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.

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The peptide hormone amylin reduces food intake and body weight, and is an attractive candidate target for novel pharmacotherapies to treat obesity. However, the short half-life of native amylin and amylin analogs like pramlintide limits these compounds' potential utility in promoting sustained negative energy balance. Here, we evaluate the ability of the novel long-acting amylin/calcitonin receptor agonist ZP5461 to reduce feeding and body weight in rats, and also test the role of calcitonin receptors (CTRs) in the dorsal vagal complex (DVC) of the hindbrain in the energy balance effects of chronic ZP5461 administration. Acute dose-response studies indicate that systemic ZP5461 (0.5-3 nmol/kg) robustly suppresses energy intake and body weight gain in chow- and high-fat diet (HFD)-fed rats. When HFD-fed rats received chronic systemic administration of ZP5461 (1-2 nmol/kg), the compound initially produced reductions in energy intake and weight gain, but failed to produce sustained suppression of intake and body weight. Using virally-mediated knockdown of DVC CTRs, the ability of chronic systemic ZP5461 to promote early reductions in intake and body weight gain was determined to be mediated in part by activation of DVC CTRs, implicating the DVC as a central site of action for ZP5461. Future studies should address other dosing regimens of ZP5461 to determine whether an alternative dose/frequency of administration would produce more sustained body weight suppression.

Short bowel syndrome can occur after extensive intestinal resection, causing intestinal insufficiency or intestinal failure, which requires long-term parenteral nutrition.Glucagon-like peptide-2 (GLP-2) pharmacotherapy is now clinically used to reduce the disease burden of intestinal failure. However, many patients still cannot be weaned off from parenteral nutrition completely. The novel dual GLP-1 and GLP-2 receptor agonist dapiglutide has previously been shown to be highly effective in a preclinical murine short bowel model. Here, we studied the effects of dapiglutide on intestinal epithelial barrier function. In the jejunum, dapiglutide increased claudin-7 expression and tightened the paracellular tight junction leak pathway. At the same time, dapiglutide promoted paracellular tight junction cation size selectivity in the jejunum. This was paralleled by extension of the cation selective tight junction proteins claudin-2 and claudin-10b and preserved claudin-15 expression and localization along the crypt-villus axis in the jejunum. In the colon, no barrier effects from dapiglutide were observed. In the colon, dapiglutide attenuated the short bowel-associated, compensatorily increased epithelial sodium channel activity, likely secondary, by improved volume status. Future studies are needed to address the intestinal adaptation of the colon.

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