| First Author | Bosma KJ | Year | 2021 |
| Journal | Mol Metab | Volume | 54 |
| Pages | 101347 | PubMed ID | 34626853 |
| Mgi Jnum | J:313696 | Mgi Id | MGI:6787497 |
| Doi | 10.1016/j.molmet.2021.101347 | Citation | Bosma KJ, et al. (2021) Pharmacological blockade of the EP3 prostaglandin E2 receptor in the setting of type 2 diabetes enhances beta-cell proliferation and identity and relieves oxidative damage. Mol Metab 54:101347 |
| abstractText | OBJECTIVE: 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 beta-cell proliferation and survival in isolated mouse and human islets ex vivo. Here, we analyzed whether systemic EP3 blockade could enhance beta-cell mass and identity in the setting of type 2 diabetes using mice with a spontaneous mutation in the leptin receptor (Lepr(db)). METHODS: 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 alpha-cell and beta-cell proliferation and beta-cell mass. Islets were isolated for transcriptomic analysis. Selected gene expression changes were validated by immunolabeling of the pancreatic tissue sections. RESULTS: EP3 blockade increased beta-cell mass in db/db mice through enhanced beta-cell proliferation. Importantly, there were no effects on alpha-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. CONCLUSIONS: The current study suggests that EP3 blockade promotes beta-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. |
