LRRC8/VRAC anion channels enhance β-cell glucose sensing and insulin secretion

Glucose homeostasis depends critically on insulin that is secreted by pancreatic beta-cells. Serum glucose, which is directly sensed by beta-cells, stimulates depolarization- and Ca2+-dependent exocytosis of insulin granules. Here we show that pancreatic islets prominently express LRRC8A and LRRC8D, subunits of volume-regulated VRAC anion channels. Hypotonicity- or glucose-induced p-cell swelling elicits canonical LRRC8A-dependent VRAC currents that depolarize beta-cells to an extent that causes electrical excitation. Glucose-induced excitation and Ca2+ responses are delayed in onset, but not abolished, in beta-cells lacking the essential VRAC subunit LRRC8A. Whereas Lrrc8a disruption does not affect tolbutamide- or high-K+-induced insulin secretion from pancreatic islets, it reduces first-phase glucoseinduced insulin secretion. Mice lacking VRAC in beta-cells have normal resting serum glucose levels but impaired glucose tolerance. We propose that opening of LRRC8/VRAC channels increases glucose sensitivity and insulin secretion of beta-cells synergistically with K-ATP closure. Neurotransmitter-permeable LRRC8D-containing VRACs might have additional roles in autocrine/paracrine signaling within islets.