Gerspach AC, Steinert RE, Schönenberger L, Graber-Maier A, Beglinger C. The role of the gut sweet taste receptor in regulating GLP-1, PYY, and CCK release in humans. Am J Physiol Endocrinol Metab 301: E317-E325, 2011. First published May 3, 2011 doi:10.1152/ajpendo.00077.2011The recent identification of sweet taste receptors in the gastrointestinal tract has important implications in the control of food intake and glucose homeostasis. Lactisole can inhibit the sweet taste receptor T1R2/T1R3. The objective was to use lactisole as a probe to investigate the physiological role of T1R2/ T1R3 by assessing the effect of T1R2/T1R3 blockade on GLP-1, PYY, and CCK release in response to 1) intragastric administration of nutrients or 2) intraduodenal perfusion of nutrients. The study was performed as a randomized, double-blind, placebo-controlled crossover study that included 35 healthy subjects. In part I, subjects received intragastrically 75 g of glucose in 300 ml of water or 500 ml of a mixed liquid meal with or without lactisole. In part II, subjects received an intraduodenal perfusion of glucose (29.3 g glucose/100 ml; rate: 2.5 ml/min for 180 min) or a mixed liquid meal (same rate) with or without lactisole. The results were that 1) lactisole induced a significant reduction in GLP-1 and PYY but not CCK secretion in both the intragastric and the intraduodenal glucose-stimulated parts (P Յ 0.05), 2) comparison of the inhibitory effect of lactisole showed a significantly greater suppression of the hormone response in the intragastric part (P ϭ 0.023), and 3) lactisole had no effect on liquid meal-stimulated parameters. We conclude that T1R2/T1R3 is involved in glucose-dependent secretion of satiation peptides. However, the results of the liquid meal-stimulated parts show that the receptor alone is not responsible for peptide secretion.glucagon-like peptide-1; peptide tyrosine-tyrosine; cholecystokinin; T1R2/T1R3; gastric emptying; lactisole; nutrient sensing ENTEROENDOCRINE CELLS IN THE HUMAN GUT sense chemical components of ingested food and secrete a number of gastrointestinal satiation peptides, including glucagon-like peptide 1 (GLP-1), peptide tyrosine-tyrosine (PYY), and cholecystokinin (CCK) (41). All of them have been demonstrated to influence gastric emptying, increase satiety, and reduce food intake (8,13,18,23,30,37). Recently, it has been shown that G protein-coupled receptors that sense chemical components of food on the tongue, including the sweet taste receptor (T1R2/ T1R3) as well as key elements like ␣-gustducin, phospholipase C␤2 (PLC␤2), and transient receptor potential channel type 5, also exist in enteroendocrine cells of the gut (2,10,16,31).It is known that glucose is an activator for the sweet taste receptor on the tongue; in addition, glucose is a strong stimulus of the secretion of gastrointestinal peptides. Because the sweet taste receptor system in the gut could be involved in the secretion of gastrointestinal peptides, lactisole, the sodium salt of 2-(4-methoxyphenoxy)-propionic acid, sho...