1248-P: Histone Deacetylase Inhibition Improves Store-Operated Calcium Entry and Glucose-Stimulated Insulin Secretion in Cytokine-Stressed Pancreatic ß-Cells

Abstract

Store-operated calcium entry (SOCE) functions to refill endoplasmic reticulum (ER) Ca2+ stores in response to ER Ca2+ depletion through gating of plasmalemmal Orai channels by the ER Ca2+ sensor STIM1. Dysfunctional β cell SOCE has been observed in response to cytokine-mediated stress, whereas select histone deacetylase (HDAC) inhibitors are able to protect against cytokine-mediated β cell death and have been shown to improve glucose homeostasis in diabetic mice. Here, we tested the relationship between HDAC inhibition and SOCE in the pancreatic β cell. To this end, we investigated the effects of the HDAC inhibitor sodium butyrate (NaB) on Ca2+ signaling, insulin secretion, and gene expression in cytokine-treated mouse islets, human islets, and STIM1 knockout (KO) 832/13 INS-1 β cells. In mouse islets treated with IL-1β, IFN-γ and TNF-⍺, NaB increased glucose-induced phase Ca2+ responses and restored Ca2+ oscillations. In IL-1β-treated INS-1 β cells, NaB rescued SOCE and ER Ca2+ store depletion, and increased glucose-stimulated insulin secretion (GSIS), while additionally improving cell viability and reducing apoptosis. Chronic (24hrs) but not acute (8hrs) NaB treatment prevented IL-1β-mediated reduction in the SOCE response, suggesting changes in gene expression may underlie these effects. To test this, RT-qPCR for SOCE molecular components was performed and revealed increased STIM1 expression in cytokine-treated mouse islets and INS-1 cells, while no change was observed in Orai1/2 levels. Consistent with these results, NaB was unable to restore SOCE in IL-1β-treated STIM1 KO INS-1 cells. Lastly, NaB treatment in human islets from donors with type 2 diabetes significantly increased levels of GSIS. Taken together, these data suggest that HDAC inhibition restores insulin secretion under pro-inflammatory conditions through improved SOCE and STIM1 upregulation. Disclosure C. Lee: None. T. Kono: None. S. A. Weaver: None. P. Sohn: None. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc.