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bioRxiv · 10.1101/2023.12.06.570443

Histone Deacetylase Inhibitors Prevent Cytokine-Induced β Cell Dysfunction Through Restoration of Stromal Interaction Molecule 1 Expression and Activation of Store-Operated Calcium Entry

Lee, C.-C.·Kono, T. M.·Syed, F.·Weaver, S. A.·Sohn, P.·Wu, W.·Chang, G.·Liu, J.·Rupnik, M. S.·Evans-Molina, C.
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Abstract

Histone deacetylase inhibitors (HDIs) modulate {beta} cell function in preclinical models of diabetes; however, the mechanisms underlying these beneficial effects have not been determined. In this study, we investigated the impact of the HDI sodium butyrate (NaB) on {beta} cell function and calcium (Ca2+) signaling using ex vivo and in vitro models of diabetes. Our results show that NaB significantly improved glucose-stimulated insulin secretion in islets from human organ donors with type 2 diabetes and in cytokine-treated INS-1 {beta} cells. Consistently, NaB partially rescued glucose-stimulated Ca2+ oscillations in mouse islets treated with proinflammatory cytokines. Because the oscillatory phenotype of Ca2+ in the {beta} cell is governed by changes in endoplasmic reticulum (ER) Ca2+ levels, next we explored the relationship between NaB and store-operated calcium entry (SOCE), a rescue mechanism that acts to refill ER Ca2+ levels through STIM1-mediated gating of plasmalemmal Orai channels. We found that NaB treatment preserved basal ER Ca2+ levels and restored SOCE in IL-1{beta}-treated INS-1 cells. Furthermore, we linked these changes with the restoration of STIM1 levels in cytokine-treated INS-1 cells and mouse islets, and we found that NaB treatment was sufficient to prevent {beta} cell death in response to IL-1{beta} treatment. Mechanistically, NaB counteracted cytokine-mediated reductions in phosphorylation levels of key signaling molecules, including AKT, ERK1/2, glycogen synthase kinase-3 (GSK-3), and GSK-3{beta}. Taken together, these data support a model whereby HDI treatment promotes {beta} cell function and Ca2+ homeostasis under proinflammatory conditions through STIM1-mediated control of SOCE and AKT-mediated inhibition of GSK-3.

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Lee, C.-C., Kono, T. M., Syed, F., Weaver, S. A., Sohn, P., Wu, W., Chang, G., Liu, J., Rupnik, M. S., Evans-Molina, C.. 2023-12-08. Histone Deacetylase Inhibitors Prevent Cytokine-Induced β Cell Dysfunction Through Restoration of Stromal Interaction Molecule 1 Expression and Activation of Store-Operated Calcium Entry. https://doi.org/10.1101/2023.12.06.570443

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