GLP-2 (1-33)

The native 33-amino-acid intestinal hormone cleaved from proglucagon that drives crypt-cell proliferation, mucosal blood flow and nutrient absorption, studied in short bowel syndrome and bone turnover but never approved; its DPP-4-resistant analog teduglutide is the approved drug.

Also referenced as: GLP-2(1-33), Proglucagon(126-158)

Also appears in: Tissue repair · Metabolic

COA Public product evidence No certificate records are bound to a tracked GLP-2 (1-33) product page A record counts here only when a vendor publishes a certificate against one of its own tracked GLP-2 (1-33) product pages. Other certificates naming this compound may still exist — search the wider certificate database. →

---

What is GLP-2 (1-33)?

Glucagon-like peptide-2 (GLP-2) is a native human gut hormone of 33 amino acids, His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp, cut from the C-terminal end of proglucagon (residues 126 to 158) in intestinal L cells. The same precursor yields glucagon in the pancreas and GLP-1 and oxyntomodulin in the gut, so GLP-2 is co-secreted with GLP-1 after a meal. The peptide was isolated from porcine ileal mucosa and sequenced as proglucagon 126-158 in 1988 (Buhl et al., Journal of Biological Chemistry, 1988;263(18):8621–8624); its intestinal-growth function was found in 1996 (Drucker et al., Proceedings of the National Academy of Sciences, 1996;93(15):7911–7916).

Native GLP-2 has never been approved as a drug anywhere. A half-life of about 7 minutes made it impractical as a medicine, and the clinical field moved to dipeptidyl peptidase-4 (DPP-4)-resistant analogs: teduglutide, the Gly2-substituted analog approved by the FDA on December 21, 2012 as Gattex under NDA 203441 for short bowel syndrome, and the longer-acting investigational analogs apraglutide and glepaglutide. The native hormone remains an academic tool in investigator-led studies of absorption, mesenteric blood flow, gastric function, gallbladder motility and bone turnover, and synthetic GLP-2(1-33) circulates on the research-peptide market as GLP-2.

How it works

• A class B GPCR of its own. GLP-2 acts through the GLP-2 receptor, a Gs-coupled receptor cloned in 1999 that maps to chromosome 17p13.3, is closely related to the glucagon and GLP-1 receptors and responds to GLP-2 with cAMP production (EC50 0.58 nM) but not to GLP-1 or related peptides (Munroe et al., Proceedings of the National Academy of Sciences, 1999;96(4):1569–1573). A cryo-EM structure of the human receptor bound to GLP-2 and Gs shows the N-terminal histidine of GLP-2 penetrating the receptor core in a unique orientation and the C-terminus attached to an unusually protruding extracellular loop 1, features the authors link to selectivity for GLP-2 over GLP-1 (Sun et al., Cell Research, 2020;30(12):1098–1108).
• Intestinotrophic through indirect signals. In nude mice bearing proglucagon-producing tumors, GLP-2 was identified as the factor driving small-bowel epithelial proliferation; it stimulated crypt-cell proliferation and increased bowel weight and villus height within 4 days (Drucker et al., Proceedings of the National Academy of Sciences, 1996;93(15):7911–7916). The receptor protein localizes to enteroendocrine cells and to enteric neurons expressing endothelial nitric oxide synthase and vasoactive intestinal polypeptide rather than to crypt cells, and GLP-2 infusion in neonatal pigs dose-dependently raised intestinal blood flow (Guan et al., Gastroenterology, 2006;130(1):150–164).
• Nutrient handling, acid and glucagon. GLP-2 increased intestinal lipid absorption and chylomicron secretion in hamsters and mice through a pathway requiring the fatty-acid translocase CD36 (Hsieh et al., Gastroenterology, 2009;137(3):997–1005). In healthy men, intravenous GLP-2 raised plasma glucagon markedly, increased postprandial triglycerides and free fatty acids, reduced pentagastrin-stimulated gastric acid output by about 15% and left gastric emptying unchanged (Meier et al., Gastroenterology, 2006;130(1):44–54).
• Rapid DPP-4 inactivation. DPP-4 removes the N-terminal His-Ala dipeptide to give inactive GLP-2(3-33); in healthy volunteers intact GLP-2 had an elimination half-life of 7.2 minutes after intravenous infusion, while a 400 µg subcutaneous injection still left 69% of circulating GLP-2 intact at 60 minutes (Hartmann et al., Journal of Clinical Endocrinology and Metabolism, 2000;85(8):2884–2888). A glycine-for-alanine substitution at position 2 made rat GLP-2 resistant to the cleavage and trophic in wild-type rats, the modification later carried into teduglutide (Drucker et al., Nature Biotechnology, 1997;15(7):673–677).

Research status

Physiology in humans. In six healthy men, bioactive GLP-2(1-33) rose 2.0- to 2.8-fold within 40 minutes of each mixed meal, driven by carbohydrate and fat but not protein (Xiao et al., Gastroenterology, 1999;117(1):99–105). Seven ileum-resected short bowel patients with intestinal failure showed almost no meal-stimulated GLP-2 response (maximum median rise 5 pmol/L versus 48 pmol/L in seven controls), the rationale for replacement therapy (Jeppesen et al., Gut, 1999;45(4):559–563). Intravenous GLP-2 lowered the superior mesenteric artery resistance index dose-dependently in 10 healthy volunteers, by 15.3% at 2.0 pmol/kg/min, reproducing the response to a meal (Bremholm et al., Scandinavian Journal of Gastroenterology, 2009;44(3):314–319), and a 1,600 µg subcutaneous dose nearly doubled flow velocity in that artery in 8 end-jejunostomy short bowel patients (Bremholm et al., Regulatory Peptides, 2011;168(1-3):32–38). Effects on the stomach and appetite are weak: in 8 volunteers GLP-2 prolonged antral emptying far less potently than GLP-1 and did not reduce hunger (Nagell et al., Scandinavian Journal of Gastroenterology, 2004;39(4):353–358), and a 4.5-hour infusion in 18 normal-weight adults changed neither appetite ratings nor ad libitum energy intake (Sørensen et al., International Journal of Obesity, 2003;27(4):450–456).

Short bowel syndrome. The only multi-week treatment study of native GLP-2 in adults was an open-label balance study at Rigshospitalet, Copenhagen: 8 patients with severe malabsorption and no terminal ileum or colon received 400 µg subcutaneously twice daily for 35 days. Absorption of energy improved from 49.9% to 53.4%, wet weight from 25% to 36% and nitrogen from 47.4% to 52.1% (all P = 0.04); body weight rose 1.2 kg and lean body mass 2.9 kg while fat mass fell 1.8 kg; time to 50% gastric emptying of solids lengthened by 30 minutes; and crypt depth and villus height increased in 5 and 6 patients respectively (Jeppesen et al., Gastroenterology, 2001;120(4):806–815). The same group then ran an early multicenter trial of teduglutide (ALX-0600), in which 16 short bowel patients treated for 21 days gained a mean 743 g/day of wet weight absorption (Jeppesen et al., Gut, 2005;54(9):1224–1231), and later compared acute continuous infusions of GLP-2, GLP-1 and the combination against placebo in short bowel patients (Madsen et al., Regulatory Peptides, 2013;184:30–39); all subsequent development used analogs. The one pediatric study, an open-label Canadian trial, gave synthetic human GLP-2(1-33) at 20 µg/kg/day subcutaneously to 7 parenteral nutrition-dependent children (mean age 4.0 years) for up to 45 days: there were no significant adverse events, pharmacokinetics matched adults, and nutritional z scores and citrulline improved only numerically, with citrulline returning to baseline after the peptide was stopped (Sigalet et al., JPEN Journal of Parenteral and Enteral Nutrition, 2017;41(5):844–852).

Bone turnover. Of GIP, GLP-1 and GLP-2 given parenterally to healthy volunteers, only GLP-2 reproduced the postprandial fall in the bone-resorption marker serum CTX, and single subcutaneous doses of 100 to 800 µg in 60 postmenopausal women lowered CTX dose-dependently without changing osteocalcin (Henriksen et al., Journal of Bone and Mineral Research, 2003;18(12):2180–2189). A four-month, double-blind, placebo-controlled trial randomized postmenopausal women with low bone mineral density to nightly 0.4, 1.6 or 3.2 mg GLP-2 or saline: all three doses blunted the nocturnal CTX rise similarly (P < 0.01 versus placebo at day 120), osteocalcin was unaffected, total hip BMD rose dose-dependently to 1.1% above baseline in the 3.2 mg group (P = 0.007), adverse-event rates were similar across arms, and there was no tachyphylaxis and no anti-GLP-2 antibody formation (Henriksen et al., Bone, 2009;45(5):833–842). No phase 3 program followed. Later work in healthy men showed that prolonged subcutaneous exposure suppressed CTX more than high-concentration intravenous boluses (Askov-Hansen et al., Regulatory Peptides, 2013;181:4–8); that the GIP-receptor antagonist GIP(3-30)NH2 did not block the CTX reduction after 800 µg GLP-2, so GLP-2 and GIP act on bone through separate routes (Skov-Jeppesen et al., Bone, 2019;125:178–185; NCT03159741, 8 participants, completed September 29, 2017); and that co-injecting GIP and GLP-2 in 10 men reduced resorption additively, the rationale for preclinical GIPR–GLP-2R co-agonists for osteoporosis (Gabe et al., Pharmacological Research, 2022;176:106058). University of Copenhagen registry entries extend this line to hypoparathyroidism (NCT03728959, 7 participants, completed April 12, 2019), spinal cord injury (NCT05181150, status unknown since May 10, 2023) and children with neuromuscular disorders (NCT07254988, terminated after 3 enrollments for poor recruitment, last updated April 16, 2026).

Gallbladder. In a four-way crossover in 15 healthy men, a GLP-2 infusion did not change fasting gallbladder volume but completely abolished cholecystokinin-induced gallbladder contraction, the authors’ proposed explanation for the gallbladder adverse events reported with GLP-2 receptor agonists (Lange et al., Journal of Clinical Endocrinology and Metabolism, 2024;110(1):123–129; NCT04651868).

Safety signals. The proliferative action that makes GLP-2 useful is also its principal theoretical risk. In mice given the colonic carcinogen 1,2-dimethylhydrazine, the stable analog Gly2-GLP-2 clearly increased tumor load, and native GLP-2 had a weaker tumor-promoting effect with more small polyps after one month of treatment (Thulesen et al., Gut, 2004;53(8):1145–1150). Human exposure has been short, at most 120 days in the osteoporosis trial, with no serious adverse events attributed to the peptide and no antibodies detected; no study has followed participants long enough to detect a neoplastic signal.

Regulatory picture as of November 2026. No product containing native GLP-2 is listed in Drugs@FDA or DailyMed, and every registered human study of the peptide is academic. Approval in this receptor class belongs to teduglutide (Gattex in the US, Revestive in Europe); apraglutide and glepaglutide, both asked by the FDA for confirmatory trials, remain investigational, and glepaglutide received a positive CHMP opinion on September 17, 2026 without a European Commission decision as of November 2026.

Common dosage forms

• No approved presentation. No product containing native GLP-2 is marketed in the US or any other country.
• Investigational peptide. Synthetic human GLP-2(1-33) has been supplied to academic study sites as a lyophilized powder for subcutaneous injection or intravenous infusion.
• Research-market vials. Lyophilized synthetic GLP-2 in multi-milligram vials labeled for laboratory use.

Key considerations

• Regulatory status. The Research Market status reflects the absence of any approved product containing native GLP-2 and of any registered sponsor-led development program for the native peptide. The approved molecule in this class is the Gly2 analog teduglutide, approved by the FDA on December 21, 2012 under NDA 203441.
• Seven-minute half-life. DPP-4 inactivates GLP-2 almost as fast as it enters the circulation, which is why every drug-development effort in this class has used an analog designed to escape that cleavage.
• Real but small efficacy evidence. The treatment database for native GLP-2 in short bowel syndrome is 8 adults and 7 children in open-label studies with absorption gains of a few points, and the bone evidence is one four-month trial that raised hip BMD by about 1% with no fracture outcomes. Neither indication was carried into a confirmatory program with the native peptide.
• Trophic risk and glucagon. GLP-2 promoted colonic neoplasm growth in carcinogen-treated mice, acutely raises glucagon secretion and relaxes the gallbladder against cholecystokinin; the long-term human safety of the native peptide has never been studied.
• Naming. GLP-2, glucagon-like peptide-2, GLP-2(1-33) and proglucagon(126-158) all denote the same 33-residue hormone; GLP-2(3-33) is the inactive DPP-4 product, and teduglutide, apraglutide and glepaglutide are distinct engineered analogs with their own regulatory records.