| Literature DB >> 30590050 |
Jin-Kui Yang1, Jing Lu2, Sha-Sha Yuan2, Xi Cao2, Hai-Yan Qiu2, Ting-Ting Shi2, Fang-Yuan Yang2, Qian Li2, Cui-Ping Liu3, Qian Wu4, Yu-Hui Wang5, Hai-Xia Huang6, Abudurexiti Kayoumu5, Jian-Ping Feng2, Rong-Rong Xie2, Xiao-Rong Zhu2, Chang Liu2, Guang-Ran Yang2, Ming-Rong Zhang7, Chun-Lan Xie7, Chen Chen8, Bo Zhang4, George Liu5, Xiu-Qing Zhang9, Aimin Xu10.
Abstract
Glucose-stimulated insulin secretion from islet β cells is mediated by KATP channels. However, the role of non-KATP K+ channels in insulin secretion is largely unknown. Here, we show that a non-KATP K+ 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. Kcnh6 knockout (KO) or Kcnh6 p.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.Entities:
Keywords: Cas9; KATP; KCNH2; KCNH6; MODY; insulin secretion; islet; maturity-onset diabetes of the young; monogenic diabetes; type 2 diabetes
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Year: 2018 PMID： 30590050 DOI： 10.1016/j.celrep.2018.12.005
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423