From hyper- to hypoinsulinemia and diabetes: effect of KCNH6 on insulin secretion

Glucose-stimulated insulin secretion from islet β cells is mediated by K channels. However, the role of non-K K channels in insulin secretion is largely unknown. Here, we show that a non-K 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.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

Additional file 1: Figure S1. of Compound heterozygous mutations in electron transfer flavoprotein dehydrogenase identified in a young Chinese woman with late-onset glutaric aciduria type II

Histological findings of a control case. (TIFF 16416 kb

Additional file 2: Table S1. of Compound heterozygous mutations in electron transfer flavoprotein dehydrogenase identified in a young Chinese woman with late-onset glutaric aciduria type II

Summary of three GA II patients with compound heterozygous mutations including p.S307C. (DOCX 20 kb