Glucose sensing in the intestinal epithelium

Abstract

Dietary sugars regulate expression of the intestinal Na + / glucose cotransporter, SGLT1, in many species. Using sheep intestine as a model, we showed that lumenal monosaccharides, both metabolisable and nonmetabolisable, regulate SGLT1 expression. This regulation occurs not only at the level of transcription, but also at the post-transcriptional level. Introduction of D-glucose and some D-glucose analogues into ruminant sheep intestine resulted in > 50-fold enhancement of SGLT1 expression. We aimed to determine if transport of sugar into the enterocytes is required for SGLT1 induction, and delineate the signal-transduction pathways involved.A membrane impermeable D-glucose analogue, di(glucos-6-yl)poly(ethylene glycol) 600, was synthesized and infused into the intestines of ruminant sheep. SGLT1 expression was determined using transport studies, Northern and Western blotting, and immunohistochemistry. An intestinal cell line, STC-1, was used to investigate the signalling pathways.Intestinal infusion with di(glucos-6-yl)poly(ethylene glycol) 600 led to induction of functional SGLT1, but the compound did not inhibit Na + /glucose transport into intestinal brush-border membrane vesicles. Studies using cells showed that increased medium glucose up-regulated SGLT1 abundance and SGLT1 promoter activity, and increased intracellular cAMP levels. Glucose-induced activation of the SGLT1 promoter was mimicked by the protein kinase A (PKA) agonist, 8Br-cAMP, and was inhibited by H-89, a PKA inhibitor. Pertussis toxin, a G-protein (G i )-specific inhibitor, enhanced SGLT1 protein abundance to levels observed in response to glucose or 8Br-cAMP.We conclude that lumenal glucose is sensed by a glucose sensor, distinct from SGLT1, residing on the external face of the lumenal membrane. The glucose sensor initiates a signalling pathway, involving a G-protein-coupled receptor linked to a cAMP-PKA pathway resulting in enhancement of SGLT1 expression.Keywords: intestine; Na + /glucose cotransport; nutrient transport; sugar sensing.The dietary monosaccharides, D-glucose and D-galactose, are transported across the brush-border membrane of intestinal absorptive cells (enterocytes) by the Na + /glucose cotransporter, SGLT1. It has been demonstrated that lumenal glucose enhances the number of functional SGLT1 molecules in the intestinal brush-border membrane, and that the metabolism of glucose is not required for the induction [1][2][3][4][5].We have used sheep intestine, which is an excellent model system, for the study of monosaccharide regulation of intestinal sugar transport [3,6]. We have shown that dietary monosaccharides regulate the expression of intestinal brushborder membrane Na + /glucose cotransporter at both the transcriptional and post-transcriptional levels [3,7,8].In preruminant lambs (birth to 3 weeks), milk sugar lactose is hydrolysed by the intestinal lactase into D-glucose and D-galactose, and these sugars are transported by SGLT1. Lambs are normally weaned at 3-10 weeks of age and, as the diet changes from milk to gra...

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