The Discovery of GLP-2 and Development of Teduglutide for Short Bowel Syndrome

The proglucagon gene encodes multiple structurally related peptides with overlapping actions promoting the absorption and assimilation of ingested energy. Notably, glucagon has been developed pharmaceutically to treat hypoglycemia, and glucagon-like peptide-1 (GLP-1) receptor agonists are used for the therapy of type 2 diabetes and obesity. Here I describe the discovery of glucagon-like peptide-2 (GLP-2), a 33 amino acid peptide cosecreted together with GLP-1 from gut endocrine cells. GLP-2 was found to exhibit robust intestinal growth-promoting activity, following serendipitous observations that proglucagon-producing tumors induced intestinal growth in mice. Key developments in the pharmaceutical development of GLP-2 included the cloning of the GLP-2 receptor, and the recognition of the importance of dipeptidyl peptidase-4 as a critical determinant of GLP-2 bioactivity. A therapeutic focus on short bowel syndrome, a serious medical disorder with compelling unmet medical need, enabled the pharmaceutical development of a simple GLP-2 analogue, teduglutide, suitable for once daily administration.