Sensing Sugar in the Gut

Science's STKE  25 Sep 2007:
Vol. 2007, Issue 405, pp. tw343
DOI: 10.1126/stke.4052007tw343

Two articles provide evidence that the same receptors and pathway that allow us to taste sweet compounds (sugars and artificial sweeteners) function in the intestinal tract to sense these same compounds as they reach the gut. Jang et al. found that signaling components of the sweet taste pathway originally characterized in the tongue could be detected in enteroendocrine cells--L cells, which secrete glucagon-like peptide-1 (GLP-1), and K cells, which secrete glucose-dependent insulinotropic peptide (GIP)--of the human duodenum. In mice, the Gα subunit gustducin was present in L cells but not in K cells. A comparison of the response to glucose delivered directly into the lumen of the stomach or the duodenum (to bypass the tongue) in wild-type mice or mice lacking the gustducin gene showed that the GLP-1 secretion into the blood was absent in the gustducin-deficient animals and that the temporal pattern of insulin secretion and glucose uptake was altered. Although minced duodenal tissue from the gustducin-deficient mice showed a glucose-stimulated increase in GLP-1 release, the fold change in GLP-1 secretion was less than that for wild-type tissue. Application of glucose or artificial sweeteners directly to the human enteroendocrine L cell line NCI-H716, in which the signaling components of the sweet taste pathway were also detected, resulted in GLP-1 release, which was blocked by an antagonist of the T1R3 receptor (one subunit of the T1R2 and T1R3 G protein-coupled receptor heterodimer that forms the sugar receptor). Thus, sugar sensing in the intestinal enteroendocrine system that contributes to the regulation of glucose handling by stimulation of GLP-1 secretion appears to involve the same pathway as sweet taste sensation on the tongue. The second article, by Margolskee et al. (see commentary by Sclafani), provides evidence for a connection between glucose absorption and glucose sensing through the T1R2/3 taste receptor pathway through increased intestinal expression and abundance of the sodium-glucose cotransporter 1 (SGLT1). Wild-type mice or mice deficient in gustducin or T1R3 were fed low-carbohydrate or high-carbohydrate diets or were fed low-carbohydrate diets with artificially sweetened water, and only the wild-type mice showed an increase in SGLT1 mRNA, protein, and glucose uptake when fed the high-carbohydrate diet or exposed to the artificial sweeteners. Experiments with the mouse enteroendocrine cell line GLUTag showed that these cells release GIP and GLP-1 tonically and that the artificial sweetener sucralose stimulates the release of these hormones through a mechanism that was blocked by an antagonist of the T1R2/3 sweet taste receptor. Together these results suggest that a similar pathway to sweet taste reception in the tongue may also sense sugars in the intestine. Interestingly, artificial sweeteners appear to stimulate processes that would increase glucose uptake and insulin secretion. Whether this mechanism affects human metabolism will be interesting to evaluate.

H.-J. Jang, Z. Kokrashvili, M. J. Theodorakis, O. D. Carlson, B.-J. Kim, J. Zhou, H. H. Kim, X. Xu, S. L. Chan, M. Juhaszova, M. Bernier, B. Mosinger, R. F. Margolskee, J. M. Egan, Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proc. Natl. Acad. Sci. U.S.A. 104, 15069-15074 (2007). [Abstract] [Full Text]

R. F. Margolskee, J. Dyer, Z. Kokrashvili, K. S. H. Salmon, E. Ilegems, K. Daly, E. L. Maillet, Y. Ninomiya, B. Mosinger, S. P. Shirazi-Beechey, T1R3 and gustducin in gut sense sugars to regulate expression of Na+-glucose cotransporter 1. Proc. Natl. Acad. Sci. U.S.A. 104, 15075-15080 (2007). [Abstract] [Full Text]

A. Sclafani, Sweet taste signaling in the gut. Proc. Natl. Acad. Sci. U.S.A. 104, 14887-14888 (2007). [Full Text]