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

Abstract

Objective

Type 2 diabetes is characterized by hyperglycemia and inflammation. Prostaglandin E ₂, 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 ^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 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.

Highlights

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  Systemic blockade of EP3 in vivo in db/db mice increase beta-cell proliferation and mass.

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  EP3 blockade has no effect on alpha-cell proliferation.

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  EP3 blockade restores islet architecture and beta-cell identity genes in db/db mice.

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  Beta cell GLP-1 receptor expression is increased by EP3 blockade.

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  EP3 blockade activates the Nrf2 anti-oxidant pathway.