Effects of Genistein on Inflammasome Induced Pancreatic β-Cell Apoptosis by Dexamethasone

Steroid-induced diabetes is a well-known side effect of prolonged glucocorticoid (GC) treatment. Endoplasmic reticulum (ER) stress has been identified as one of the mechanisms underlying GC-induced pancreatic β-cell apoptosis. Recent studies suggest a connection between ER stress and the NLRP3 inflammasome, which promotes cell apoptosis. Genistein, a phytoestrogen, has demonstrated protective effects against pancreatic β-cell apoptosis induced by toxic agents. This study aims to investigate whether genistein protects against dexamethasone-induced pancreatic β-cell apoptosis by reducing ER stress and NLRP3 inflammasome activation. This study demonstrates that dexamethasone induces pancreatic β-cell apoptosis by increasing cPARP protein expression. Dexamethasone upregulates SERCA, IRE1-α, and sXBP expressions, while increasing pJNK and Bax and decreasing Bcl-2 protein expressions. Furthermore, dexamethasone upregulates TXNIP, a link protein between ER stress and the NLRP3 inflammasome, and increases NLRP3 and ASC, components of the NLRP3 inflammasome, leading to increase IL-1β expressions. Co-treatment of dexamethasone with genistein decreases cPARP expression, reduces SERCA, IRE1-α, sXBP, pJNK, and Bax, and induces Bcl-2 expressions. Co-treatment significantly decreases TXNIP, NLRP3, ASC, and IL-1β expressions. Similar results were observed in pancreatic islets for cPARP, NLRP3, and IL-1β. This study demonstrates that genistein protects against dexamethasone-induced pancreatic β-cell apoptosis by decreasing ER stress and the NLRP3 inflammasome.