Abstract
Store-operated calcium entry (SOCE) is a mechanism that functions to refill endoplasmic reticulum (ER) Ca2+ stores in response to ER Ca2+ depletion, through gating of plasmallemal Ora channels by the ER Ca2+ sensor STIM1. Dysfunctional β cell SOCE has been observed in response to cytokine-mediated stress and in models of diabetes. To identify compounds capable of modulating SOCE, a screening was performed in INS-1 cells treated with interleukin-1β (IL-1β). Two HDAC inhibitors (HDACi), sodium butyrate (NaB) and MS275, rescued SOCE in a dose-dependent manner in IL-1β-treated INS-1 cells. While dysregulation of HDACs has been linked with metabolic disease, the relationship between HDACs and SOCE has not been tested in the pancreatic β cell. To this end, we explored the effect of HDACi on Ca2+ signaling, insulin secretion, and gene expression in cytokine-treated islets and β cells. In mouse islets treated with IL-1 β and interferon-𝛾;, NaB and MS275 increased first phase Ca2+ responses in response to glucose, while NaB restored glucose-induced Ca2+ oscillations. Consistent with this, NaB, but not MS275, restored GSIS in IL-1β-treated INS-1 cells and in human islets from donors with type 2 diabetes. Chronic (24 hrs) but not acute (8 hrs) HDACi treatment restored cytokine-mediated reductions in SOCE, raising the possibility that changes in gene expression may underlie these effects. To test this, qRT-PCR for SOCE molecular components was performed. Both NaB and MS275 restored STIM1 expression but had no effect on Orai1, Orai2 and Orai3 levels. Consistent with this, HDACi were unable to restore SOCE in IL-1β-treated STIM1 knockout INS-1 cells. Taken together, these data suggest that HDAC inhibition restores insulin secretion under pro-inflammatory conditions through improved SOCE and upregulated STIM1 expression. Thus, our findings identify a novel pathway through which HDAC inhibition exerts protective effects in the diabetic β cell. Disclosure C. Lee: None. T. Kono: None. S.A. Weaver: None. P. Sohn: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. Funding National Institute of Diabetes and Digestive and Kidney Diseases (2R01DK093954)
Published Version
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