TY - JOUR
T1 - Site-specific and temporal effects of apraglutide, a novel long-acting glucagon-like peptide-2 receptor agonist, on intestinal growth in mice
AU - Martchenko, S. E.
AU - Sweeney, M. E.
AU - Dimitriadou, V.
AU - Murray, J. A.
AU - Brubaker, P. L.
N1 - Publisher Copyright:
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2020/6
Y1 - 2020/6
N2 - 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 intestine and colon after 3, 7, and 10 weeks of treatment in male and female mice. Apraglutide (3 mg/kg; three 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 an unexpected marked ability to increase intestinal length as well as exert timeand location-dependent specificity in its intestinotrophic actions.
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 intestine and colon after 3, 7, and 10 weeks of treatment in male and female mice. Apraglutide (3 mg/kg; three 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 an unexpected marked ability to increase intestinal length as well as exert timeand location-dependent specificity in its intestinotrophic actions.
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U2 - 10.1124/jpet.119.263947
DO - 10.1124/jpet.119.263947
M3 - Article
C2 - 32144124
AN - SCOPUS:85084694254
SN - 0022-3565
VL - 373
SP - 347
EP - 352
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -