Key result
Dysfunction of KCNH6 causes overstimulation of insulin secretion in the short term and β cell failure in the long term, leading to diabetes.
Why the study?
The role of non-K ATP K+ channels in glucose-stimulated insulin secretion from islet β cells is largely unknown.
Does KCNH6 dysfunction affect insulin secretion and glucose homeostasis?
Does KCNH6 dysfunction affect insulin secretion and glucose homeostasis?
KCNH6 plays a critical role in insulin secretion, where its dysfunction leads to initial hyperinsulinemia followed by beta cell failure and diabetes.
KCNH6 dysfunction may drive diabetes progression; animal data leave open human therapeutic targeting.
Glucose-stimulated insulin secretion from islet β cells is mediated by K ATP channels. However, the role of non-K ATP K + channels in insulin secretion is largely unknown. Here, we show that a non-K ATP 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.
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Yang et al. (2018) studied Diabetes. KCNH6 mutation or knockout was evaluated on Insulin secretion and glucose homeostasis. Dysfunction of KCNH6 causes overstimulation of insulin secretion in the short term and β cell failure in the long term, leading to diabetes.
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