Pharmacological blockade of the EP3 prostaglandin E2 receptor in the setting of type 2 diabetes enhances β-cell proliferation and identity and relieves oxidative damage

作者：Karin J. Bosma, Spencer R. Andrei, Liora S. Katz, Ashley A. Smith, Jennifer C. Dunn, Valerie Ricciardi, Marisol Ramirez, Sharon Baumel-Alterzon, William A. Pace, Darian T. Carroll, Emily M. Overway, Elysa M. Wolf, Michelle E. Kimple, Quanhu Sheng, Donald K. Scott, Richard Breyer, Maureen Gannon · 发表于：Molecular Metabolism · 年份：2021 · DOI：10.1016/j.molmet.2021.101347 · 被引用次数：27 · 研究领域：Pancreatic function and diabetes、Diabetes and associated disorders、Diabetes Treatment and Management

Type 2 diabetes is characterized by hyperglycemia and inflammation. Prostaglandin E2, which signals through four G protein-coupled receptors (EP1-4), is a mediator of inflammation and is upregulated in diabetes. We have shown previously that EP3 receptor blockade promotes β-cell proliferation and survival in isolated mouse and human islets ex vivo. Here, we analyzed whether systemic EP3 blockade could enhance β-cell mass and identity in the setting of type 2 diabetes using mice with a spontaneous mutation in the leptin receptor (Leprdb). Four- or six-week-old, db/+, and db/db male mice were treated with an EP3 antagonist daily for two weeks. Pancreata were analyzed for α-cell and β-cell proliferation and β-cell mass. Islets were isolated for transcriptomic analysis. Selected gene expression changes were validated by immunolabeling of the pancreatic tissue sections. EP3 blockade increased β-cell mass in db/db mice through enhanced β-cell proliferation. Importantly, there were no effects on α-cell proliferation. EP3 blockade reversed the changes in islet gene expression associated with the db/db phenotype and restored the islet architecture. Expression of the GLP-1 receptor was slightly increased by EP3 antagonist treatment in db/db mice. In addition, the transcription factor nuclear factor E2-related factor 2 (Nrf2) and downstream targets were increased in islets from db/db mice in response to treatment with an EP3 antagonist. The markers of oxidative stress were decreased. Th...