GLP-2

Glucagon-like peptide 2 (GLP-2) is a 33-amino acid intestinal hormone co-produced with GLP-1 by L-cells of the distal small intestine and colon in response to luminal nutrients. Despite being discovered decades after GLP-1 and sharing the same proglucagon precursor, GLP-2 has a remarkably specific and powerful biological function: it is the primary hormonal trophic signal for the intestinal mucosa.

GLP-2 is unique in human physiology as an endocrine hormone whose primary action is to promote growth and repair of a specific organ system. While many growth factors and hormones affect the gut secondarily, GLP-2 appears to have evolved primarily to regulate intestinal adaptation to nutrient intake - expanding mucosal surface area during periods of adequate nutrition and reducing it during starvation. This trophic function is mediated through the GLP-2 receptor (GLP-2R), a G-protein-coupled receptor expressed on enteric neurons, subepithelial myofibroblasts, and intestinal smooth muscle - notably not directly on intestinal epithelial cells, meaning GLP-2's effects are mediated through secondary signals including IGF-1, EGF, and KGF released from GLP-2R-expressing stromal cells.

The intestinal effects of GLP-2 are impressive in scale and rapidity. A single injection of GLP-2 in rodents measurably increases crypt cell proliferation within 4 hours and produces significant increases in villus height and mucosal mass within 24-48 hours. Chronic GLP-2 administration in both animals and humans increases intestinal wet weight, protein content, DNA content, and mucosal surface area. In humans with short bowel syndrome, teduglutide treatment significantly increases intestinal wet weight (measured by CT imaging) and improves absorptive capacity.

Short bowel syndrome (SBS) represents the primary clinical application of GLP-2 pharmacology. SBS results from massive small intestinal resection (due to Crohn's disease, vascular events, trauma, or cancer) and produces severe malabsorption requiring long-term parenteral nutrition (PN). PN is associated with major complications including central line infections, liver disease, and poor quality of life. Teduglutide (Gattex in the US, Revestive in Europe), a DPP-4-resistant GLP-2 analogue developed by NPS Pharmaceuticals, was approved by the FDA in 2012 as the first pharmacological treatment for SBS. In clinical trials, teduglutide reduced parenteral nutrition requirements by an average of 4-5 litres/week, and approximately 27% of patients achieved PN independence. Long-term follow-up studies show maintained benefits with continued treatment.

The "leaky gut" research applications of GLP-2 have attracted considerable interest beyond its approved SBS indication. Intestinal barrier dysfunction - characterised by increased paracellular permeability between epithelial cells due to tight junction disruption - is implicated in multiple conditions including Crohn's disease, type 2 diabetes, obesity, liver disease, and sepsis. GLP-2 consistently reduces intestinal permeability in preclinical models through upregulation of tight junction proteins (claudin-3, occludin, ZO-1) and reduction of pro-inflammatory cytokines in the lamina propria. Multiple human trials have demonstrated that GLP-2 or teduglutide reduces surrogate markers of intestinal permeability.

The potential applications of GLP-2 in conditions beyond SBS represent active research frontiers. In Crohn's disease, GLP-2 analogues have shown pilot clinical efficacy in reducing disease activity and promoting mucosal healing. In necrotising enterocolitis (NEC) - a devastating condition of premature infants causing intestinal necrosis - GLP-2 has been shown to prevent NEC in animal models and is in early clinical trials. In chemotherapy-induced mucositis, GLP-2 has shown efficacy in reducing the severity of intestinal damage from cytotoxic chemotherapy.