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Sodium Channel β1 Regulatory Subunit Deficiency Reduces Pancreatic Islet Glucose-Stimulated Insulin and Glucagon Secretion

Developmental Neurogenetics Laboratory, Departments of Molecular and Human Genetics (S.J.E., J.L.N.) and Neurology (S.J.E., J.L.N.), Baylor College of Medicine, Houston, Texas 77030; and Pacific Northwest Research Institute (L.A.-B.), Seattle, Washington 98122

Address all correspondence and requests for reprints to: Jeffrey L. Noebels, M.D., Ph.D., One Baylor Plaza, Department of Neurology, NB220, Houston, Texas 77030. E-mail: jnoebels{at}bcm.edu.

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.