Casselbrant Anna, Malinauskas Mantas, Marschall Hanns-Ulrich, Wallenius Ville, Fändriks Lars
Department of Gastrosurgical Research and Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.
Scand J Gastroenterol. 2015;50(9):1068-75. doi: 10.3109/00365521.2015.1019557. Epub 2015 Apr 10.
Intestinal glucose absorption is mainly mediated via the sodium-glucose transporter 1 (SGLT1) at the apex of the enterocytes, whereas the glucose transporter 2 (GLUT2) provides a basolateral exit. It has been shown in rats that Angiotensin II (AngII), the principal mediator of renin-angiotensin system (RAS), inhibits jejunal SGLT1-mediated glucose absorption. The aim of the present study was to investigate if a similar mechanism exists also in the human jejunal mucosa.
Enteroscopy with mucosal biopsy sampling was performed in 28 healthy volunteers. Functional assessments were performed in Ussing chambers using a pharmacological approach. Western blotting and immunohistochemistry were used to assess the presence of the AngII type 1 (AT1R) and type 2 receptor (AT2R), as well as the glucose transporters SGLT1 and GLUT2.
Exposure of the mucosa to 10 mM glucose elicited a ≈50% increase in the epithelium-generated current (Iep). This glucose-induced electrogenic response was sensitive to the competitive SGLT1 inhibitor phlorizin, but not to AngII when given alone. AngII combined with the AT2R blocker PD123319 markedly inhibited the response. AngII in combination with the AT1R antagonist losartan tended to increase the electrogenic response, whereas direct activation of AT2R using the agonist C21 significantly enhanced the mucosal response to glucose. The AT1R and AT2R as well as SGLT1 and GLUT2 were detected inside the human enterocytes.
The pharmacological analysis indicated that activation of AT1R inhibits, whereas activation of AT2R enhances SGLT1-mediated glucose transport in the human jejunal mucosa.
肠道葡萄糖吸收主要通过肠上皮细胞顶端的钠葡萄糖转运体1（SGLT1）介导，而葡萄糖转运体2（GLUT2）则提供基底外侧的葡萄糖输出途径。在大鼠中已表明，肾素-血管紧张素系统（RAS）的主要介质血管紧张素II（AngII）可抑制空肠SGLT1介导的葡萄糖吸收。本研究的目的是调查人类空肠黏膜中是否也存在类似机制。
对28名健康志愿者进行了带黏膜活检采样的小肠镜检查。使用药理学方法在尤斯灌流小室中进行功能评估。采用蛋白质免疫印迹法和免疫组织化学法评估血管紧张素II 1型受体（AT1R）和2型受体（AT2R）以及葡萄糖转运体SGLT1和GLUT2的表达情况。
将黏膜暴露于10 mM葡萄糖可使上皮产生的电流（Iep）增加约50%。这种葡萄糖诱导的电反应对竞争性SGLT1抑制剂根皮苷敏感，但单独给予AngII时则不敏感。AngII与AT2R阻滞剂PD123319联合使用可显著抑制该反应。AngII与AT1R拮抗剂氯沙坦联合使用倾向于增加电反应，而使用激动剂C21直接激活AT2R可显著增强黏膜对葡萄糖的反应。在人类肠上皮细胞内检测到了AT1R和AT2R以及SGLT1和GLUT2。
药理学分析表明，激活AT1R会抑制，而激活AT2R会增强人类空肠黏膜中SGLT1介导的葡萄糖转运。
