Glucagon-Like Peptide (GLP-1)
A 30-31 amino acid hormone produced by intestinal L-cells after eating that stimulates insulin secretion, suppresses glucagon, slows gastric emptying, and promotes satiety. Natural GLP-1 has a half-life of only 1-2 minutes due to DPP-4 degradation. All GLP-1 receptor agonists are designed to overcome this limitation.
Technical Context
GLP-1 is produced by post-translational processing of the proglucagon gene in intestinal L-cells. Proglucagon processing is tissue-specific: in gut L-cells, prohormone convertase 1/3 produces GLP-1 and GLP-2; in pancreatic alpha cells, prohormone convertase 2 produces glucagon. Active GLP-1 exists in two forms: GLP-1(7-36) amide (the major circulating form) and GLP-1(7-37). DPP-4 rapidly cleaves both to inactive GLP-1(9-36) amide or GLP-1(9-37). GLP-1 receptor activation on beta cells increases cAMP → PKA/Epac2 → potentiation of glucose-stimulated insulin secretion (glucose dependence is conferred by requiring glucose-mediated ATP production and KATP channel closure). Additional GLP-1R effects include beta cell proliferation and anti-apoptotic signalling (preclinical), glucagon suppression, delayed gastric emptying, and central appetite suppression.