T1R3 and gustducin in gut sense sugars to regulate expression of Na ⁺ -glucose cotransporter 1

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 ␣-gustducin. Artificial sweeteners, acting on sweet taste receptors expressed on enteroendocrine GLUTag cells, stimulated secretion of gut hormones implicated in SGLT1 upregulation. 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.carbohydrate absorption ͉ gastrointestinal chemosensation ͉ glucose sensor ͉ glucose uptake T o date, the only identified sugar sensors in the mammalian gastrointestinal tract are those involved in taste transduction (1). Although the gut epithelium senses luminal sugars and modulates its glucose absorptive capacity accordingly, the nature of the sugar-sensing molecule(s) and downstream events remain unknown. Several studies have shown that in many species expression of the intestinal sodium-dependent glucose transporter 1 (SGLT1) is directly regulated by monosaccharides in the lumen of the gut independently of metabolism and appears to involve a G protein-linked second messenger pathway (2-6). Furthermore, the addition of membrane-impermeable glucose analogues to the lumen of the intestine stimulates SGLT1 expression, implying that a glucose sensor on luminal membranes is involved (6).In taste cells, the detection of sugars and sweeteners depends on T1R2ϩT1R3, a heterodimer of type 1 taste receptor subunits (T1Rs) (7,8). The taste receptor cells of the anterior tongue that express T1R2ϩT1R3 typically also express gustducin, a transducin-like heterotrimeric G protein (9). Gustducin's ␣-subunit (G␣ gust ) has been detected in brush cells of the rat stomach, duodenum, and pancreatic ducts (10). G␣ gust and bitter-responsive type 2 taste receptors (T2Rs) are expressed in mouse intestinal endocrine cells and in the murine enteroendocrine cell line STC-1 (11).We reported previously that T1R taste receptors and G␣ gust are expressed in the mouse small intestinal epithelium and proposed that they function as luminal sugar sensors to control SGLT1 expression in response to dietary sugar (12). Here, we provide three lines of evidence in favor of T1R taste receptors an...

Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects

“…Supplementation of the diet with sucralose increases SGLT1 mRNA and glucose absorption in wild-type mice but not in T1R3 or ␣-gustducin knockout mice (28). Furthermore, sucralose, acesulfame potassium, and saccharin stimulate glucose absorption in rats by enhancing apical insertion of GLUT2 (25).…”

“…The T1R2ϩ3 heterodimer should, by analogy to the tongue, respond to various sweet-tasting molecules as diverse as sucrose, saccharin, acesulfame K, and sucralose (32,47). Furthermore, it has been demonstrated in two mouse enteroendocrine cell lines, GLUTag and STC-1, that sweet taste receptors are colocalized with GLP-1 and GIP (22,37) and that sucralose stimulates secretion of GLP-1 and GIP from GLUTag cells (28). Mice that lack ␣-gustducin show markedly defective GLP-1 secretion in response to glucose (21).…”

Effect of the artificial sweetener, sucralose, on small intestinal glucose absorption in healthy human subjects

“…Recent studies indicate the presence of G-protein-coupled taste receptors, T1R2 and T1R3, and their taste signal transduction partners, the G-protein gustducin and the transient receptor potential ion channel TRPM5, in the mucosa of the mouse and human gastrointestinal tract (1,2) . These receptors, analogous to sweet taste receptors on the tongue, broadly respond to sugars and artificial sweeteners, and among several cell types, they appear to co-localise with glucagon-like peptide-1 (GLP-1)-secreting L cells (3) .It has been reported that the artificial sweetener, sucralose, stimulates the secretion of both GLP-1 and glucose-dependent insulinotrophic polypeptide from the mouse enteroendocrine cell line GLUTag (4) , and it stimulates GLP-1 secretion from the human L cell line NCI-H716 (3) , a response that is blocked by the sweet receptor antagonist, lactisole, and siRNA for a-gustducin (3) . However, we recently demonstrated that sucralose, in two different loads, had no effect on GLP-1, glucose-dependent insulinotrophic polypeptide or insulin secretion, and that it did not elicit any feedback response on gastric emptying in healthy human subjects (5) .…”

Sweet taste signaling in the gut

“…Digestive and absorptive processing of the ingested food is further coordinated by sugar sensing in the intestinal tract, which modulates nutrient absorption, hormone release, and gastrointestinal motility, and generates satiation signals to the brain that terminate the meal (3,4). In this issue of PNAS, Margolskee et al (5) report that the same T1R2ϩT1R3 sweet taste receptor that initiates sugar ingestion in the mouth also detects sugar in the intestinal lumen and triggers physiological responses that promote sugar absorption and metabolism.…”