<b>Dual modulation of prostaglandin E</b><sub><strong>2</strong></sub><b> receptors, EP3 and EP4, protects beta-cell mass in a model of aggressive autoimmune inflammation</b>

Type 1 diabetes is driven by both beta-cell dysfunction and an autoreactive immune system, resulting in beta-cell destruction and hyperglycemia. We previously showed that pharmacological modulation of prostaglandin E2 (PGE2) receptor (EP) signaling protects beta cells from cytokine-mediated death ex vivo and relieves oxidative stress and maintains beta-cell identity in a mouse model of type 2 diabetes. Here we show that EP modulation protects against cytokine-mediated beta-cell death in islets from nonobese diabetic (NOD) mice. As PGE2 can also alter immune cell phenotypes, we tested whether EP modulation prevents beta-cell destruction in a setting of aggressive autoimmunity in vivo. Simultaneous blockade of the inhibitory EP3 receptor and activation of the stimulatory EP4 receptor delayed onset of hyperglycemia, prevented loss of beta-cell mass, and reduced insulitis in cyclophosphamide-treated female NOD mice. Despite reduced insulitis, there were no changes in several systemic T cell populations, including regulatory T cells (Tregs). However, EP modulation altered islet cytokine expression, and within beta cells, preserved identity, sustained activation of the antioxidant factor, NRF2, and reduced evidence of senescence. Thus, the PGE2 signaling pathway is a potential target for protecting beta-cell mass under aggressive autoimmune attack to treat or prevent type 1 diabetes.