展示了一个非KATPK+通道，KCNH6，在人类和小鼠的胰岛素分泌和葡萄糖止血中起着关键作用。Kcnh6基因敲除(KO)或Kcnh6p.P235L敲门基因(KI)小鼠的表型特征是从低血糖伴高胰岛素血症向高血糖伴胰岛素缺乏转变。幼年KO小鼠的胰岛细胞内钙浓度增加，胰岛素分泌增加。然而，成年KO小鼠的胰岛不仅细胞内钙水平升高，而且存在显著的内质网应激和细胞凋亡，与β细胞质量损失和胰岛素分泌减少有关。因此，KCNH6功能障碍在短期内会导致胰岛素分泌的过度刺激，而在长期内会导致β细胞衰竭。

Glucose-stimulated insulin secretion from islet β cells is mediated by KATPchannels. However, the role of non-KATPK+channels in insulin secretion is largely unknown. Here, we show that a non-KATPK+channel, KCNH6, plays a key role in insulin secretion and glucose hemostasis in humans and mice. KCNH6 p.P235L heterozygous mutation co-separated with diabetes in a four-generation pedigree.Kcnh6knockout (KO) orKcnh6p.P235L knockin (KI) mice had a phenotype characterized by changing from hypoglycemia with hyperinsulinemia to hyperglycemia with insulin deficiency. Islets from the young KO mice had increased intracellular calcium concentration and increased insulin secretion. However, islets from the adult KO mice not only had increased intracellular calcium levels but also had remarkable ER stress and apoptosis, associated with loss of β cell mass and decreased insulin secretion. Therefore, dysfunction of KCNH6 causes overstimulation of insulin secretion in the short term and β cell failure in the long term.

From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion.

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