Strategies based on activating GLP-1 receptor (GLP-1R) are intensively developed for the treatment of type 2 diabetes. The exhaustive knowledge of the signaling pathways linked to activated GLP-1R within the ␤-cells is of major importance. In ␤-cells, GLP-1 activates the ERK1/2 cascade by diverse pathways dependent on either G␣ s /cAMP/cAMP-dependent protein kinase (PKA) or ␤-arrestin 1, a scaffold protein. Using pharmacological inhibitors, ␤-arrestin 1 small interfering RNA, and islets isolated from ␤-arrestin 1 knock-out mice, we demonstrate that GLP-1 stimulates ERK1/2 by two temporally distinct pathways. The PKA-dependent pathway mediates rapid and transient ERK1/2 phosphorylation that leads to nuclear translocation of the activated kinases. In contrast, the ␤-arrestin 1-dependent pathway produces a late ERK1/2 activity that is restricted to the ␤-cell cytoplasm. We further observe that GLP-1 phosphorylates the cytoplasmic proapoptotic protein Bad at Ser-112 but not at Ser-155. We find that the ␤-arrestin 1-dependent ERK1/2 activation engaged by GLP-1 mediates the Ser-112 phosphorylation of Bad, through p90RSK activation, allowing the association of Bad with the scaffold protein 14-3-3, leading to its inactivation. ␤-Arrestin 1 is further found to mediate the antiapoptotic effect of GLP-1 in ␤-cells through the ERK1/2-p90RSK-phosphorylation of Bad. This new regulatory mechanism engaged by activated GLP-1R involving a ␤-arrestin 1-dependent spatiotemporal regulation of the ERK1/2-p90RSK activity is now suspected to participate in the protection of ␤-cells against apoptosis. Such signaling mechanism may serve as a prototype to generate new therapeutic GLP-1R ligands.GLP-1 (glucagon-like peptide-1), produced by post-translational processing of the proglucagon in enteroendocrine L-cells, is a potent gluco-regulatory peptide hormone. GLP-1 is released into the blood stream in response to nutrient ingestion, such as carbohydrates, amino acids, and fats, during the early postprandial period (1, 2). A major target for GLP-1 actions is the pancreatic ␤-cell. One of the main physiological roles of this endocrine hormone is to enhance insulin secretion in a glucose-dependent manner (1-5). Besides its insulinotropic action, GLP-1 also favors the maintenance of a correct ␤-cell glucose sensing, regulates transcriptional synthesis, induces ␤-cell proliferation, and is protective against apoptosis (6 -9). Strategies based on activating GLP-1 receptor 3 are intensively developed for the treatment of type 2 diabetes and studies aiming at a better and exhaustive understanding of GLP-1 actions within the ␤-cells are of great importance (1-5).GLP-1 exerts its intracellular effects through binding to its specific receptor that spans the plasma membrane. The GLP-1R belongs to the class II (or B) secretin/glucagon/vasoactive intestinal peptide superfamily of heptahelical transmembrane G protein-coupled receptors (GPCRs) (10, 11). The GLP-1R is positively coupled to adenylate cyclase, through G␣ s -containing heterotrimeric G-prot...

Graphical Abstract Highlights d Adipocyte DPP4 contributes to circulating sDPP4, but not to glucose homeostasis d Hepatocyte DPP4 contributes to its circulating activity and hepatic/adipose inflammation d Circulating, soluble DPP4 is markedly induced by systemic DPP4 enzymatic inhibition d DPP4 activity and sDPP4 levels do not correlate with extent of metabolic inflammation