Opposite functions of beta-arrestin2 for the potentiation of insulin secretion by GLP-1 and GIP

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 (p 25 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<0.05).Conclusion: Our study revealed a differential role of ARRB2 in GLP-1R and GIPR signalling, and therefore a specificity of action for two GPCR positively coupled to cAMP. ARRB2 contributes to a partial uncoupling of cAMP/PKA signalling in the pM range of GLP-1, and consequently reduced insulin secretion. By contrast, ARRB2 plays a crucial role in GIP potentiation of insulin secretion that is independent and/or distal to cAMP, [Ca2+]c and ERK1/2 changes. Therefore, any variation in the expression of ARRB2, as observed in diabetic states, should functionally impact the incretin effect.