Glucose stimulates calcium-activated chloride secretion in small intestinal cells

Abstract

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.

Glucose promotes secretion-dependent renal cyst growth

“…Recently, Yin et al showed that glucose may regulate the expression of ANO1 [16]. Therefore, we analyzed mRNA expression of ANO1 and other candidates involved in chloride secretion, including anoctamin 6 (ANO6), the purinergic receptor P2Y2R, the Na + -K + -Cl − cotransporter 1 (NKCC1), and CFTR in the presence of low and high glucose in the embryonic kidney cyst model (Fig.…”

Calcium-induced chloride secretion is decreased by Resveratrol in ileal porcine tissue

“…Additionally, this part of the study may give some new indications that RSV may affect Ca 2+ -induced Cl − secretion since the glucose-induced I sc for ctrl/Cl − -free chambers was decreased compared to ctrl/Cl − chambers (p = 0.014). It has been shown that glucose stimulates Ca 2+ -induced Cl − secretion in intestinal cells [26, 27]. Therefore, this difference may indicate that a part of the ΔI sc under control conditions may be due to glucose-mediated stimulation of Ca 2+ -induced Cl − secretion especially since there is a correlation between the glucose-induced ΔI sc under ctrl and Cl − -free conditions (R 2  = 0.846, p = 0.0004).…”

An amino acid-based oral rehydration solution (AA-ORS) enhanced intestinal epithelial proliferation in mice exposed to radiation

“…We recently found that electrolytes, glucose, and some amino acids are poorly absorbed in the GI tract following irradiation. In addition, we observed that glucose and some amino acids can stimulate electrogenic Cl − secretion in addition to Na + absorption and can increase paracellular permeability, which further complicates radiation-induced diarrhea and increased gut permeability2030. Increased paracellular permeability is known to increase translocation of antigenic substances from the gut lumen into the systemic compartment, causing an increase in pro-inflammatory cytokines20.…”