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

Yang Gao ,Bo Zhang,Jing Lü ,Haixia Huang ,Conghua Xie ,Abudurexiti Kayoumu,Cuiping Liu ,Qian Wu,Haiyan Qiu ,Chen Chen,Jin-Kui Yang,Yuhui Wang ,Qian Li,Ming‐Rong Zhang ,Asan Asan,Jiafu Feng ,Chang Liu,Xun Zhu ,Aimin Xu,Shaohua Yuan ,Xiuqing Zhang ,Ri-Hua Xie ,George Liu,Tingting Shi ,Fengying Yang ,Xi Cao

doi:10.1016/j.celrep.2018.12.005

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.

Highlights

Glucose-stimulated insulin secretion (GSIS) from pancreatic islet b cells is regulated by a series of electrogenic events
Reports have shown that the ether-a-go-gorelated gene (ERG) channel is an active participant in the regulation of b cell electrical activity and insulin secretion in the rat pancreas and b cells in vitro (Mu€hlbauer et al, 2007)
In 2010, we performed whole-exome sequencing on four affected individuals (II-1, III-3, III-9, and III-14) who were diagnosed with diabetes at 30, 23, 30, and 35 years of age, respectively (Figure 1A; Tables S1 and S2)

Summary

Introduction

Glucose-stimulated insulin secretion (GSIS) from pancreatic islet b cells is regulated by a series of electrogenic events. This electrogenic mechanism is generally referred to as the ATP-sensitive potassium (KATP) channel pathway. Metabolism of glucose leads to an increase in the ATP/ADP ratio. This increase causes closure of KATP channels, depolarization of the plasma membrane, influx of calcium through voltage-gated calcium channels (VDCCs), and exocytosis of insulin secretory granules. Studies in vitro have shown evidence for non-KATP channel stimulation of insulin secretion by glucose, especially a role for voltage-dependent K+ (Kv) channels as modulators of insulin secretion (Felix-Martınez and Godınez-Fernandez, 2014; Yang et al, 2014). Glucosedependent stimulation of insulin secretion from Kv channel blockers has been reported in rodent islets and insulinoma cells (MacDonald et al, 2001, 2002)

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Discussion

Conclusion