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

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Author(s)
Yang, Jin-Kui
Lu, Jing
Yuan, Sha-Sha
Asan
Cao, Xi
Qiu, Hai-Yan
Shi, Ting-Ting
Yang, Fang-Yuan
Li, Qian
Liu, Cui-Ping
Wu, Qian
Wang, Yu-Hui
Huang, Hai-Xia
Kayoumu, Abudurexiti
Feng, Jian-Ping
Xie, Rong-Rong
Zhu, Xiao-Rong
Liu, Chang
Yang, Guang-Ran
Zhang, Ming-Rong
Xie, Chun-Lan
Chen, Chen
Zhang, Bo
Liu, George
Zhang, Xiu-Qing
Xu, Aimin
Griffith University Author(s)
Year published
2018
Metadata
Show full item recordAbstract
Glucose-stimulated insulin secretion from islet β cells is mediated by K ATP channels. However, the role of non-K ATP K + channels in insulin secretion is largely unknown. Here, we show that a non-K ATP 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 ...
View more >Glucose-stimulated insulin secretion from islet β cells is mediated by K ATP channels. However, the role of non-K ATP K + channels in insulin secretion is largely unknown. Here, we show that a non-K ATP 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.
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View more >Glucose-stimulated insulin secretion from islet β cells is mediated by K ATP channels. However, the role of non-K ATP K + channels in insulin secretion is largely unknown. Here, we show that a non-K ATP 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.
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Journal Title
Cell Reposrts
Volume
25
Issue
13
Copyright Statement
© 2018 The Author(s).This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Subject
Biochemistry and cell biology
Medical physiology
Science & Technology
Life Sciences & Biomedicine
Cell Biology
PANCREATIC BETA-CELLS
POTASSIUM CHANNEL