Pharmacological or genetic inhibition of <i>Scn9a</i> protects beta-cells while reducing insulin secretion in type 1 diabetes
Bibliographic record
Abstract
Abstract Pancreatic β 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 β cells in vitro and in vivo . Here, we confirmed the protective effects of carbamazepine and other Na + channel inhibitors in human β cells and investigated the specific role of the Na + channel α subunit gene Scn9a (Nav1.7) in β cell function and survival. We generated β cell-specific knockout mice on the non-obese diabetic (NOD) background both Ins1 Cre knock-in and AAV8- Ins1 -Cre approaches resulting in significant reduction of β cell Na + currents. Ca 2+ responses and insulin secretion were significantly reduced, but only under the highest glucose conditions. Notably, carbamazepine treatment did not further alter insulin secretion or β cell survival in Scn9a -knockout islets, indicating that β cell Scn9a primarily mediates this drug’s measured effects. Consistent with this, β 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 β cells. Collectively, our data show that Scn9a plays important roles in β cell excitability and survival during type 1 diabetes, thereby supporting this ion channel as a potential therapeutic target for β cell preservation. Article Highlights Hyperactivity has been proposed as a driver of β cell dysfunction and death in type 1 diabetes, but the specific role of Na + currents has not been addressed. Targeted Scn9a deletion in β cells using Ins1 Cre knock-in mice reduced Na + channel currents, reduced insulin release at high glucose concentrations, and protected β cells from apoptosis. Targeted deletion of Scn9a in β cells at 6 weeks of age using AAV8- Ins1 Cre reduced diabetes incidence in NOD mice. These findings support the Scn9a Na + channel as a novel therapeutic target in type 1 diabetes.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".