Glucagon in glucose homeostasis and metabolic disease: from physiology to therapeutics

Glucagon, a key hormone in glucose homeostasis, plays a central role in maintaining blood glucose levels through hepatic glycogenolysis and gluconeogenesis. Historically, glucagon secretion was believed to be primarily regulated by insulin via the "insulin switch-off" hypothesis, where reduced insulin levels triggered glucagon release. However, this view has been revisited as emerging evidence highlights the complexity of glucagon regulation. New studies demonstrate that glucose itself, along with amino acids and fatty acid oxidation, directly influences glucagon secretion, challenging the insulin-centric perspective. These findings reveal the metabolic versatility of pancreatic α-cells and their capacity to adapt to nutrient availability. Recent therapeutic innovations, such as glucagon receptor antagonists, dual GLP-1/glucagon receptor agonists, and modulators of hepatic glucagon signalling, offer promising strategies to mitigate hyperglycemia, improve energy balance, and address metabolic dysregulation. This review provides an in-depth analysis of glucagon's role in health and disease, emphasizing its therapeutic potential in managing diabetes and related metabolic conditions.