Teduglutide

Teduglutide is a 33-amino-acid analogue of glucagon-like peptide-2 (GLP-2), a hormone released by enteroendocrine L-cells of the distal intestine. It differs from native human GLP-2 by a single substitution of glycine for alanine at position 2. That change protects the peptide from cleavage by dipeptidyl peptidase-4, the enzyme that rapidly inactivates natural GLP-2, and substantially extends its activity. Teduglutide was developed by NPS Pharmaceuticals, later acquired by Shire and then Takeda.

Teduglutide was approved in 2012 in both the EU, as Revestive, and the US, as Gattex, for short bowel syndrome in people dependent on parenteral support. It was the first approved agent targeting the GLP-2 receptor. Its scientific roots lie in the mid-1990s discovery, by Daniel Drucker and colleagues, that GLP-2 is strongly intestinotrophic in rodents, expanding villus height and crypt depth. Research with teduglutide focuses on intestinal adaptation after resection, mucosal growth signalling and the theoretical concern that sustained trophic stimulation could promote growth of pre-existing intestinal neoplasms.

Teduglutide activates the GLP-2 receptor, a Gs-coupled GPCR. Notably, the receptor is expressed not on the absorptive enterocytes themselves but mainly on enteroendocrine cells, enteric neurons and subepithelial myofibroblasts. Its trophic effects are therefore largely indirect, mediated by downstream factors such as insulin-like growth factor-1, keratinocyte growth factor and nitric oxide. In animal models, receptor activation increases crypt cell proliferation, reduces enterocyte apoptosis, lengthens villi and enhances barrier function. Additional reported effects include increased intestinal blood flow and slowed gastric emptying. Together these changes enlarge the absorptive surface, which is the focus of research in short bowel models.