GLP-2
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Intestinal trophic peptide co-secreted with GLP-1 from L-cells; activates GLP-2R to drive crypt cell proliferation, villus elongation, and mucosal adaptation
Quick Facts
| Property | Value |
|---|---|
| Also Known As | Glucagon-Like Peptide-2, proglucagon fragment 126-158; Teduglutide (Gattex/Revestive) is the DPP-4-resistant analog |
| Category | GI / Recovery |
| Sequence | HADGSFSDEMNTILDNLAARDFINWLIQTKITD (33 amino acids) |
| Molecular Weight | ~3765 Da |
| Molecular Formula | C₁₆₄H₂₅₂N₄₄O₅₅S |
| PubChem CID | 16132342 |
| Administration | SubQ |
| Typical Dose Range | Native: not used clinically; Teduglutide: 0.05 mg/kg/day SubQ |
| Half-Life | ~7 minutes (native GLP-2); ~2-3 hours (teduglutide, Gly2-substituted DPP-4-resistant analog) |
| Storage | Lyophilized: -20°C, stable 1-2 years; Reconstituted: 2-8°C, use within 28 days |
| FDA Status | Teduglutide (Gattex) FDA-APPROVED December 2012 for adults with Short Bowel Syndrome with Intestinal Failure (SBS-IF); pediatric indication approved 2019. Native GLP-2 is not approved as a drug |
| WADA Status | Not listed |
Mechanism of Action
GLP-2 is a 33-amino-acid peptide produced by post-translational processing of proglucagon in intestinal L-cells. It is co-secreted with GLP-1 in response to nutrient ingestion, but whereas GLP-1 orchestrates metabolic and appetite responses, GLP-2 is the body's primary intestinotrophic signal — driving intestinal mucosal growth, barrier integrity, and absorptive capacity (PMID-16602931).
GLP-2 activates the GLP-2 receptor (GLP-2R), a class B GPCR expressed predominantly on intestinal subepithelial myofibroblasts, enteric neurons, and to a lesser extent in the CNS, lung, and lymph nodes. Notably, the GLP-2R is not expressed on intestinal epithelial cells themselves — the trophic effects on the epithelium are mediated indirectly through paracrine signaling. Upon GLP-2R activation, subepithelial myofibroblasts release ErbB ligands (EGF family) and insulin-like growth factor-1 (IGF-1), which act on adjacent crypt epithelial cells to stimulate proliferation and inhibit apoptosis. The net result is crypt cell expansion, villus elongation, increased mucosal surface area, and enhanced absorptive capacity (PMID-16602931, PMID-29202475).
GLP-2 also increases mesenteric blood flow through eNOS-dependent nitric oxide production, enhancing nutrient delivery and absorption. It upregulates expression of brush border nutrient transporters (SGLT1, GLUT2, PEPT1) and digestive enzymes, directly improving the functional capacity of the absorptive epithelium. Additionally, GLP-2 reduces intestinal permeability by enhancing tight junction protein expression, providing a barrier-protective function relevant to inflammatory bowel conditions (PMID-16602931).
Like GLP-1, native GLP-2 is rapidly degraded by DPP-4, with a half-life of approximately 7 minutes. Teduglutide, the therapeutic analog, incorporates a glycine-for-alanine substitution at position 2 (Gly2-GLP-2) that confers DPP-4 resistance and extends the half-life to approximately 2-3 hours, enabling once-daily subcutaneous dosing (PMID-22982184).
Key Research Areas
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Short Bowel Syndrome & Intestinal Failure — The pivotal Phase III RCT (n=86) demonstrated that teduglutide 0.05 mg/kg/day significantly reduced parenteral support volume vs placebo (63% vs 30% responder rate, p=0.002), leading to FDA approval in December 2012. Some patients achieved full enteral autonomy (PMID-22982184).
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Pediatric Intestinal Failure — Phase III trials in children aged 1-17 confirmed 57-67% responder rates, with some children achieving complete parenteral nutrition independence. Pooled long-term data (n=85, up to 96 weeks) showed 82.1% response rate with progressive, durable reductions (PMID-37364133, PMID-38873891).
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Intestinal Adaptation & Mucosal Growth — GLP-2 is the key mediator of intestinal adaptation after bowel resection. It drives crypt cell proliferation, villus elongation, and functional maturation of the absorptive epithelium, establishing the mechanistic basis for pharmacological intervention (PMID-16602931).
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Proglucagon Biology & Drug Development — GLP-2 was identified as an intestinotrophic factor by the Drucker laboratory in 1996. Its clinical development into teduglutide represents one of the most successful examples of basic proglucagon biology translating into an approved therapy (PMID-29202475).
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Pediatric Long-Term Outcomes — The largest pooled pediatric dataset (96 weeks) demonstrated progressive parenteral support reductions without plateau, appropriate growth trajectories, and no new safety signals, supporting extended treatment courses (PMID-38873891).
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Barrier Protection & Permeability — GLP-2 enhances intestinal tight junction integrity and reduces mucosal permeability, with preclinical evidence of cytoprotection against NSAIDs, chemotherapy-induced mucositis, and inflammatory bowel disease models (PMID-16602931).
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Systematic reviews | 1 | Pediatric teduglutide for SBS-IF (PRISMA methodology) |
| Human RCTs | 2 | Pivotal adult Phase III (n=86) and pediatric Phase III trials |
| Human observational | 1 | Pooled pediatric post hoc analysis (n=85, up to 96 weeks) |
| Animal in vivo | 0 | Extensive rodent data integrated into narrative reviews |
| Narrative reviews | 2 | Foundational GLP-2 biology (Drucker) and proglucagon history |
Clinical Applications
- Gut Health — GLP-2 is the primary intestinotrophic peptide; teduglutide is FDA-approved for SBS-IF and promotes mucosal adaptation, villus growth, and nutrient absorption
- Gastric Ulcers — GLP-2's cytoprotective and barrier-enhancing properties are relevant to mucosal protection, though not an approved indication
- NAFLD — Emerging research on GLP-2's role in hepatic lipid metabolism and intestinal barrier function in metabolic liver disease
Protocols Using This Peptide
- Gut Healing Protocol — GLP-2 serves as the intestinotrophic anchor for mucosal regeneration and barrier restoration
Ageless Peps Products
Note: The GLP-2 Vial (WC ID 752, $75) is currently in DRAFT status on the Ageless Peps store and is not published. No product note has been created. When this product goes live, a Product note should be created.
WARNING — Website Copy Error: The WooCommerce product description for the GLP-2 Vial incorrectly describes GLP-2 as a "dual agonist mimicking GIP and GLP-2." This is scientifically inaccurate. GLP-2 is an intestinal trophic factor that activates the GLP-2 receptor — it is NOT a GIP agonist. The product description appears to conflate GLP-2 with Tirzepatide (the actual GIP/GLP-1 dual agonist). Recommend correcting the website copy before publishing this product.
Dosing Reference
Research Dosing Ranges (from literature)
| Route | Dose Range | Frequency | Duration | Source |
|---|---|---|---|---|
| SubQ (teduglutide) | 0.05 mg/kg/day | Once daily | 24 weeks minimum; extensions up to 96+ weeks | PMID-22982184 |
| SubQ (native GLP-2) | Not used clinically | N/A | N/A | Half-life too short (~7 min) |
Cycling
Teduglutide is used as continuous daily therapy, not cycled. In clinical trials, parenteral support reductions were progressive through 96 weeks without evidence of tachyphylaxis or a treatment plateau. Discontinuation may lead to regression of intestinal adaptation, though this has not been extensively studied. Clinical monitoring for intestinal polyps is recommended during treatment.
Contraindications & Safety
- Contraindications: Active or suspected intestinal malignancy; hypersensitivity to teduglutide or any excipient
- Common side effects: Abdominal pain, nausea, injection site reactions, vomiting, intestinal obstruction, fluid overload (as parenteral support is reduced)
- Drug interactions: As parenteral nutrition volumes decrease, oral medication absorption may change; dose adjustments may be needed for concomitant medications. Monitor closely when reducing parenteral fluids
- Pregnancy/nursing: Teduglutide is Pregnancy Category B; limited human data; use only if clearly needed
- Special populations: Intestinal polyp surveillance (colonoscopy) recommended within 6 months of starting teduglutide and at least every 5 years during treatment. Pediatric: approved for ages 1+; growth parameters should be monitored. Renal impairment: reduce dose by 50% if CrCl <50 mL/min
Synergistic Combinations
- GLP-1 (Native) — Co-secreted from the same proglucagon precursor in L-cells; GLP-1 manages metabolic/appetite signaling while GLP-2 drives intestinal trophic effects. Understanding this co-secretion is fundamental to proglucagon biology
- BPC-157 — Complementary gut healing mechanisms: BPC-157 provides cytoprotection and angiogenesis while GLP-2 drives mucosal proliferation and villus growth
- KPV — Anti-inflammatory tripeptide that may complement GLP-2's trophic effects by reducing intestinal inflammation in IBD-related scenarios
- LL-37 — Antimicrobial peptide that supports intestinal barrier defense alongside GLP-2's barrier-enhancing properties
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| PMID-16602931 | Glucagon-Like Peptide-2 | 2006 | Narrative Review |
| PMID-22982184 | Randomised Placebo-Controlled Trial of Teduglutide in Reducing Parenteral Nutrition in SBS | 2012 | Phase III RCT |
| PMID-29202475 | Discovery, Characterization, and Clinical Development of the Glucagon-Like Peptides | 2017 | Narrative Review |
| PMID-35774551 | Teduglutide in Children With Intestinal Failure Associated With SBS: A Systematic Review | 2022 | Systematic Review |
| PMID-37364133 | Teduglutide Efficacy and Safety in Infants and Children With SBS-IF | 2023 | Phase III RCT |
| PMID-38873891 | Long-term Outcomes of Teduglutide in Pediatric Patients With SBS-IF | 2024 | Pooled Post Hoc Analysis |
References
- PMID-16602931: Estall JL, Drucker DJ. Glucagon-Like Peptide-2. Annu Rev Nutr. 2006;26:391-411.
- PMID-22982184: Jeppesen PB et al. Randomised Placebo-Controlled Trial of Teduglutide in Reducing Parenteral Nutrition in SBS. Gastroenterology. 2012;143(6):1473-1481.
- PMID-29202475: Drucker DJ, Habener JF, Holst JJ. Discovery, Characterization, and Clinical Development of the Glucagon-Like Peptides. J Clin Invest. 2017;127(12):4217-4227.
- PMID-35774551: Gigola F et al. Teduglutide in Children With Intestinal Failure Associated With SBS: A Systematic Review. Front Nutr. 2022;9:866518.
- PMID-37364133: Chiba M et al. Teduglutide Efficacy and Safety in Infants and Children With SBS-IF. J Pediatr Gastroenterol Nutr. 2023;77(4):525-532.
- PMID-38873891: Wales PW et al. Long-term Outcomes of Teduglutide in Pediatric Patients With SBS-IF. J Pediatr Gastroenterol Nutr. 2024;79(1):94-103.
Related
#peptide #gastrointestinal #subq