Ibuprofen inhibits human sweet taste and glucose detection implicating an additional mechanism of metabolic disease risk reduction

Abstract

Background and purpose: The human sweet taste receptor, TAS1R2-TAS1R3, conveys sweet taste in the mouth and may help regulate glucose metabolism throughout the body. Ibuprofen and naproxen are structurally similar to known inhibitors of TAS1R2-TAS1R3 and have been associated with metabolic benefits. Here, we determined if ibuprofen and naproxen inhibited TAS1R2-TAS1R3 responses to sugars in vitro and their elicited sweet taste in vivo, in humans under normal physiological conditions, with implications for effects on glucose metabolism.

Experimental approach: Human psychophysical taste testing and in vitro cellular calcium assays in HEK293 cells were performed to determine the effects of ibuprofen and naproxen on sugar taste signalling.

Key results: Ibuprofen and naproxen inhibited the sweet taste of sugars and non-nutritive sweeteners in humans, dose-dependently. Ibuprofen reduced cellular signalling of sucrose and sucralose in vitro with heterologously expressed human TAS1R2 (hTAS1R2)-TAS1R3 in human kidney cells. To mirror internal physiology, low concentrations of ibuprofen, which represent human plasma levels after a typical dose, inhibit the sweet taste and oral detection of glucose at concentrations nearing post-prandial plasma glucose levels.

Conclusion and implications: Ibuprofen and naproxen inhibit activation of TAS1R2-TAS1R3 by sugar in humans. Long-term ibuprofen intake is associated with preserved metabolic function and reduced risk of metabolic diseases such as Alzheimer's, diabetes and colon cancer. In addition to its anti-inflammatory properties, we present here a novel pathway that could help explain the associations between metabolic function and chronic ibuprofen use.

Keywords: TAS1R2–TAS1R3; fructose; naproxen; plasma glucose; sucralose; sucrose; sweetness inhibition; taste.

FIGURE 1

Lactisole, ibuprofen and naproxen share a common phenylpropionic acid moiety. Lactisole (a), ibuprofen (b) and naproxen (c) are structurally similar in their propionic acid group (grey box).

FIGURE 2

Ibuprofen and naproxen reduced perceived sweetness intensity from a variety of sweeteners in a dose-dependent manner in vivo; 13.5- and 57-mM ibuprofen (IBP) significantly reduced rated sweetness intensity ratings (general labelled magnitude scale [Y axis]) for sucrose, sucralose and fructose (a–c); 13.5- and 57-mM naproxen (NAP) significantly reduced sweetness intensity ratings for sucrose, sucralose and fructose (d–f). Data shown are means ± SEM; n = 9–11, tested in duplicate. *P < 0.05, significantly different from 0 mM; two-way ANOVA or mixed-effects analysis was performed with a Greenhouse–Geisser correction and post hoc Dunnett’s multiple comparison tests.

FIGURE 3

Ibuprofen had no effect on taste stimuli that elicit other qualities of taste in vivo; 57-mM ibuprofen had no effect on general labelled magnitude scale intensity ratings for salty (NaCl), bitter (quinine), savoury (MPG) or sour (citric acid) stimuli. The black bar indicates the average taste intensity ratings after the water rinse treatment, and the grey bar indicates the average taste intensity ratings after the ibuprofen rinse treatment. Repeated measures two-way ANOVAs were performed with a Greenhouse–Geisser correction and post hoc Šidák multiple comparison test (n = 10, tested in duplicate).

FIGURE 4

Ibuprofen washes reduced cellular signalling of the sweeteners sucrose, fructose and sucralose in vitro; 0.12-mM ibuprofen reduced the change in fluorescence responses of HEK293 cells stably expressing TAS1R2, TAS1R3 and the chimeric G protein Gα16–gust44 to sucrose (at 25, 50 and 75 mM) (a) and sucralose (0.1 mM) (b). Responses of cells pre-incubated with 0-, 0.12- and 0.24-mM ibuprofen are represented by the black, grey and white bars, respectively. The sucrose responses were analysed with a two-way ANOVA and post hoc Šidák multiple comparison test (a). Sucralose responses were analysed with a one-way ANOVA and post hoc Šidák multiple comparison test (b). Each bar represents an average of five experiments (n = 5), with each datum representing an average of technical triplicates. *P < 0.05, **P < 0.01, ****P < 0.0001, significantly different as indicated.

FIGURE 5

Oral ibuprofen rinses reduced perceived sweetness intensity of low glucose concentrations. Ibuprofen reduced general labelled magnitude scale (gLMS) sweetness intensity ratings for glucose compared to water. Repeated measures two-way ANOVAs were performed with a Greenhouse–Geisser correction and post hoc Dunnett’s multiple comparison tests. *P < 0.05, significantly different as indicated. Data shown are means ± SEM; n = 10, tested in duplicate.

FIGURE 6

Ibuprofen increased glucose detection thresholds. In the first experiment (a), 0.24-mM ibuprofen (the plasma concentration resulting from ingestion of 3 × 200-mg tablets) (dots on right side) significantly increased glucose detection thresholds compared to water (dots on left side) (n = 12, tested in duplicate). **P < 0.01, significantly different as indicated. In (b), the second experiment showed that 0.12-mM ibuprofen (the plasma concentration resulting from ingestion of 2 × 200-mg tablets) tended to elevate glucose detection thresholds, P = 0.08 (n = 14, tested in duplicate). Data shown are means; one-tailed, paired Student’s t tests were performed.