These last years, loss of β cell-specific traits has been proposed as a cause of β cell failure during type 2 diabetes (T2D) development, but the molecular mechanisms remain unclear. Our lab identified an important role for E2F1, cell cycle regulator, in the control of a regulatory gene network essential for maintaining the functional and molecular traits of mature β cells. The E2f1 inactivation in β cells (E2f1β-/-) caused glucose intolerance and hypoinsulinemia associated with altered islet morphology. Immunofluorescence assays demonstrated an increase of α-cell number in E2f1-deficient islets, suggesting a molecular link between E2F1 and β-cell identity. Since E2F1 levels are reduced in human T2D islets, we suggest that E2F1 could represent a key transcription factor necessary to maintain β-cell identity. Since Glucagon-like peptide-1 receptor (Glp-1R) deficient mice also have altered islet morphology (Z Ling, et al, 2001), as observed for E2f1-deficient islets, we hypothesized that E2F1 could play a critical role in mediating the GLP-1 effects in β cells. Compared to control mice, oral glucose tolerance tests (OGTT) demonstrated that E2f1β-/- mice are intolerant to glucose. Conversely, mice overexpressing hE2F1 specifically in β cells have improved tolerance to glucose during OGTT, suggesting that the GLP-1 pathway may be affected by E2F1. These metabolic alterations are linked to variation in Glp-1R expression in pancreatic islets of these mice. Bioinformatic analysis of the Glp-1R promoter further revealed the presence of an E2F1 DNA-binding site. Chromatin immunoprecipitation demonstrated differential epigenetic regulation of the Glp-1R promoter in the absence of E2f1. Finally, treatment of human islets with an E2F inhibitor led to decreased GLP-1R expression. Altogether our data suggest that E2F1 could be a crucial transcription factor necessary to maintain β-cell function and identity through the control of β-cell gene markers including Glp-1R levels.