Dapiglutide, a novel dual GLP‐1 and GLP‐2 receptor agonist, attenuates intestinal insufficiency in a murine model of short bowel

Abstract

Background: Extensive intestinal resection may lead to short bowel (SB) syndrome, resulting in intestinal insufficiency or intestinal failure (IF). Intestinal insufficiency and IF involve deficiency of the proglucagon-derived hormones glucagon-like peptide-1 (GLP-1) and GLP-2. Two major problems of SB are epithelial surface loss and accelerated transit. Standard treatment now targets intestinal adaptation with a GLP-2 analogue to enlarge absorptive surface area. It is possible that additional benefit can be gained from a combination of GLP-1 and GLP-2 activity, with the aim to enlarge intestinal surface area and slow intestinal transit. Methods: The GLP-1-and GLP-2-specific effects of the novel dual GLP-1 receptor (GLP-1R) and GLP-2 receptor (GLP-2R) agonist dapiglutide (rINN) were characterized in rodents. Furthermore, in a murine SB model of intestinal insufficiency with 40% ileocecal resection, the influence of dapiglutide on intestinal growth, body weight, food intake, volume status, and stool water content was tested against vehicle and shamoperated male mice. Results: Dapiglutide significantly improves oral glucose tolerance, reduces intestinal transit time, and promotes intestinal growth. In the SB mouse model, dapiglutide promotes body weight recovery, despite unchanged intake of liquid diet. Dapiglutide promotes significant intestinal growth, as indicated by significantly increased villus height as well as intestinal length. Furthermore, dapiglutide reduces stool water losses, resulting in reduced plasma aldosterone. Conclusion: Dapiglutide possesses specific and potent GLP-1R and GLP-2R agonist effects in rodents. In the murine SB model, combined unimolecular GLP-1R andThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

The dual GLP‐1 and GLP‐2 receptor agonist dapiglutide promotes barrier function in murine short bowel

“…This likely results from enhanced nutrient and water absorption in the remnant intestine. The two major mechanisms for such increased absorption are likely prolonged epithelial contact time, largely mediated by the GLP‐1 effect, and increased epithelial mass, largely mediated by the GLP‐2 effect 14,31 . However, experimental evidence that an increased epithelial mass directly translates into increased epithelial function is lacking.…”

“…Histological quantification of crypt‐villus geometry was performed as previously described 14 . In brief, 1‐cm jejunum segments were immediately placed in MorFFFix (Morphisto, Germany) for 24 h and then paraffin embedded.…”

“…This combined receptor agonist treatment has previously been shown to significantly alleviate intestinal insufficiency in a short bowel (SB) mouse model. Of note, fecal water content is significantly reduced, while nutritional status is significantly improved, likely due to a major effect on increased intestinal absorption 14 . It is not known to what extent this novel peptide affects the epithelial barrier.…”

“…Of note, fecal water content is significantly reduced, while nutritional status is significantly improved, likely due to a major effect on increased intestinal absorption. 14 It is not known to what extent this novel peptide affects the epithelial barrier. In the intestinal tract, the highest expression of the GLP-2 receptor is found in the jejunum and to a lesser extent in the colon.…”

Glucagon-like peptide-2 analogues for Crohn’s disease patients with short bowel syndrome and intestinal failure

“…Elsiglutide is a GLP-2 analogue with a long half-life that reduced diarrhoea induced by lapatinib, a tyrosine kinase inhibitor, in a rat model[ 86 ]. Dapiglutide is a dual GLP-1 and GLP-2 agonist that showed beneficial effects in a rat model of SBS by improving body weight, promoting intestinal growth, increasing villous height and intestinal length, and reducing watery stool losses[ 87 ].…”