ABSTRACT
Here, we demonstrate that the voltage-gated proton channel Hv1 represents a regulatory mechanism for insulin secretion of pancreatic islet β cell. In vivo, Hvl-deficient mice display hyperglycemia and glucose intolerance due to reduced insulin secretion, but normal peripheral insulin sensitivity. In vitro, islets of Hv1-deficient and heterozygous mice, INS-1 (832/13) cells and islets with siRNA-mediated knockdown of Hv1 exhibit a marked defect in glucose-, sulfonylurea-, K+-, arginine-induced insulin secretion. Hv1 deficiency decreases both insulin and proinsulin contents, and has an impairment on glucose- and sulfonylurea-induced intracellular Ca2+ homeostasis and membrane depolarization. Furthermore, loss of Hv1 decreases insulin-containing granule pH and increases cytosolic pH in INS-1 (832/13) cells. In addition, histologic studies show a decrease in a and β cell masses in islets of Hv1-deficient mice, and a significant reduction at Hv1 expression levels in pancreatic β cells of streptozotocin (STZ)-induced diabetes mice and high-glucose induced INS-1 (832/13) cell dysfunction. Collectively, our in vitro and in vivo results indicate that Hv1 is required for insulin secretion in the β cell and a major link between β cell dysfunction and diabetes. Our study sheds light on a new biological function of the proton channel.