LRRC8 channel complexes counterbalance K_ATP channels to mediate swell-secretion coupling in mouse pancreatic β cells

Insulin secretion from pancreatic β cells is initiated by membrane potential depolarization, followed by activation of voltage-gated Ca²⁺ channels to trigger Ca²⁺-mediated insulin vesicle fusion with the β cell plasma membrane. Here, we show that β cell swelling associated with glucose metabolism was sensed by LRRC8 channel complexes and contributed to insulin secretion. Hypertonic perfusate (360–380 mOsm) dose dependently impaired glucose-stimulated insulin secretion by counteracting β cell swelling. Hypotonic perfusate alone, independent of glucose stimulation or K_ATP channel closure, was sufficient to increase β cell intracellular Ca²⁺ and trigger insulin secretion. Inhibition of sodium-potassium-chloride cotransporter-1 with bumetanide, which diminished the intracellular Cl– concentration in β cells and consequently reduced Cl– efflux via LRRC8 channel complexes, also significantly reduced hypotonic-stimulated insulin secretion. Finally, stimulation of insulin secretion by the glucokinase activator GKA50, which is known to induce β cell swelling, was entirely suppressed in β cell–targeted Lrrc8a KO islets. These data support a model wherein the LRRC8 channel complex senses β cell swelling triggered by glucose metabolism and regulates β cell insulin secretion through activation of LRRC8-mediated Cl– efflux.