GLP-2 (Glepaglutide)
GLP-2 (Glucagon-Like Peptide-2) is an endogenous intestinal hormone produced by L-cells in the gut. It is the primary trophic hormone for the intestinal epithelium — stimulating growth, repair, and nutrient absorption. Glepaglutide is a long-acting GLP-2 analogue in active clinical development for short bowel syndrome and gut atrophy.
Common Dosage
1mg - 8mg subcutaneous 3x weekly (research phase)
Category
Recovery
- Intestinal epithelial growth and repair
- Short bowel syndrome management
- Nutrient absorption improvement
- Gut mucosal integrity restoration
- Reduced intestinal inflammation
Glucagon-Like Peptide-2 (GLP-2) was identified in 1983 as a product of the proglucagon gene alongside GLP-1. Unlike its more famous sibling GLP-1, GLP-2 exerts its primary effects on the intestine rather than the pancreas. It was established as the principal intestinal trophic hormone — a signal from the gut's own L-cells that tells the intestinal epithelium to grow, maintain its integrity, and absorb nutrients efficiently. Teduglutide (Gattex/Revestive), a GLP-2 analogue with a modified N-terminus giving it a longer half-life, received FDA approval in 2012 for short bowel syndrome — the first approved drug for this condition. Glepaglutide is a newer long-acting GLP-2 analogue (subcutaneous injection, 3x weekly) in Phase 3 development, designed to require less frequent dosing than teduglutide.
GLP-2 binds to GLP-2 receptors (GLP2R) expressed on enteric neurons and subepithelial myofibroblasts, not directly on epithelial cells. Receptor activation triggers the release of downstream mediators — primarily keratinocyte growth factor (KGF/FGF-7) and IGF-1 — that act on intestinal crypt cells to stimulate proliferation and on villus enterocytes to reduce apoptosis. The net result is increased villus height, crypt depth, and absorptive surface area. GLP-2 also reduces intestinal permeability by upregulating tight junction proteins (occludin, claudin-3), decreases intestinal motility (slowing transit to improve absorption), reduces intestinal inflammation via reduced NF-κB signaling, and promotes mesenteric blood flow.
- Short bowel syndrome — reducing parenteral nutrition dependence after major bowel resection
- Crohn's disease — mucosal healing and intestinal barrier restoration
- Chemotherapy and radiation-induced mucositis — protecting and repairing intestinal epithelium during cancer treatment
- NSAID-induced intestinal damage — gut barrier restoration
- Inflammatory bowel disease — villus recovery and mucosal integrity
- Celiac disease — promoting intestinal recovery after gluten withdrawal
- Intestinal failure — any condition resulting in inadequate absorptive surface area
- Post-bariatric surgery gut adaptation support
Teduglutide (GLP-2 Analogue) FDA Approval
The STEPS trial — the pivotal Phase 3 study for teduglutide in short bowel syndrome — showed that 63% of patients receiving teduglutide achieved ≥20% reduction in parenteral nutrition volume after 24 weeks, compared to 30% in the placebo group. Some patients were able to discontinue parenteral nutrition entirely, a remarkable outcome for a condition previously considered permanent.
Intestinal Adaptation Research
Multiple studies in animal models of massive small bowel resection showed that GLP-2 administration produced villus hyperplasia and crypt hyperplasia within 7–14 days of treatment — measurably increasing absorptive surface area. This structural remodeling is distinct from the anti-inflammatory effects of BPC-157 and suggests complementary mechanisms when studied in combination.
Radiation Mucositis Protection
GLP-2 administered prophylactically to rodents before abdominal radiation significantly preserved intestinal architecture and reduced the severity of radiation-induced mucositis. The mechanism involved both reduced enterocyte apoptosis and maintenance of tight junction integrity. This application is under active clinical investigation for cancer patients undergoing abdominal/pelvic radiation.
- Benign intestinal polyp formation — GLP-2's proliferative effects on intestinal tissue have produced colonic polyps in long-term animal studies; surveillance colonoscopy is recommended for patients on prolonged therapy
- Accelerated growth of pre-existing colorectal neoplasia — the trophic effect raises theoretical concerns in individuals with CRC history or high genetic risk
- Stoma complications in post-resection patients — fluid output changes may require management
- Not currently FDA-approved for research use outside short bowel syndrome (teduglutide is approved; glepaglutide is not yet approved)
- GLP-2 receptor stimulation may affect gallbladder motility — cholelithiasis (gallstones) risk with prolonged use
- Nausea
- Abdominal discomfort
- Potential benign polyp formation with chronic use (animal data)