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

Jin-Kui Yang1, Jing Lu1, Sha-Sha Yuan1

  • 1Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.

Cell Reports
|December 28, 2018
PubMed

Insights

A novel non-ATP-sensitive potassium channel, KCNH6, is crucial for insulin secretion and glucose balance. Its dysfunction leads to initial hyperinsulinemia followed by beta cell failure and diabetes.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Insulin secretion is primarily regulated by ATP-sensitive potassium (KATP) channels in pancreatic islet beta cells.
  • The function of non-ATP-sensitive potassium (non-KATP) channels, such as KCNH6, in insulin secretion remains largely uncharacterized.

Purpose of the Study:

  • To investigate the role of the non-KATP K+ channel KCNH6 in insulin secretion and glucose homeostasis.
  • To elucidate the molecular mechanisms underlying KCNH6 dysfunction in diabetes.

Main Methods:

  • Human genetic analysis of a four-generation pedigree with a KCNH6 mutation.
  • Generation and analysis of Kcnh6 knockout (KO) and knockin (KI) mouse models.
  • Assessment of islet function, intracellular calcium levels, endoplasmic reticulum (ER) stress, and apoptosis in mouse models.

Main Results:

  • A heterozygous KCNH6 p.P235L mutation was linked to diabetes in humans.
  • Kcnh6 KO/KI mice exhibited a progression from hypoglycemia with hyperinsulinemia to hyperglycemia with insulin deficiency.
  • Early-stage KO islets showed increased intracellular calcium and insulin secretion, while adult KO islets displayed ER stress, apoptosis, reduced beta cell mass, and impaired insulin secretion.

Conclusions:

  • KCNH6 is a critical regulator of insulin secretion and glucose homeostasis in both humans and mice.
  • KCNH6 dysfunction initially causes insulin hypersecretion, leading to beta cell exhaustion, ER stress, apoptosis, and ultimately, diabetes.
Keywords:
Cas9KATPKCNH2KCNH6MODYinsulin secretionisletmaturity-onset diabetes of the youngmonogenic diabetestype 2 diabetes

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