| Proglucagon, encoded by the Gcg gene, is a precursor polypeptide that serves as the source of multiple peptide hormones with important roles in metabolism and gut function. It is synthesized as a single chain protein of approximately 158–160 amino acids, with the glucagon sequence embedded internally and flanked by N and C terminal regions that harbor additional bioactive peptide domains. In pancreatic α cells, proglucagon undergoes proteolytic cleavage by prohormone convertase 2 (PC2) at paired basic residues to yield mature glucagon, a 29 amino acid peptide that activates the glucagon receptor on hepatocytes and stimulates glycogenolysis and gluconeogenesis through cAMP–PKA signaling. In intestinal L cells and certain brainstem neurons, the same precursor is processed by prohormone convertase 1/3 (PC1/3) to generate glucagon like peptide 1 (GLP 1), glucagon like peptide 2 (GLP 2), oxyntomodulin, and glicentin, each of which engages distinct receptors and downstream pathways. GLP 1 acts on the GLP 1 receptor in pancreatic β cells and the central nervous system to enhance glucose dependent insulin secretion, suppress glucagon release, delay gastric emptying, and promote satiety, whereas GLP 2 signals via the GLP 2 receptor on intestinal epithelial and subepithelial cells to support mucosal growth and barrier integrity. The tissue specific expression of PC2 and PC1/3 determines which peptide products dominate in the pancreas versus the gut, thereby shaping the balance between glucagon driven catabolism and GLP 1–mediated anabolic and gut protective effects. Dysregulated proglucagon processing or peptide secretion contributes to metabolic disease, as inappropriate glucagon release in α cells can exacerbate fasting and postprandial hyperglycemia, while reduced GLP 1 secretion or receptor responsiveness in the enteroinsular axis is associated with impaired glucose control and weight gain. |
