Glucagon-like peptide 2 (GLP-2): gut-lining repair hormone
A natural gut hormone released after meals that protects and repairs the intestinal lining, helping the gut absorb nutrients; studied as a drug for intestinal diseases, not a standalone approved drug.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Glucagon-like peptide-2 (GLP-2) is a gut hormone released after meals from L-cells lining the lower small intestine and colon. Its main job is to protect and grow the intestinal lining — it promotes the repair and expansion of the mucosa that absorbs nutrients, making it distinct from GLP-1, which controls blood sugar and appetite. GLP-2 is encoded by the same proglucagon gene that also produces glucagon and GLP-1; the three hormones arise from tissue-specific processing of the same precursor protein. The sequence stored here corresponds to a 35-residue proglucagon-derived GLP-2 variant of rat (Rattus norvegicus) origin; the canonical human GLP-2 sequence is 33 residues and differs at several positions, including position 19 (threonine in rat, alanine in human). Because native GLP-2 is degraded within minutes by the enzyme DPP-4, it is impractical as a drug itself — a DPP-4-resistant analog, teduglutide (/card/pep-04435), was developed from this scaffold and is FDA-approved for short bowel syndrome.
History
GLP-2 was first identified in the early 1980s as part of the structural characterization of the proglucagon gene. Seino and colleagues (FEBS Letters, 1986) showed that mutations in the guinea pig preproglucagon gene are restricted to a specific portion of the prohormone sequence, advancing understanding of the evolutionary conservation of these proglucagon-derived peptides. The intestinotrophic activity of GLP-2 — its ability to stimulate growth of the intestinal mucosa — was characterized in rodent models during the 1990s by Daniel Drucker and colleagues at the University of Toronto, who demonstrated that GLP-2 administration enhanced small bowel structure and function, improved nutrient absorption, and could reverse intestinal atrophy caused by total parenteral nutrition. These findings established GLP-2 as a potentially therapeutic target for intestinal insufficiency conditions, motivating the development of teduglutide.
What it does
GLP-2 acts on GLP-2 receptors located on subepithelial myofibroblasts, enteric neurons, and enteroendocrine cells in the intestinal wall. Activation of these receptors triggers the release of growth factors including keratinocyte growth factor (KGF), insulin-like growth factor-1 (IGF-1), and epidermal growth factor (EGF), which in turn drive crypt cell proliferation, inhibit enterocyte apoptosis, and increase villus height. The net result is a larger absorptive surface area and improved capacity for nutrient uptake. GLP-2 also increases mesenteric blood flow, inhibits gastric acid secretion, slows gastric emptying, and — perhaps counterintuitively — stimulates glucagon secretion from the pancreas. In the liver and adipose tissue, GLP-2 has been shown to enhance lipid absorption from the gut. These combined effects make GLP-2 a regulator of both intestinal architecture and postprandial nutrient partitioning.
Evidence
- Human: Native GLP-2 has been studied in humans as an infused peptide in controlled research settings, demonstrating inhibition of gastric emptying, enhancement of lipid absorption, and stimulation of glucagon secretion. The clinical therapeutic evidence base belongs largely to teduglutide, the DPP-4-resistant analog, which completed pivotal Phase III trials (STEPS, STEPS-2, STEPS-3) for short bowel syndrome. No clinical trials of native GLP-2 for therapeutic use have been identified.
- Animal: Extensive. GLP-2 administration in rodents on total parenteral nutrition restores small bowel structure and function, increases villus height and crypt depth, enhances absorptive capacity, and prevents intestinal atrophy. GLP-2 has also been shown to reduce mucosal injury in animal models of radiation enteritis and inflammatory bowel conditions.
- In vitro: GLP-2 receptors have been characterized on intestinal subepithelial myofibroblasts, enteric neurons of the myenteric and submucosal plexus, and enteroendocrine cells; receptor activation induces downstream KGF and IGF-1 signaling that drives epithelial proliferation and survival.
Mechanism
GLP-2 is a member of the glucagon-secretin superfamily (also called the pituitary adenylate cyclase-activating peptide/glucagon hormone superfamily), a class of structurally related hormones that act through class B G protein-coupled receptors. Yang and colleagues (Journal of Biological Chemistry, 2016) characterized the structural determinants by which GLP-1 — a closely related proglucagon-derived peptide — binds the seven-transmembrane domain of its class B GPCR, work that illuminates how small sequence differences among glucagon-family peptides translate into distinct receptor selectivity. GLP-2 itself binds the GLP-2 receptor (GLP-2R), a distinct class B GPCR expressed primarily in the gastrointestinal tract, where its activation couples to Gαs/adenylyl cyclase signaling, increasing intracellular cAMP and activating downstream growth-factor cascades.
The short half-life of native GLP-2 results from DPP-4 cleavage at the bond after the second residue (Ala²), which removes the first two amino acids and destroys biological activity. This rapid degradation is the structural vulnerability that motivated the development of teduglutide, in which Ala² is substituted with glycine to confer DPP-4 resistance and substantially extend the circulating half-life.
Known effects
- Intestinal mucosal growth — Preclinical (extensive rodent data); mechanistic in humans
- Inhibition of gastric acid secretion — Human research studies
- Enhancement of lipid absorption — Human research studies
- Glucagon secretion stimulation — Human research studies
- Inhibition of gastric emptying — Human research studies
- Restoration of intestinal structure in short bowel syndrome — Phase III (teduglutide analog; no approved indication for native GLP-2)
Regulatory status
- US: Native GLP-2 has no approved therapeutic indication. The approved clinical application of this peptide class belongs to teduglutide (Gattex), the DPP-4-resistant GLP-2 analog, which received FDA approval for short bowel syndrome in adults (December 2012) and children (2019).
- EU/International: Teduglutide is approved as Revestive by EMA and in multiple other jurisdictions for short bowel syndrome. Native GLP-2 itself has no approved indication.
- Research use: The rat-origin 35-residue sequence stored in this card (HADGSFSDEMNTILDNLATRDFINWLIQTKITDRK) is used in preclinical research; it is not a pharmaceutical entity.
Related peptides
- Teduglutide — DPP-4-resistant GLP-2 analog with Ala²→Gly substitution; FDA-approved for short bowel syndrome as Gattex/Revestive; the clinical translation of the GLP-2 scaffold.
- Glucagon-like peptide-2 (1–33), human — The canonical 33-residue human GLP-2 sequence; differs from the rat variant stored here at multiple positions.
- Glucagon — The 29-residue counter-regulatory hormone encoded by the same proglucagon precursor gene; acts on GCGR rather than GLP-2R.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.7426857352256775 | openfold3-mlx |
| ranking score | 0.8144311904907227 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.781 | global PDE — lower = better |
| disorder | 0.158 | fraction disordered |
| chain pair ipTM (A, B) | 0.743 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | aedd8f3eb814e392… |
| hardware | apple_m4_base_16gb |
| mlx version | 0.31.1 |
| python | 3.14.3 |
| random seed | 42 |
| msa strategy | colabfold |
| diffusion samples | 1 |
| runtime | 455s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-23 |
python3 openfold3/run_openfold.py predict --query_json {query.json} --runner_yaml examples/example_runner_yamls/mlx_runner.yml --output_dir {output_dir} --num_diffusion_samples 1 ▸citationbibtex
@peptide{pep10572,
sequence = {HADGSFSDEMNTILDNLATRDFINWLIQTKITDRK},
target = {gcgr},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}