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

• Published in: Molecular metabolism (Germany) Vol. 54; p. 101347
• Main Authors: Bosma, Karin J, Andrei, Spencer R, Katz, Liora S, Smith, Ashley A, Dunn, Jennifer C, Ricciardi, Valerie F, Ramirez, Marisol A, Baumel-Alterzon, Sharon, Pace, William A, Carroll, Darian T, Overway, Emily M, Wolf, Elysa M, Kimple, Michelle E, Sheng, Quanhu, Scott, Donald K, Breyer, Richard M, Gannon, Maureen
• Format: Journal Article
• Language: English
• Published: Germany 01.12.2021
• Subjects: Animals; Cell Proliferation - drug effects; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Oxidative Stress - drug effects; Receptors, Prostaglandin E, EP3 Subtype - antagonists & inhibitors; Receptors, Prostaglandin E, EP3 Subtype - metabolism; Type 2 diabetes; Beta cell proliferation; Mouse model; Prostaglandin E; Nrf2
• ISSN: 2212-8778
• DOI: 10.1016/j.molmet.2021.101347

Type 2 diabetes is characterized by hyperglycemia and inflammation. Prostaglandin E , 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 (Lepr ). 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. The current study suggests that EP3 blockade promotes β-cell mass expansion in db/db mice. The beneficial effects of EP3 blockade may be mediated through Nrf2, which has recently emerged as a key mediator in the protection against cellular oxidative damage.