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Histone Deacetylase Inhibitors Prevent Cytokine-Induced ß Cell Dysfunction Through Restoration of Stromal Interaction Molecule 1 Expression and Activation of Store-Operated Calcium Entry.
Lee, Chih-Chun; Kono, Tatsuyoshi; Syed, Farooq; Weaver, Staci A; Sohn, Paul; Wu, Wenting; Chang, Garrick; Liu, Jing; Rupnik, Marjan Slak; Evans-Molina, Carmella.
Afiliación
  • Lee CC; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Kono T; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Syed F; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Weaver SA; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Sohn P; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Wu W; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Chang G; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Liu J; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Rupnik MS; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • Evans-Molina C; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
bioRxiv ; 2023 Dec 08.
Article en En | MEDLINE | ID: mdl-38106138
ABSTRACT
Histone deacetylase inhibitors (HDIs) modulate ß 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 ß 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 ß cells. Consistently, NaB partially rescued glucose-stimulated Ca2+ oscillations in mouse islets treated with proinflammatory cytokines. Because the oscillatory phenotype of Ca2+ in the ß 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-1ß-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 ß cell death in response to IL-1ß treatment. Mechanistically, NaB counteracted cytokine-mediated reductions in phosphorylation levels of key signaling molecules, including AKT, ERK1/2, glycogen synthase kinase-3α (GSK-3α), and GSK-3ß. Taken together, these data support a model whereby HDI treatment promotes ß 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos