enteroendocrine cells ͉ gastrointestinal chemosensation ͉ glucose sensor ͉ incretin G lucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins, peptide hormones secreted from enteroendocrine L and K cells, respectively, that augment insulin secretion after oral intake of glucose (1). How carbohydrates in the gut lumen elicit the release of GLP-1 from L cells and GIP from K cells is unknown (2). Because i.v. glucose administration does not induce secretion of GLP-1 (3) it appears that glucose within the lumen of the gut acts on the luminal surface to stimulate secretion. Thus, we sought to determine what glucose-sensing mechanism in the gut lumen might underlie this L cell response.One mechanism for sensing glucose is by sweet taste receptors in taste receptor cells of the lingual epithelium (4). Sweet compounds bind to and activate specific G protein coupled receptors that couple through the G protein gustducin (5) to specific second messenger cascades (4, 6). Two type 1 taste G protein coupled receptors (T1Rs) heterodimerize to form the T1R2ϩT1R3 sweet taste receptor (7-11). Key elements of the taste transduction pathways are the ␣, , and ␥ subunits of gustducin (␣-gustducin, G 3 , and G␥ 13 ) (5, 12), phospholipase C2 (PLC2) (13), and transient receptor potential channel type M5 (14), a Ca 2ϩ -activated cation channel (15-17). ␣-Gustducin has been detected in brush cells of the stomach, duodenum, and pancreatic ducts in rat (18, 19), T1R2 and T1R3 are present in rodent gut and the enteroendocrine STC-1 cell line (20), and ␣-gustducin and GLP-1 are present in enteroendocrine cells of the human colon (21). However, the functional significance of expression of taste signaling elements in cells of the gastrointestinal (GI) tract had been unclear. Here, we present data that indicate that T1R3 and gustducin have a role in glucosemediated incretin release and may serve as the previously unknown gut lumen glucose sensor.
ResultsWe examined L cells of the gut for the presence of taste receptors and elements of taste transduction pathways. In human duodenal biopsy sections ␣-gustducin was detected by immunofluorescence (
Our findings show that PYY and GLP-1 are colocalized and cosecreted from L cells and that total secretion of PYY is higher in females than in males, but fasting PYY levels and PYY secretion in response to oral glucose were not in any way correlated with BMI.
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