The expanding landscape of the glucagon signaling network: mechanisms and outcomes

Glucagon is a peptide hormone mainly secreted by the alpha cells of the pancreatic islets in response to nutritional stimuli. Traditionally recognized for its hyperglycemic function counteracting insulin action, it mainly acts on the liver to affect glycogen, amino acid, lipid, and energy metabolism. Beyond its metabolic effects, glucagon also increases hepatocyte cell survival and reduces viral replication. Peptides with glucagon activity have recently emerged as a promising therapeutic candidate for obesity, type 2 diabetes, and associated liver disease, with several glucagon-based agents currently in phase 2/3 clinical trials. Despite this progression, and although discovered roughly the same time as insulin, how glucagon exerts its pleiotropic effects on metabolism and beyond remains relatively poorly understood. Knowledge of these signaling pathways could pave the way for further refinement of glucagon-based pharmacotherapy with more pronounced effects or reduced side effects. This review aims to address established literature and its limitations on glucagon signaling mechanisms and provides an update on the state of the art on glucagon signaling pathways to help in understanding the mechanisms behind glucagon action.