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Prolonged Gastrointestinal Transit in a Patient with a Glucagon-Like Peptide (GLP)-1- and -2-Producing Neuroendocrine Tumor

Departments of Physiology (P.L.B.), Medicine (P.L.B., D.J.D., G.R.G.), Lab Medicine and Pathobiology (S.L.A., M.R.), Surgery (C.S.), and the Banting and Best Diabetes Centre (D.J.D.), University of Toronto, Toronto, Ontario M5S 1A8, Canada

Address all correspondence and requests for reprints to: Dr. P. L. Brubaker, Room 3366 Medical Sciences Building, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada. E-mail: . p.brubaker{at}utoronto.ca

Abstract

Neuroendocrine tumors overexpressing the proglucagon- derived peptides have been associated with severe constipation. The relationship between two of the intestinal proglucagon-derived peptides, glucagon-like peptide (GLP)-1 and -2, and delayed gastrointestinal transit, was characterized in a patient with a neuroendocrine proglucagon-derived peptide tumor. A 60-yr-old female presented with intractable constipation and intermittent vomiting. Gastric, oral-ileal and colonic transit times, and plasma hormone levels were determined before tumor resection. Expression of the proglucagon-derived peptides by the tumor was determined by immunohistochemistry, Northern blot analysis, HPLC, and RIA. Oral-cecal transit was more than 3 h, and a barium follow-through study showed dilated and thickened folds with most of the barium concentrated in the ileum at 24 h; residual barium was identified in the colon at 14 d post ingestion. Circulating levels of GLP-1 and -2 were 300- to 400-fold elevated compared with levels in normal human subjects. Normal bowel function was restored by tumor resection. Consistent with the elevated plasma hormone levels, the tumor was found to express the proglucagon gene, and immunoreactive GLP-1 and -2 were detected by both immunohistochemistry and RIA. Overexpression of glucagon-like peptide-1 and -2 is associated with markedly prolonged gastrointestinal transit in humans. These findings are consistent with a role for these peptides in the regulation of gastrointestinal motility.

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