International audience; Background and aims : The scaffold protein beta-arrestin2 (ARRB2) is known to uncouple G protein coupled receptors (GPCRs) from the G protein and to recruit new signaling pathways (such as ERK1/2). It has been reported in non beta cells a direct interaction of ARRB2 with the GLP-1 receptor (GLP-1R), while its interaction with the GIP receptor (GIPR) is unclear. Our aim was to determine if ARRB2 is involved in both incretin receptor signaling in mouse beta cells.Materials and methods : The experiments were carried out in beta cells from five-month-old Arrb2+/+ and Arrb2-/- male mice. cAMP production (CAMPS-epac), endogeneous PKA (AKAR3) and ERK1/2 (EKAR) activations were measured by live microscopy after adenoviral infection of cells with FRET-based sensors of interest. Epac2 (Epac2-GFP) recruitment to the plasma membrane was assessed by TIRF microscopy. Cytosolic Ca2+ concentration ([Ca2+]c) was measured by Fura2-LR.Results: The genetic deletion of Arrb2 in mice was associated with a better oral glucose tolerance and a concomitant increase in plasma insulin concentration (p25 min vs 5min) suggesting slow versus fast recycling receptors, respectively, that were independent of ARRB2 expression. Finally, glucolipotoxic conditions induced a 20% decrease of ARRB2 expression in human islets (p