The role of the gut sweet taste receptor in regulating GLP-1, PYY, and CCK release in humans

Abstract

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...

The Bitter Taste Receptor Agonist Quinine Reduces Calorie Intake and Increases the Postprandial Release of Cholecystokinin in Healthy Subjects

“…Various studies have tried to elucidate the physiological role of gut taste receptors in humans. Gerspach et al 37 demonstrated that lactisole, a T1R1/T1R3 (sweet) antagonist, induced a significant reduction in GLP-1 and PYY but not CCK secretion, in response to intragastric and intraduodenal glucose administration. Our study demonstrates, for the first time, that bitter taste receptors are also involved in the physiological mechanisms that control appetite in humans.…”

MECHANISMS IN ENDOCRINOLOGY: Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion

“…These include GPR119 (40), which is activated by N-acylethanolamines (41), GPR120 (42) and GPR40 (43), which are activated by long-chain fatty acids (LCFAs), GPR41 (44), GPR43 (45) and FFAR2 (46), which are activated by short-chain fatty acids (SCFA), and TGR5 (8), which is activated by bile acids. In addition, taste receptors (primarily T1R2/T1R3 and a-gustducin) in the stomach and intestine seem to regulate the secretion of GLP1 (47,48,49). Paracrine, neuronal and neurohormonal mechanisms may also be important for the facilitation of postprandial GLP1 secretion (50,51,52,53).…”

Lipid-Lowering Pharmaceutical Clofibrate Inhibits Human Sweet Taste

“…T1R2-T1R3 agonists enhance intestinal glucose absorption ), incretin response (Brown et al 2009), insulin secretion (Pepino et al 2013), and adipocyte differentiation (Masubuchi et al 2013). Sodium lactisole, a T1R2-T1R3 inhibitor, has been shown to lower insulin secretion and GLP-1 secretion in vitro (Jang et al 2007;Nakagawa 2011) and in vivo (Gerspach et al 2011). Given that clofibric acid inhibits T1R2-T1R3, it is possible that its metabolic effects may be due, in part, to T1R inhibition.…”

“…Genetic knock-out studies represent the ultimate loss of function of the T1R2-T1R3 receptors, but pharmacological inhibition may have similar, albeit less potent, effects on metabolism. It has been shown that the T1R3 inhibitor sodium lactisole increases plasma glucose 'area under the curve' (AUC) response to a glucose load (Gerspach et al 2011). This effect is consistent with reduced stimulation of insulin by T1Rs (Jiang et al 2005;Hamano et al 2015).…”