Pharmacological or genetic inhibition of Scn9a protects beta-cells while reducing insulin secretion in type 1 diabetes

Abstract Pancreatic β-cells are critical for systemic glucose homeostasis, and most of them undergo cell death during the pathogenesis of type 1 diabetes. We previously showed that a Na + channel inhibitor, carbamazepine, could protect β-cells in vitro and in vivo . Here, we confirmed the effects of carbamazepine and other Na + channel inhibitors on human islets and focused on the specific role of the Na + channel gene, Scn9a (Nav1.7), in β-cell function and survival. Because Scn9a can be found in multiple human and mouse islet cell types, we generated a β-cell specific knockout of Scn9a on the non-obese diabetic (NOD) background. We crossed an Scn9a flox/flox allele onto the Ins1 Cre knock-in mouse line resulting in the following genotypes: knockout (NOD. Ins1 Cre ; Scn9a flox/flox ), heterozygous (NOD. Ins1 Cre ; Scn9a flox/wt ), and wildtype littermate controls (NOD. Ins1 Cre ; Scn9a wt/wt ). We observed near complete ablation of Na + currents in knockout β-cells, and intermediate Na + currents in the heterozygotes. Insulin secretion in response to 15 mM glucose, but not lower concentrations, was significantly reduced from NOD. Ins1 Cre ; Scn9a flox/flox and NOD. Ins1 Cre ; Scn9a wt/wt islets from both male and female mice. These effects of carbamazepine on insulin secretion in vitro were not additive to the effects of Scn9a knockout, suggesting that Scn9a is the main target of carbamazepine in β-cells that is relevant for insulin secretion. Complete Scn9a deletion also protected β-cells from death in vitro , similarly and non-additively to carbamazepine treatment. Finally, we assessed diabetes incidence in Nod. Scn9a flox/flox mice and NOD. Ins1 Cre ; Scn9a wt/wt mice injected with AAV8- Ins1 Cre virus and a found significant reduction in diabetes incidence in β-cell specific knockout mice compared with littermate controls. Collectively, our data show the Scn9a plays important roles in β-cell function, but also contributes to β-cell death and type 1 diabetes progression. Scn9a is a novel drug target to preserve β-cells in type 1 diabetes.