期刊
MOLECULAR METABOLISM
卷 54, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.molmet.2021.101347
关键词
Type 2 diabetes; Mouse model; Prostaglandin E-2; Beta cell proliferation; Nrf2
资金
- National Institutes of Health [DK-20593]
- Vanderbilt Integrated Biological Systems Training in Oncology Training Grant [T32CA119925-01A2]
- Vanderbilt University Training Program in Molecular Endocrinology [5T32 DK7563-30]
- NRSA from NIH/NIDDK [1F31 DK127613-01]
- NIH [K01 DK102598]
- Department of Veterans Affairs [I01 BX003700, 1IO1 BX0037440-01, R01 DK120626, R01 DK114338, R01 HL134895, R21 AG065859, R03 AG063217]
- Vanderbilt Institute of Chemical Biology, Chemical Synthesis Core, Vanderbilt University, Nashville, TN
EP3 blockade promotes an increase in beta cell mass in db/db mice with type 2 diabetes, without affecting alpha cell proliferation. This effect may be mediated through the regulation of Nrf2, which plays a key role in protection against oxidative damage.
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 13-cell proliferation and survival in isolated mouse and human islets ex vivo. Here, we analyzed whether systemic EP3 blockade could enhance 13cell 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 a-cell and 13-cell proliferation and 13-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 13-cell mass in db/db mice through enhanced 13-cell proliferation. Importantly, there were no effects on a-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 13-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. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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