Departments of Physiology (S.E.M., M.E.S., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, Canada; VectivBio AG, Basel, Switzerland (V.D.); and Division of Gastroenterology Mayo Clinic, Rochester, Minnesota (J.A.M.).
Departments of Physiology (S.E.M., M.E.S., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, Canada; VectivBio AG, Basel, Switzerland (V.D.); and Division of Gastroenterology Mayo Clinic, Rochester, Minnesota (J.A.M.)
J Pharmacol Exp Ther. 2020 Jun;373(3):347-352. doi: 10.1124/jpet.119.263947. Epub 2020 Mar 6.
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 ( < 0.001) and length ( < 0.001) after 3 weeks of administration, with a further increase in effectiveness after 10 weeks ( < 0.01). Crypt depth and villus height were both markedly increased after 3 weeks of apraglutide administration ( < 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 ( < 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 ( < 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 time- and location-dependent specificity in its intestinotrophic actions. SIGNIFICANCE STATEMENT: The novel long-acting glucagon-like peptide 2 receptor agonist, apraglutide, enhances intestinal weight as well as intestinal length in a time- and site-dependent fashion.
长效胰高血糖素样肽 2 受体（GLP-2R）激动剂已被证实可促进啮齿动物和短肠综合征患者的肠道生长，尤其是在人类中。GLP-2R 激动剂的大多数营养作用据报道是通过增加隐窝-绒毛轴的生长来介导的，从而导致黏膜质量增加和肠道功能改善。本研究在雄性和雌性小鼠中，检查了新型 GLP-2R 激动剂阿普拉肽在治疗 3、7 和 10 周后对小肠和结肠生长的影响。阿普拉肽（3mg/kg；每周三次）在给药 3 周后显著增加小肠重量（<0.001）和长度（<0.001），10 周后效果进一步增加（<0.01）。阿普拉肽给药 3 周后，隐窝深度和绒毛高度均明显增加（<0.001），但随着治疗时间的延长并未进一步增加，而隐窝数量和肠周径在 7 和 10 周后增加（<0.01），但在阿普拉肽治疗 3 周后没有增加。阿普拉肽治疗还增强了结肠的重量和长度，3 周时（<0.001），这些作用在继续阿普拉肽治疗时保持但没有进一步改善。本研究结果表明，新型长效 GLP-2R 激动剂阿普拉肽具有显著增加肠长度的能力，并且其肠营养作用具有时间和位置依赖性特异性。意义陈述：新型长效胰高血糖素样肽 2 受体激动剂阿普拉肽以时间和部位依赖的方式增强肠重和肠长。
