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Introduction and Objective: Loss of beta-cells is a common feature for both type 1 and type 2 diabetes. In pancreatic islets, G protein-coupled receptors (GPCRs) work via neural, endocrine, and immune pathways, thereby regulating beta-cell apoptosis and survival. Recent data argues that GPR75 affects pancreatic islet physiology, however, its direct effect on beta-cell proliferation remains unclear. Methods: To explore the role of GPR75 signaling in beta-cell regeneration, we generated both inducible and non-inducible beta-cell specific GPR75 knockout (BG75KO) mouse models. GTT, ITT, GSIS, BW, and BG were measured. IHC/IF staining was performed for beta-cell proliferation, area, apoptosis, and mass under regular and challenged (HFD) conditions. Moreover, RNA sequencing analyses were performed on control and BG75KO islets. Results: While inducible BG75KO mice (75-80% recombination efficacy) did not show a difference regarding beta-cell regeneration, we observed a dramatic increase in both male and female non-inducible BG75KO animals compared to controls. Ki67 staining revealed higher beta-cell proliferation in 6-, 12-, and 52-week-old male and female BG75KO mice compared to age-matched controls (>2.5-fold, p<0.01) and were independent of blood glucose or apoptosis. Although beta-cell apoptosis was not changed between groups (both genders), beta-cell area and mass increased >1.5-fold (p<0.01) in 6-week-old βG75KO mice. In a separate cohort, challenging these animals with a high-fat diet further increased beta-cell regeneration (>4-fold, p<0.01). High-fat fed βG75KO mice also exhibited improved glucose tolerance and insulin sensitivity without changes in body weight. No change was observed in other tissues. RNA sequencing results showed that genes involved in the cell cycle and mitosis were upregulated and pathways related to insulin and insulin function were dramatically downregulated. Conclusion: GPR75 plays a critical role in beta cell regeneration and dissecting the mechanism(s) underlying the replication would be an important advance in treating diabetes. Disclosure M. Khan: None. S. Islam: None. J.L. Campanella: None. C. DeFrancesco: None. S.J. Youssef: None. T. Bilgen: None. E. Dirice: None. Funding Breakthrough T1D (3-SRA-2022-1163-S-B)