The connection between increased secretion of the glucagon-related peptides and the development of intestinal villus hyperplasia was first established following clinical reports of patients with glucagon-secreting tumors who presented with small bowel villus hyperplasia. The group of Dowling and colleagues reported a women who presented with a glucagon-producing tumor of the kidney and small bowel enlargement Endocrine tumour in kidney affecting small bowel structure, motility, and absorptive function. Gut. 1971 12(10):773-82. The intestinal abnormalities receded when the tumor was removed.
A subsequent case of a glucagonoma with villus hyperplasia was reported almost 10 years later, Remarkably, the association of intestinal villus hyperplasia and glucagonoma can be detected by CT scanning, with careful attention to the small bowel epithelium, as reported in Villous hypertrophy of the small bowel in a patient with glucagonoma. J Comput Assist Tomogr. 1983 Apr;7(2):334-7. A third case of glucagonoma and intestinal hyperplasia was diagnosed in a 39 y.o. man with giant duodenal villi, in Glucagonoma syndrome demonstrating giant duodenal villi. Gut. 1984 Jul;25(7):784-9.
These cases stimulated considerable interest in the relationship between increased secretion of intestinal glucagon-related peptides and the response to intestinal injury in both rodents and in human subjects with intestinal disease .
Despite an extensive series of experiments linking increased proglucagon gene expression and increased secretion of the intestinal proglucagon-derived peptides (PGDPs) with experimental intestinal injury , the identity of the specific PGDP with intestinotrophic activity proved elusive. Following the observation that mice harboring subcutaneous glucagonomas exhibited significant villus hyperplasia of the small bowel epithelium, peptide injection experiments identified GLP-2 as the PGDP with significant intestinotrophic activity in vivo Induction of intestinal epithelial proliferation by glucagon-like peptide 2. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7911-6.
Plurihormonal endocrine tumor secreting GLP-2
Byrne and colleagues have reported an additional case of glucagonoma and bowel growth and show for the first time that massively elevated levels of circulating GLP-2 are associated with mucosal hyperplasia in the jejunum. See Intestinal Proliferation and Delayed Intestinal Transit in a Patient with a GLP-1-, GLP-2- and PYY-Producing Neuroendocrine Carcinoma. Digestion. 2001;63(1):61-68