PT - JOURNAL ARTICLE AU - Sarah E Martchenko AU - Maegan E Sweeney AU - Violetta Dimitriadou AU - Joseph A Murray AU - Patricia L Brubaker TI - Site-specific and temporal effects of apraglutide, a novel long-acting glucagon-like peptide-2 receptor agonist, on intestinal growth in mice AID - 10.1124/jpet.119.263947 DP - 2020 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - jpet.119.263947 4099 - http://jpet.aspetjournals.org/content/early/2020/03/06/jpet.119.263947.short 4100 - http://jpet.aspetjournals.org/content/early/2020/03/06/jpet.119.263947.full AB - Long-acting glucagon-like peptide-2 receptor (GLP-2R) agonists are well-established to increase intestinal growth in rodents and, most notably, humans with short bowel syndrome. Most of the trophic effects of GLP-2R agonists are reported to be mediated through increased growth of the crypt-villus axis, resulting in enhanced mucosal mass and improved intestinal function. The present study examined the effects of apraglutide, a novel GLP-2R agonist, on the growth of the small and large intestines, after 3, 7 and 10 weeks of treatment in male and female mice. Apraglutide (3mg/kg; 3-times per week) significantly increased small intestinal weight (p<0.001) and length (p<0.001) after 3 weeks of administration, with a further increase in effectiveness after 10 weeks (p<0.01). Crypt depth and villus height were both markedly increased after 3 weeks of apraglutide administration (p<0.001) but did not show any further increase with duration of treatment, whereas crypt number and intestinal circumference were increased after 7 and 10 weeks (p<0.01) but not after 3 weeks of apraglutide treatment. Both the weight and the length of the colon were also enhanced by apraglutide treatment for 3 weeks (p<0.001), and these effects were maintained but did not improve further with continued apraglutide administration. The results of this study demonstrate that the novel, long-acting GLP-2R agonist, apraglutide demonstrates unexpected marked ability to increase intestinal length, as well as exerting time- and location-dependent specificity in its intestinotrophic actions.SIGNIFICANCE STATEMENT The novel long-acting GLP-2R agonist, apraglutide, enhances intestinal weight as well as intestinal length in a time- and site-dependent fashion.