GLP-1 Receptor in Pancreatic α-Cells Regulates Glucagon Secretion in a Glucose-Dependent Bidirectional Manner

Glucagon-like peptide 1 (GLP-1) is known to suppress glucagon secretion, but the mechanism by which GLP-1 exerts this effect is unclear. In this study, we demonstrated GLP-1 receptor (GLP-1R) expression in α-cells using both antibody-dependent and antibody-independent strategies. A novel α-cell-specific GLP-1R knockout (αGLP-1R^-/-) mouse model was created and used to investigate its effects on glucagon secretion and glucose metabolism. Male and female αGLP-1R^-/- mice both showed higher nonfasting glucagon levels than their wild-type littermates, whereas insulin and GLP-1 levels remained similar. Female αGLP-1R^-/- mice exhibited mild glucose intolerance after an intraperitoneal glucose administration and showed increased glucagon secretion in response to a glucose injection compared with the wild-type animals. Furthermore, using isolated islets, we confirmed that αGLP-1R deletion did not interfere with β-cell function but affected glucagon secretion in a glucose-dependent bidirectional manner: the αGLP-1R^-/- islets failed to inhibit glucagon secretion at high glucose and failed to stimulate glucagon secretion at very low glucose condition. More interestingly, the same phenomenon was recapitulated in vivo under hypoglycemic and postprandial (fed) conditions. Taken together, this study demonstrates that GLP-1 (via GLP-1R in α-cells) plays a bidirectional role, either stimulatory or inhibitory, in glucagon secretion depending on glucose levels.