Elsevier

Surgery

Volume 150, Issue 2, August 2011, Pages 217-223
Surgery

Society of University Surgeons
Administration of a dipeptidyl peptidase IV inhibitor enhances the intestinal adaptation in a mouse model of short bowel syndrome

https://doi.org/10.1016/j.surg.2011.05.013Get rights and content

Background

Glucagon-like peptide-2 induces small intestine mucosal epithelial cell proliferation and may have benefit for patients who suffer from short bowel syndrome. However, glucagon-like peptide-2 is inactivated rapidly in vivo by dipeptidyl peptidase IV. Therefore, we hypothesized that selectively inhibiting dipeptidyl peptidase IV would prolong the circulating life of glucagon-like peptide-2and lead to increased intestinal adaptation after development of short bowel syndrome.

Methods

Eight-week old C57BL/6J mice underwent a 50% proximal small bowel resection and were treated with either sitagliptin, a dipeptidyl peptidase IV-inhibitor, starting 1 day before surgery versus placebo. The efficacy of dipeptidyl peptidase IV-inhibitor was assessed 3 days after resection, including intestinal morphology, epithelial cell apoptosis, and epithelial cell proliferation. Adaptive mechanisms were assessed with quantitative real-time polymerase chain reaction, and plasma bioactive glucagon-like peptide-2 was measured by radioimmunoassay.

Results

Body weight loss and peripheral blood glucose levels did not change compared with short bowel syndrome controls. Dipeptidyl peptidase IV-inhibitor treatment led to significant increases in villus height and crypt depth. Dipeptidyl peptidase IV-inhibitor treatment did not change EC apoptosis rates significantly, but it did increase crypt epithelial cell proliferation significantly versus placebo-short bowel syndrome controls. Dipeptidyl peptidase IV-inhibitor treatment markedly increased messenger RNA expression of β-catenin and c-myc in ileal mucosa. Plasma glucagon-like peptide-2 levels increased significantly (∼40.9%) in dipeptidyl peptidase IV-inhibitor short bowel syndrome mice.

Conclusion

Dipeptidyl peptidase IV-inhibitor treatment increased short bowel syndrome adaptation and might potentially be useful for short bowel syndrome patients.

Section snippets

Chemical

Sitagliptin phosphate, which is an orally active inhibitor of the DPPIV enzyme (DPPIV-I), is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5- trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate. The empirical formula is C16H15F6N5O•H3PO4•H2O and the molecular weight is 523.32.

Animals

Specific pathogen-free, 8-week-old, 20–22 g C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME) were used and maintained in a 12-h day–night rhythm

Body weight changes

All mice were active and healthy throughout the study. No differences were found in survival (>90%) between groups. Both sham and SBS mice showed some degree of weight loss after surgery; however, the loss in each of these mice plateaued by the latter 2 days after the surgery period. The loss of body weight in the SBS group was significantly greater than the sham (percent change from weight at surgery: −13.06% ± 1.10% vs −6.22% ± 1.69%, respectively; P < .05). However, this loss was attenuated

Discussion

GLP-2, which is derived from intestinal L-cells in response to food intake and intestinotrophic stimulation, is one of the strongest mediators of intestinal adaptation after intestinal resection.5, 6 Precisely what drives secretion of GLP-2, however, is not known fully. A major counterregulatory control mechanism for GLP-2 is its cleavage and inactivation by the serine protease DPPIV.7 Such action is rapid, resulting in a relatively short half-life of native GLP-2 to approximately seven minutes.

Acknowledgments

We wish to thank for the help the National Cancer Institute for processing histologic samples.

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    • Cited by (0)

    Supported by Grant 2R01AI-44076-11(to D.H.T.) from the National Institutes of Health and by Grant 5 P03 CA46592 from the University of Michigan’s Cancer Center.

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