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 alpha-cells using both antibody-dependent and antibody-independent strategies. A novel alpha-cell-specific GLP-1R knockout (alpha GLP-1R(-/-)) mouse model was created and used to investigate its effects on glucagon secretion and glucose metabolism. Male and female alpha GLP-1R(-/-) mice both showed higher nonfasting glucagon levels than theirwild-type littermates, whereas insulin and GLP-1 levels remained similar. Female alpha GLP-1R(-/-) mice exhibited mild glucose intolerance after an intraperitoneal glucose administration and showed increased glucagon secretion in response to a glucose injection comparedwith thewild-type animals. Furthermore, using isolated islets, we confirmed that alpha GLP-1R deletion did not interfere with beta-cell function but affected glucagon secretion in a glucose-dependent bidirectional manner: the alpha GLP-1R(-/-) islets failed to inhibit glucagon secretion at high glucose and failed to stimulate glucagon secretion at very lowglucose 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 alpha-cells) plays a bidirectional role, either stimulatory or inhibitory, in glucagon secretion depending on glucose levels.