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

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  • Additional Information
    • Affiliation:
      1 Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
      2 Binhai Genomics Institute & Tianjin Translational Genomics Center, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China
      3 Guangzhou Key Laboratory of Cancer Trans-Omics Research, BGI-Guangzhou, BGI-Shenzhen, Guangzhou 510006, China
      4 Department of Endocrinology, Beijing Chuiyangliu Hospital, Beijing 100022, China
      5 Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing 100871, China
      6 Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Institute of Cardiovascular Science, Peking University, Beijing 100083, China
      7 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
      8 School of Biomedical Sciences, University of Queensland, Brisbane 4072, Australia
      9 The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen 518083, China
      10 State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Pokfulam, Hong Kong
      11 Department of Medicine, University of Hong Kong, Pokfulam, Hong Kong
    • Note:
      Published: December 26, 2018
    • Keywords:
      maturity-onset diabetes of the young
      MODY
      monogenic diabetes
      type 2 diabetes
      islet
      insulin secretion
      KCNH6
      KCNH2
      KATP
      Cas9
    • Abstract:
      Summary 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.
    • Abstract:
      @@@@Highlights •KCNH6 regulates insulin secretion and glucose hemostasis in humans and mice•KCNH6 dysfunction causes a phenotype from hyper- to hypoinsulinemia and diabetes•KCNH6 dysfunction increases intracellular calcium levels and hyperinsulinemia•Chronic elevation of intracellular calcium causes β cell loss and hypoinsulinemia
    • Abstract:
      @@@@Yang et al. show that KCNH6 plays a key role in insulin secretion and glucose hemostasis in humans and mice. Dysfunction of KCNH6 results in a hyperinsulinemia phenotype in the short term and hypoinsulinemia and diabetes in the long term.
    • ISSN:
      2211-1247
    • Accession Number:
      10.1016/j.celrep.2018.12.005
    • Accession Number:
      S2211124718319168
    • Copyright:
      © 2018 The Author(s).
  • Citations
    • ABNT:
      YANG, J.-K. et al. From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion. Cell Reports, [s. l.], v. 25, n. 13, p. 3800–3810, 2018. Disponível em: . Acesso em: 14 out. 2019.
    • AMA:
      Yang J-K, Lu J, Yuan S-S, et al. From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion. Cell Reports. 2018;25(13):3800-3810. doi:10.1016/j.celrep.2018.12.005.
    • APA:
      Yang, J.-K., Lu, J., Yuan, S.-S., Asan, Cao, X., Qiu, H.-Y., … Xu, A. (2018). From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion. Cell Reports, 25(13), 3800–3810. https://doi.org/10.1016/j.celrep.2018.12.005
    • Chicago/Turabian: Author-Date:
      Yang, Jin-Kui, Jing Lu, Sha-Sha Yuan, Asan, Xi Cao, Hai-Yan Qiu, Ting-Ting Shi, et al. 2018. “From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion.” Cell Reports 25 (13): 3800–3810. doi:10.1016/j.celrep.2018.12.005.
    • Harvard:
      Yang, J.-K. et al. (2018) ‘From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion’, Cell Reports, 25(13), pp. 3800–3810. doi: 10.1016/j.celrep.2018.12.005.
    • Harvard: Australian:
      Yang, J-K, Lu, J, Yuan, S-S, Asan, Cao, X, Qiu, H-Y, Shi, T-T, Yang, F-Y, Li, Q, Liu, C-P, Wu, Q, Wang, Y-H, Huang, H-X, Kayoumu, A, Feng, J-P, Xie, R-R, Zhu, X-R, Liu, C, Yang, G-R, Zhang, M-R, Xie, C-L, Chen, C, Zhang, B, Liu, G, Zhang, X-Q & Xu, A 2018, ‘From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion’, Cell Reports, vol. 25, no. 13, pp. 3800–3810, viewed 14 October 2019, .
    • MLA:
      Yang, Jin-Kui, et al. “From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion.” Cell Reports, vol. 25, no. 13, Dec. 2018, pp. 3800–3810. EBSCOhost, doi:10.1016/j.celrep.2018.12.005.
    • Chicago/Turabian: Humanities:
      Yang, Jin-Kui, Jing Lu, Sha-Sha Yuan, Asan, Xi Cao, Hai-Yan Qiu, Ting-Ting Shi, et al. “From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion.” Cell Reports 25, no. 13 (December 26, 2018): 3800–3810. doi:10.1016/j.celrep.2018.12.005.
    • Vancouver/ICMJE:
      Yang J-K, Lu J, Yuan S-S, Asan, Cao X, Qiu H-Y, et al. From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion. Cell Reports [Internet]. 2018 Dec 26 [cited 2019 Oct 14];25(13):3800–10. Available from: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edselp&AN=S2211124718319168&custid=s8280428