AbstractInsulin secretion from the pancreatic β-cell initiated by activation of voltage-gated Ca2+channels (VGCC) to trigger Ca2+-mediated insulin vesicle fusion with the β-cell plasma membrane. The firing of VGCC depends on the β-cell membrane potential, which is in turn mediated by the balance of depolarizing (excitatory) and hyperpolarizing (inhibitory) ionic currents1-3. While much attention has focused on inhibitory potassium currents4-10there is little knowledge about the excitatory currents required to depolarize the β-cell, including the molecular identity of these excitatory currents3. Here we show that SWELL1 (LRRC8a) mediates a swell-activated, depolarizing chloride current (ICl,SWELL)in β-cells. Hypotonic and glucose-stimulated β-cell swelling activates SWELL1-mediated ICl,SWELLand this is required for both glucose-stimulated and hypotonic swell-mediated activation of VGCC-dependent intracellular calcium signaling in β-cells. SWELL1 KO MIN6 cells and β-cell targeted SWELL1 KO murine islets exhibit significantly impaired glucose-stimulated insulin secretion, with preserved insulin contentin vitro. Tamoxifen-inducible β-cell targetedSWELL1KO mice have normal fasting insulin levels but display markedly impaired glucose-stimulated insulin secretion. Our results reveal a physiological role for SWELL1 as a glucose sensor - linking glucose-mediated β-cell swelling to SWELL1-dependent activation of VGCC-triggered calcium signaling, and highlights SWELL1-mediated “swell-secretion” coupling as required for glucose-stimulated insulin secretion.