ArticleDiabetes2026
Dual Modulation of Prostaglandin E2 Receptors EP3 and EP4 Protects β-Cell Mass in a Model of Aggressive Autoimmune Inflammation.
Article in Diabetes, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Type 1 diabetes is driven by both β-cell dysfunction and an autoreactive immune system, resulting in β-cell destruction and hyperglycemia. We previously showed that pharmacological modulation of prostaglandin E2 (PGE2) receptor (EP) signaling protects β-cells from cytokine-mediated death ex vivo and relieves oxidative stress and maintains β-cell identity in a mouse model of type 2 diabetes. Here we show that EP modulation protects against cytokine-mediated β-cell death in islets from nonobese diabetic (NOD) mice. Because PGE2 can also alter immune cell phenotypes, we tested whether EP modulation prevents β-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 β-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. However, EP modulation altered islet cytokine expression and, within β-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 β-cell mass under aggressive autoimmune attack to treat or prevent type 1 diabetes. ARTICLE HIGHLIGHTS: Modulation of prostaglandin E2 (PGE2) signaling improves β-cell health and survival. In this study, we examined whether these β-cell effects could be harnessed alongside known PGE2-mediated immunomodulation to ameliorate β-cell loss in a model of severe islet autoimmunity. Simultaneous pharmacological blockade of the EP3 receptor and activation of the EP4 receptor maintain mature β-cell mass, ameliorate the proinflammatory insulitic microenvironment, and alter β-cell stress responses in female nonobese diabetic mice undergoing aggressive inflammatory assault. EP modulation shows promise to support β-cell resiliency and reduce inflammation in a setting of autoimmune attack, such as type 1 diabetes.
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