Search bioRxiv⌕ Search
Home/Archive/bioRxiv

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.
View original source ↗Export metadata ↓

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.

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

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

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Trunk muscle activity across various trunk-limb coordination patterns in centipede locomotion

Animals coordinate movements of their limbs and flexible bodies, yet how trunk muscle activity changes across locomotor patterns remains unclear. We simultaneously recorded electromyograms from trunk muscles (deep dorsal oblique muscles) and trunk-limb kinematics in two centipede species exhibiting retrograde and direct locomotor waves during swimming and walking. During swimming, trunk muscle activity followed a similar phase relationship with trunk bending in both species despite opposite wave directions and different involvement of limbs, suggesting common active generation of undulation. During fast walking, trunk muscle activity was strongest around the ipsilateral swing phase in the undulatory retrograde-wave gait of Scolopendra mutilans, but weaker and associated with the ipsilateral stance phase despite the nearly straight trunk in the direct-wave gait of Scolopocryptops rubiginosus. Together, our findings suggest that the same trunk muscles serve two contrasting mechanical roles depending on locomotor mode: either generating trunk undulation or actively straightening the trunk against limb-induced deformation.

physiology↗
bioRxiv2026

Quantifying and Visualizing the Invisible Hazard of Infant Rebreathing

BACKGROUND: Rebreathing of expired gases during prone infant sleeping contributes to hypoxic and hypercapnic exposure, even without airway obstruction. We investigated how anatomical, physiological, and environmental factors influence aerodynamic rebreathing. METHODS: A dynamically scaled in vitro model simulated prone nasal breathing corresponding to infants weighing 2 to 5 kg, with nostril diameters of 3.2 to 6.0 mm and breathing frequencies of 25 to 40 breaths/min. Ambient temperature and sleep-surface characteristics were varied. Rebreathing was quantified using tracer measurements, while flow visualization revealed the underlying aerodynamic mechanisms. RESULTS: Rebreathing exceeded 60% despite unobstructed nasal openings. Increasing ambient temperature from 23 to 30 degrees C increased rebreathing by 68 to 77%, while reducing simulated infant mass from 5 to 2 kg increased rebreathing by 39 to 46%. Fibrous surfaces increased rebreathing, particularly near inclined nasal openings. A novel finding was that increasing nostril diameter from 3.2 to 6.0 mm increased rebreathing by up to 50%. Flow visualization revealed vortical structures that retained expired fluid near the nasal openings, facilitating re-inspiration. CONCLUSIONS: Aerodynamic rebreathing depends strongly on simulated infant characteristics and sleeping environments. These findings are consistent with established safe-sleep recommendations and identify nostril diameter, for the first time, as a potentially important anatomical factor warranting clinical investigation.

physiology↗
bioRxiv2026

Epigenetic Rescue of Disuse Muscle Atrophy by Histone Deacetylase Inhibitor Trichostatin A

Mechanical unloading rapidly induces skeletal muscle atrophy and functional deterioration, yet how the loss of mechanical input influences nuclear architecture, chromatin organization, and associated transcriptional programs remains poorly understood. Here, we investigated whether pharmacological inhibition of histone deacetylases (HDACs) using Trichostatin A (TSA) could attenuate the consequences of continued mechanical unloading in a murine hindlimb suspension model. Following 14 days of unloading, mice exhibited impaired locomotor activity, altered muscle architecture, and widespread transcriptional reprogramming characterized by increased expression of atrophy associated genes, inflammatory mediators, and extracellular matrix remodeling pathways, alongside suppression of mitochondrial metabolic programs. Super resolution imaging further revealed irregular Lamin A/C organization and disruption of discrete H3K9me3 associated heterochromatin foci. Systemic TSA treatment significantly attenuated the decline in locomotor activity, accompanied by trends toward reduced body weight loss, and preservation of muscle morphology. Transcriptomic analysis demonstrated a substantial shift toward the baseline expression profile, with high-dose TSA attenuating FOXO associated catabolic programs, inflammatory, and extracellular matrix-related signatures, while enhancing mitochondrial oxidative phosphorylation pathways. Quantitative gene level and pathway analyses further revealed dose dependent and selective reversal of unloading associated transcriptional changes. Notably, TSA treatment also partially preserved nuclear lamina organization and the focal distribution of H3K9me3 associated heterochromatin. Despite these muscle specific benefits, TSA did not prevent trabecular bone loss over the 14-day unloading period, although several muscle-expressed genes potentially involved in muscle to bone communication were altered by treatment. Together, these findings demonstrate that HDAC inhibition counteracts multiple functional and molecular consequences of skeletal muscle unloading and is associated with partial preservation of nuclear and heterochromatin organization. This study supports a link between mechanical unloading, nuclear architectural remodeling, and HDAC sensitive transcriptional regulation, providing a foundation for epigenetic strategies to counter disuse induced muscle deterioration.

physiology↗