Glucagon Switches between GLP-1 and Glucagon Receptors in Normal and Hyperglycemic Mice

Despite the well-known role of the GLP-1 receptor (GLP-1R) in potentiating glucose-stimulated insulin secretion (GSIS) and as a therapeutic drug target in diabetes treatment, how GLP-1R is activated under physiological and pathological conditions remains elusive. Against preconceptions in the field, we prove that glucagon released from pancreatic α-cells serves as the principal ligand for GLP-1R on β-cells and is essential for GSIS in normal mice. Activation of the cognate glucagon receptor (GCGR) by glucagon amplifies GSIS evoked by intermediate concentrations of glucose only, as high glucose bypasses GCGR in increasing cytosolic cAMP from the same downstream pool. As the endogenous dual-receptor agonist, glucagon switches from GLP-1R to GCGR in β-cells of mice fed a high-fat diet, which significantly enhances GSIS and reduces body weight. Therefore, developing dual-receptor agonists that target balanced activation of GCGR and GLP-1R in vivo may better preserve glycemic control than the activation of GLP-1R alone.