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bioRxiv · 10.1101/2023.06.11.544521

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

Overby, P.·Provenzano, S.·Nahirney, N. S.·Dai, X.-Q.·Sun, W. G.·Xia, Y.·Kolic, J.·Macdonald, P. E.·Johnson, J. D.
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Abstract

Pancreatic {beta} cells are essential for glucose homeostasis and are progressively lost during the development of type 1 diabetes. We previously demonstrated that the use-dependent Na+ channel inhibitor, carbamazepine, protects mouse {beta} cells in vitro and in vivo. Here, we confirmed the protective effects of carbamazepine and other Na+ channel inhibitors in human {beta} cells and investigated the specific role of the Na+ channel {beta} subunit gene Scn9a (Nav1.7) in {beta} cell function and survival. We generated {beta} cell-specific knockout mice on the non-obese diabetic (NOD) background both Ins1Cre knock-in and AAV8-Ins1-Cre approaches resulting in significant reduction of {beta} cell Na+ currents. Ca2+ responses and insulin secretion were significantly reduced, but only under the highest glucose conditions. Notably, carbamazepine treatment did not further alter insulin secretion or {beta} cell survival in Scn9a-knockout islets, indicating that {beta} cell Scn9a primarily mediates this drug's measured effects. Consistent with this, {beta} cell-specific deletion of Scn9a using AAV8-Ins1-Cre significantly reduced diabetes incidence in NOD mice. scRNAseq showed that this protection was associated with reduced Ins2 and increased Cdk8 in {beta} cells. Collectively, our data show that Scn9a plays important roles in {beta} cell excitability and survival during type 1 diabetes, thereby supporting this ion channel as a potential therapeutic target for {beta} cell preservation.

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Overby, P., Provenzano, S., Nahirney, N. S., Dai, X.-Q., Sun, W. G., Xia, Y., Kolic, J., Macdonald, P. E., Johnson, J. D.. 2023-06-12. Pharmacological or genetic inhibition of Scn9a protects beta-cells while reducing insulin secretion in type 1 diabetes. https://doi.org/10.1101/2023.06.11.544521

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