2064-P: Pharmacological Modulation of Prostaglandin E2 Receptor Activity Enhances ß-Cell Mass and Maintains ß-Cell Identity in a Mouse Model of Type 2 Diabetes

Type 2 diabetes (T2D) is a chronic condition characterized by hyperglycemia and inflammation. This condition arises in response to a failure to increase β-cell mass in the face of insulin resistance. Prostaglandin E2 (PGE2), which signals through four receptors (EP1-4), is a mediator of inflammation that has been shown to be upregulated in diabetes. Previous data from our lab has shown that EP3 receptor blockade promotes β-cell proliferation and survival in isolated mouse and human islets ex vivo. In the current study, six week-old db/db mice were treated with the EP3 antagonist DG-041 (20 mg/kg) daily for two weeks. Pancreata were excised and analyzed using immunohistochemistry. We found that treatment with DG-041 leads to improved β-cell mass (2.8 ± 1.5 mg) compared to mice treated with vehicle alone (1.0 ± 0.7 mg). Additionally, we also observed increased β-cell proliferation in DG-041-treated mice (2.2 ± 0.6% Ki67+/Ins+ β-cells) compared to vehicle-treated mice (1.6 ± 0.3%). Further analysis demonstrated that the β- to α-cell ratio was altered in mice treated with DG-041 (2.13:1) compared to vehicle-treated mice (1.78:1). We also immunolabeled for MafA and Nkx6.1, as loss of these transcription factors has been correlated with β-cell dysfunction and diabetes progression in db/db mice and humans. DG-041-treated mice had a higher percentage of MafA positive β-cells (50.3 ± 3.8%) compared to vehicle-treated mice (40.7 ± 3.8%) while there were similar numbers of Nkx6.1 positive β-cells in DG-041-treated and vehicle-treated groups (81.3 ± 4.7% and 81 ± 5.1%, respectively). The current results provide evidence that EP3 receptor blockade promotes β-cell mass expansion and proliferation while preserving homeostatic endocrine islet composition. Disclosure A.A. Christensen: None. S.R. Andrei: None. J.C. Dunn: None. V.F. Ricciardi: None. W.A. Pace: None. R.M. Breyer: None. M. Gannon: None. Funding U.S. Department of Veterans Affairs (1I01BX003744-01); National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK120626-01A1)