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

Karin J. Bosma, Spencer R. Andrei, Liora S. Katz, Ashley A. Smith, Jennifer C. Dunn, Valerie F. Ricciardi, Marisol A. 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 M. Breyer, Maureen Gannon

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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 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). 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 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. Results: 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. Conclusions: 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.

Original languageEnglish
Article number101347
JournalMolecular Metabolism
Volume54
DOIs
StatePublished - Dec 2021

Keywords

  • Beta cell proliferation
  • Mouse model
  • Nrf2
  • Prostaglandin E
  • Type 2 diabetes

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