GLP-2

GLP-2 is the 33-amino-acid peptide hormone — HADGSFSDEMNTILDNLAARDFINWLIQTKITD — cleaved from the proglucagon precursor by prohormone convertases in intestinal L-cells of the distal small intestine and colon. The molecule's identity as a discrete intestinal proglucagon-derived peptide was established by Buhl T, Thim L, Kofod H et al., J Biol Chem 1988, 263:8621–8624, which isolated and sequenced proglucagon(126-158) from porcine ileal mucosa, building on the tissue-specific proglucagon processing characterized in the landmark Mojsov S, Heinrich G, Wilson IB et al., J Biol Chem 1986, 261:11880–11889 — the report that established why the same gene yields glucagon in pancreatic α-cells and GLP-1 / GLP-2 in intestinal L-cells.

The intestinotrophic identity was established by Drucker DJ, Erlich P, Asa SL, Brubaker PL, Proc Natl Acad Sci USA 1996, 93:7911–7916, which documented marked increases in bowel weight and jejunal and ileal villus height in mice within four days of GLP-2 administration, alongside crypt cell proliferation by BrdU incorporation. The receptor was cloned three years later in Munroe DG, Gupta AK, Kooshesh F et al., Proc Natl Acad Sci USA 1999, 96:1569–1573 — a class B G-protein-coupled receptor (GLP2R) signaling through Gαs to adenylate cyclase and the cAMP / protein kinase A cascade, most closely related to the glucagon and GLP-1 receptors. The receptor is expressed on intestinal subepithelial myofibroblasts, enteric neurons, and a subset of enteroendocrine cells, but notably not on the intestinal epithelial cells whose proliferation it ultimately drives — GLP-2's effect on crypt cells propagates indirectly through paracrine intermediaries including IGF-1, keratinocyte growth factor, and ErbB-family ligands released by myofibroblasts and neuronal populations in response to receptor engagement. The unusual cell-type architecture is reviewed in Drucker DJ, Yusta B, ACS Pharmacol Transl Sci 2019, 2:468–484.

The downstream phenotype is the intestinotrophic signature: crypt cell proliferation, increased villus height, reduced enterocyte apoptosis, slowed gastric emptying, increased mesenteric blood flow, and reduced intestinal permeability. The pharmacology is mechanistically distinct from the GLP-1 receptor agonist class anchored by semaglutide, tirzepatide, and liraglutide — GLP-2 is not an incretin, does not act on pancreatic β-cells, and does not produce the central-vagal appetite signal that drives the GLP-1-class weight-loss phenotype. Both peptides are tandemly encoded on the same precursor, but the receptor systems diverge sharply. The pancreatic glucagon hormone shares only the proglucagon backbone; its receptor pharmacology is non-overlapping with GLP-2's.

The pharmacokinetic ceiling on native GLP-2's therapeutic use is rapid degradation by dipeptidyl peptidase-IV (DPP-IV). Cleavage at the Ala2-Asp3 bond yields GLP-2(3-33), a largely inactive fragment lacking the intestinotrophic potency of the intact peptide. The kinetics were quantified in humans by Hartmann B, Harr MB, Jeppesen PB et al., J Clin Endocrinol Metab 2000, 85:2884–2888, which reported an intravenous elimination half-life of 7.2 ± 2.0 minutes for intact GLP-2, abolishable by a DPP-IV inhibitor in vitro — the empirical foundation for the conclusion that chronic GLP-2 pharmacology would require a DPP-IV-resistant analog. That conclusion drove the development of teduglutide (Ala2-to-Gly2 substitution, ~2-hour half-life) and apraglutide (additional non-natural substitutions plus engineered protein binding, ~30–50-hour half-life, once-weekly subcutaneous dosing).