Role of the voltage-gated proton channel Hv1 in insulin secretion, glucose homeostasis, and obesity

Abstract

Diabetes is characterized by an absolutely inadequate insulin secretion (type 1 diabetes mellitus) or a relative deficit in insulin secretion due to insulin resistance (type 2 diabetes mellitus), both of which result in elevated blood glucose. Understanding the molecular mechanisms underlying the pathophysiology of diabetes could lead to the development of new therapeutic approaches. The voltage-gated proton channel Hv1 is an ion channel with specific selectivity for protons, which is regulated by membrane potential and intracellular pH. Recently, our studies showed that Hv1 is expressed in β cells of the endocrine pancreas. Knockout of Hv1 reduces insulin secretion and results in hyperglycemia and glucose intolerance, but not insulin resistance. Furthermore, knockout of Hv1 leads to diet-induced obesity due to inflammation and hepatic steatosis. Increasing evidence suggests that Hv1 plays a pivotal role in glucose homeostasis and lipid metabolism. This review aims to summarize advances made so far in our understanding of the roles of Hv1 in the regulation of insulin secretion in β cells, glucose homeostasis, and obesity.