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

Cell Rep. 2018 Dec 26;25(13):3800-3810.e6. doi: 10.1016/j.celrep.2018.12.005.


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.

Keywords: Cas9; KATP; KCNH2; KCNH6; MODY; insulin secretion; islet; maturity-onset diabetes of the young; monogenic diabetes; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Adolescent
  • Adult
  • Animals
  • Base Sequence
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / pathology*
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / metabolism*
  • Female
  • Genes, Dominant
  • HEK293 Cells
  • Humans
  • Hyperinsulinism / pathology*
  • Insulin Secretion*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Ion Channel Gating
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation / genetics
  • Pedigree
  • Young Adult


  • Ether-A-Go-Go Potassium Channels
  • KCNH6 protein, human
  • Kcnh6 protein, mouse