The transcription factor E2F1 controls the GLP-1 receptor pathway in pancreatic β cells
Cyril Bourouh, Émilie Courty, Laure Rolland, Gianni Pasquetti, Xavier Gromada, Nabil Rabhi, Charlène Carney, Maeva Moreno, Raphaël Boutry, Émilie Caron, Zohra Benfodda, Patrick Meffre, Julie Kerr‐Conte, François Pattou, Philippe Froguel, Amélie Bonnefond, Frédérik Oger, Jean‐Sébastien Annicotte
Abstract
The glucagon-like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential in type 2 diabetes (T2D) treatment, notably by improving β cell functions. The cell-cycle regulator and transcription factor E2f1 is involved in glucose homeostasis by modulating β cell mass and function. Here, we report that β cell-specific genetic ablation of E2f1 ( E2f1 β−/− ) impairs glucose homeostasis associated with decreased expression of the Glp-1 receptor ( Glp1r ) in E2f1 β−/− pancreatic islets. Pharmacological inhibition of E2F1 transcriptional activity in nondiabetic human islets decreases GLP1R levels and blunts the incretin effect of GLP1R agonist exendin-4 (ex-4) on insulin secretion. Overexpressing E2f1 in pancreatic β cells increases Glp1r expression associated with enhanced insulin secretion mediated by ex-4. Interestingly, ex-4 induces retinoblastoma protein (pRb) phosphorylation and E2f1 transcriptional activity. Our findings reveal critical roles for E2f1 in β cell function and suggest molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways.