Division of Gastroenterology and Endocrinology, Rostock University Medical Center, Rostock, 18057, Germany.
Research and Development, Zealand Pharma, Søborg, 2860, Denmark.
JPEN J Parenter Enteral Nutr. 2022 Jul;46(5):1107-1118. doi: 10.1002/jpen.2286. Epub 2021 Nov 18.
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.
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 sham-operated male mice.
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.
Dapiglutide possesses specific and potent GLP-1R and GLP-2R agonist effects in rodents. In the murine SB model, combined unimolecular GLP-1R and GLP-2R stimulation with dapiglutide potently attenuates intestinal insufficiency and potentially also IF.
广泛的肠道切除术可能导致短肠（SB）综合征，从而导致肠道功能不全或肠道衰竭（IF）。肠道功能不全和 IF 涉及到前胰高血糖素衍生激素胰高血糖素样肽-1（GLP-1）和 GLP-2 的缺乏。SB 的两个主要问题是上皮表面损失和转运加速。目前的标准治疗方法是使用 GLP-2 类似物来促进肠道适应，以扩大吸收表面积。通过 GLP-1 和 GLP-2 活性的联合，有可能获得额外的益处，其目的是扩大肠道表面积并减缓肠道转运。
在啮齿动物中，对新型双重 GLP-1 受体（GLP-1R）和 GLP-2 受体（GLP-2R）激动剂 dapiglutide（rINN）的 GLP-1 和 GLP-2 特异性作用进行了表征。此外，在 40%回盲肠切除术导致的肠道功能不全的 SB 小鼠模型中，与载体和假手术雄性小鼠相比，dapiglutide 对肠道生长、体重、食物摄入、容量状态和粪便含水量的影响进行了测试。
dapiglutide 显著改善了口服葡萄糖耐量，降低了肠道转运时间，并促进了肠道生长。在 SB 小鼠模型中，尽管液体饮食的摄入量没有改变，dapiglutide 仍促进了体重的恢复。dapiglutide 促进了显著的肠道生长，表现为绒毛高度和肠长度显著增加。此外，dapiglutide 减少了粪便水分流失，导致血浆醛固酮降低。
在啮齿动物中，dapiglutide 具有特异性和强大的 GLP-1R 和 GLP-2R 激动作用。在 SB 小鼠模型中，dapiglutide 联合单分子 GLP-1R 和 GLP-2R 刺激强烈减轻了肠道功能不全，并且可能也减轻了 IF。
