Central hallmarks of type 2 diabetes (T2D) such as hyperglycemia, lipotoxicity, inflammation, and insulin resistance drive chronic β-cell stress, particularly through the accumulation of reactive oxygen species (ROS), which eventually leads to β-cell death and demise. Nrf2 is a master antioxidant transcription factor that regulates ROS accumulation and ROS-induced damage by promoting the transcription of crucial antioxidants such as SOD1, HO-1, and Gpx. Activation of Nrf2 in the β cell enhances β-cell proliferation and preserves β-cell mass in murine models. Our lab has shown that pharmacological blockade of the Gi coupled GPCR, EP3, stimulates β-cell proliferation and increases β-cell specific Nrf2 expression in the db/db mouse. Our group also found that expression of the Gs coupled GPCR, GLP-1R, is similarly enhanced with EP3 blockade. GLP-1R agonism is well known for its role in enhancing GSIS and promoting β-cell proliferation. However, GLP-1R agonism is also shown to activate Nrf2 and exert an additive effect on cAMP accumulation and insulin secretion when paired with EP3 blockade. Together, this has led us to determine whether EP3 antagonism and GLP-1R agonism activate Nrf2, thereby enhancing β-cell proliferation and functional mass.