Glucose-stimulated insulin and glucagon release regulates glucose homeostasis by an excitation-secretion coupling pathway beginning with ATP-sensitive K⁺ channel closure, membrane depolarization, and entry of calcium ions to stimulate exocytosis. The contribution of voltage-gated sodium channels to this release pathway is still being elucidated. We demonstrate that loss of Scn1b, a major regulatory subunit expressed with Na_v1.7 protein in mouse pancreatic islets, reduces glucose-stimulated insulin and glucagon secretion in vitro and in vivo, resulting in severe fed and fasting hypoglycemia. This genetic mouse model is the first to demonstrate that sodium channelopathy impairs the physiological excitation-release coupling pathway for pancreatic insulin and glucagon release.

This genetic mouse model establishes an essential role for voltage-gated sodium channels in the physiological excitation-release pathway mediating pancreatic glucose homeostasis.