Department of Radiation Oncology, University of Florida Shands Cancer Center, Cancer and Genetics Research Complex, Gainesville, Florida;
Am J Physiol Cell Physiol. 2014 Apr 1;306(7):C687-96. doi: 10.1152/ajpcell.00174.2013. Epub 2014 Jan 29.
The sodium-coupled glucose transporter-1 (SGLT1)-based oral rehydration solution (ORS) used in the management of acute diarrhea does not substantially reduce stool output, despite the fact that glucose stimulates the absorption of sodium and water. To explain this phenomenon, we investigated the possibility that glucose might also stimulate anion secretion. Transepithelial electrical measurements and isotope flux measurements in Ussing chambers were used to study the effect of glucose on active chloride and fluid secretion in mouse small intestinal cells and human Caco-2 cells. Confocal fluorescence laser microscopy and immunohistochemistry measured intracellular changes in calcium, sodium-glucose linked transporter, and calcium-activated chloride channel (anoctamin 1) expression. In addition to enhancing active sodium absorption, glucose increased intracellular calcium and stimulated electrogenic chloride secretion. Calcium imaging studies showed increased intracellular calcium when intestinal cells were exposed to glucose. Niflumic acid, but not glibenclamide, inhibited glucose-stimulated chloride secretion in mouse small intestines and in Caco-2 cells. Glucose-stimulated chloride secretion was not seen in ileal tissues incubated with the intracellular calcium chelater BAPTA-AM and the sodium-potassium-2 chloride cotransporter 1 (NKCC1) blocker bumetanide. These observations establish that glucose not only stimulates active Na absorption, a well-established phenomenon, but also induces a Ca-activated chloride secretion. This may explain the failure of glucose-based ORS to markedly reduce stool output in acute diarrhea. These results have immediate potential to improve the treatment outcomes for acute and/or chronic diarrheal diseases by replacing glucose with compounds that do not stimulate chloride secretion.
钠-葡萄糖协同转运蛋白-1（SGLT1）为基础的口服补液盐（ORS）用于治疗急性腹泻，并不能显著减少粪便量，尽管葡萄糖能刺激钠和水的吸收。为了解释这一现象，我们研究了葡萄糖是否也可能刺激阴离子分泌的可能性。我们采用 Ussing 室中的跨上皮电测量和同位素通量测量来研究葡萄糖对小鼠小肠细胞和人 Caco-2 细胞中活性氯和液体分泌的影响。共聚焦荧光激光显微镜和免疫组织化学测量细胞内钙、钠-葡萄糖协同转运蛋白和钙激活氯通道（anoctamin 1）的表达变化。除了增强主动钠吸收外，葡萄糖还增加了细胞内钙并刺激了电致氯分泌。钙成像研究表明，当肠道细胞暴露于葡萄糖时，细胞内钙增加。尼氟灭酸，但不是格列本脲，抑制了小鼠小肠和 Caco-2 细胞中葡萄糖刺激的氯分泌。在用细胞内钙螯合剂 BAPTA-AM 和钠-钾-2 氯共转运蛋白 1（NKCC1）阻滞剂布美他尼孵育的回肠组织中未观察到葡萄糖刺激的氯分泌。这些观察结果表明，葡萄糖不仅刺激了已被充分证实的主动 Na 吸收，而且还诱导了 Ca 激活的氯分泌。这可能解释了基于葡萄糖的 ORS 在急性腹泻中不能显著减少粪便量的原因。这些结果具有立即改善急性和/或慢性腹泻疾病治疗结果的潜力，可通过用不刺激氯分泌的化合物替代葡萄糖来实现。
