Glucose stimulates calcium-activated chloride secretion in small intestinal cells.
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.
Department of Radiation Oncology, University of Florida Shands Cancer Center, Cancer and Genetics Research Complex, Gainesville, Florida;
Liangjie
L
Yin
Pooja
P
Vijaygopal
Gordon G
GG
MacGregor
Rejeesh
R
Menon
Perungavur
P
Ranganathan
Sreekala
S
Prabhakaran
Lurong
L
Zhang
Mei
M
Zhang
Henry J
HJ
Binder
Paul
P
Okunieff
Sadasivan
S
Vidyasagar
D000818:Animals; D000075369:Anoctamin-1; D001692:Biological Transport; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D017097:Electric Impedance; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D051379:Mice; D018613:Microscopy, Confocal; D009363:Neoplasm Proteins / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism
C476213:ANO1 protein, human; C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D002614:Chelating Agents; D018118:Chloride Channels; D002712:Chlorides; D049990:Membrane Transport Modulators; D009363:Neoplasm Proteins; C495674:SLC5A1 protein, human; C495675:Slc5a1 protein, mouse; D051269:Sodium-Glucose Transporter 1; D012964:Sodium; D005947:Glucose; D002118:Calcium
SGLT1; calcium; glucose-stimulated chloride secretion; glucose-stimulated sodium absorption