T1R3 and gustducin in gut sense sugars to regulate expression of Na+-glucose cotransporter 1
- Robert F. Margolskee*,†,
- Jane Dyer‡,
- Zaza Kokrashvili*,
- Kieron S. H. Salmon‡,
- Erwin Ilegems*,
- Kristian Daly‡,
- Emeline L. Maillet*,
- Yuzo Ninomiya§,
- Bedrich Mosinger*, and
- Soraya P. Shirazi-Beechey‡,¶
- *Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029;
- ‡Epithelial Function and Development Group, Department of Veterinary Preclinical Sciences, University of Liverpool, Liverpool L69 7ZJ, United Kingdom; and
- §Section of Oral Neuroscience, Graduate School of Dental Science, Kyushu University, Fukuoka 812-8582, Japan
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Communicated by Linda M. Bartoshuk, University of Florida, Gainesville, FL, July 16, 2007 (received for review May 16, 2007)
Abstract
Dietary sugars are transported from the intestinal lumen into absorptive enterocytes by the sodium-dependent glucose transporter isoform 1 (SGLT1). Regulation of this protein is important for the provision of glucose to the body and avoidance of intestinal malabsorption. Although expression of SGLT1 is regulated by luminal monosaccharides, the luminal glucose sensor mediating this process was unknown. Here, we show that the sweet taste receptor subunit T1R3 and the taste G protein gustducin, expressed in enteroendocrine cells, underlie intestinal sugar sensing and regulation of SGLT1 mRNA and protein. Dietary sugar and artificial sweeteners increased SGLT1 mRNA and protein expression, and glucose absorptive capacity in wild-type mice, but not in knockout mice lacking T1R3 or α-gustducin. Artificial sweeteners, acting on sweet taste receptors expressed on enteroendocrine GLUTag cells, stimulated secretion of gut hormones implicated in SGLT1 up-regulation. Gut-expressed taste signaling elements involved in regulating SGLT1 expression could provide novel therapeutic targets for modulating the gut's capacity to absorb sugars, with implications for the prevention and/or treatment of malabsorption syndromes and diet-related disorders including diabetes and obesity.
Footnotes
- †To whom correspondence may be addressed at: Mount Sinai School of Medicine, Box 1065, Department of Neuroscience. 1425 Madison Avenue, New York, NY 10029. E-mail: robert.margolskee{at}mssm.edu
- ¶To whom correspondence may be addressed at: Epithelial Function and Development Group, Department of Veterinary Preclinical Sciences, University of Liverpool, Liverpool L69 7ZJ, United Kingdom. E-mail: spsb{at}liverpool.ac.uk
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Author contributions: R.F.M., J.D., Z.K., K.S.H.S., E.I., K.D., E.L.M., B.M., and S.P.S.-B. designed research; J.D., Z.K., K.S.H.S., E.I., K.D., E.L.M., and B.M. performed research; Y.N. contributed new reagents/analytic tools; R.F.M., J.D., Z.K., K.S.H.S., E.I., K.D., E.L.M., B.M., and S.P.S.-B. analyzed data; and R.F.M. and S.P.S.-B. wrote the paper.
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Conflict of interest statement: R.F.M. has a personal financial interest in the form of stock ownership in the Redpoint Bio company, receives consulting fees from the Redpoint Bio company, and is an inventor on patents and patent applications which have been licensed to the Redpoint Bio company. S.P.S.-B. is the inventor on the subject matter of this paper “intestinal glucose sensor,” which is protected by a patent filed with the European Patent Office, EP04077610.6 and the U.S. Patent and Trademark Office, PCT/EP2005/054760.
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See Commentary on page 14887.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0706678104/DC1.
- Abbreviations:
- BBMV,
- brush-border membrane vesicles;
- GIP,
- glucose-dependent insulinotrophic peptide;
- GLP-1,
- glucagon like peptide-1;
- SGLT1,
- sodium-dependent glucose transporter isoform 1;
- T1R,
- type 1 taste receptor.
- © 2007 by The National Academy of Sciences of the USA
