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. Author manuscript; available in PMC: 2026 Feb 17.
Published in final edited form as: Br J Pharmacol. 2025 Feb 25;182(12):2682–2693. doi: 10.1111/bph.70004

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

Emily C Hanselman 1, Caroline P Harmon 1, Daiyong Deng 1, Sarah M Sywanycz 1, Lauren Caronia 2, Peihua Jiang 2, Paul A S Breslin 1,2
PMCID: PMC12908860  NIHMSID: NIHMS2146256  PMID: 39999478

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: fructose, naproxen, plasma glucose, sucralose, sucrose, sweetness inhibition, TAS1R2–TAS1R3, taste

1 |. INTRODUCTION

The human sweet taste receptor, taste receptor class 1, receptor number 2 (TAS1R2)–taste receptor class 1, receptor number 3 (TAS1R3), is a G protein-coupled heterodimer expressed in taste bud cells that conveys sweetener taste signals via an inositol trisphosphate (IP3) and calcium signalling pathway (Nelson et al., 2001). TAS1R2–TAS1R3 is activated by sugars, non-nutritive sweeteners, certain amino acids and metal salts (Yang et al., 2021). TAS1R2–TAS1R3 is inhibited by gymnemic acid (Sanematsu et al., 2014) and zinc salts (Keast et al., 2004). Additionally, TAS1R2–TAS1R3 is inhibited by sodium lactisole (Jiang et al., 2005), its structural derivative 2-(2,4-dichlorophenoxy)propionic acid (2,4-DP) (Nakagita et al., 2019), and phenoxy herbicides and fibrates (Kochem & Breslin, 2017; Maillet et al., 2009). These latter four categories are negative allosteric modulators that bind in the transmembrane domain of TAS1R3 via a phenylpropionic acid-like moiety and act as inverse agonists (Galindo-Cuspinera et al., 2006; Jiang et al., 2005), though only lactisole elicits a clear sweet-water taste.

Phenylpropionic non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, share the phenylpropionic acid moiety of lactisole (Figure 1) and have been shown to inhibit the activation, by aspartame, of human TAS1R2 (hTAS1R2)–TAS1R3 in vitro (Nakagita et al., 2020). There have not yet been in vivo psychophysical experiments to determine whether these NSAIDs inhibit sweet taste in humans and whether they inhibit sugar stimulation at physiologically relevant levels found in blood plasma. If NSAIDs inhibit TAS1R2–TAS1R3 in humans, there is the potential for them to have metabolic consequences via action on this receptor, expressed in regulatory tissues.

FIGURE 1.

FIGURE 1

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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).

Beyond their obvious influence within the oral cavity on taste perception, taste receptors are expressed extra-orally in a wide range of tissues, in which their modulation is pertinent to health and physiology. For example, TAS1R2–TAS1R3 expression has been identified in the intestines, colon, pancreas, skeletal muscle, adipose tissue, brain and testes (Egan, 2024). TAS1R2–TAS1R3 serves physiological roles in sensing and modulating the absorption of dietary sugars (Mace et al., 2007), insulin secretion (Nakagawa et al., 2009), lipid metabolism and adipocyte function (Simon et al., 2014), adipogenesis and osteogenesis in bone (Simon et al., 2014), and reproductive health (Mosinger et al., 2013).

The main objective of the present work was to determine if ibuprofen could inhibit TAS1R2–TAS1R3 signalling using physiologically relevant stimuli both in vivo and in vitro. Our first question was whether oral rinses with ibuprofen affect sweet taste perception in humans. We asked participants to rate sweetness intensity of both caloric and non-caloric sweeteners, with and without ibuprofen oral pre-rinses. Our preliminary data showed that ibuprofen was more effective as a pre-rinse than an admixture. We further noted that ibuprofen does not elicit a sweet-water taste. We also wished to know if physiological plasma concentrations of ibuprofen, those that would result from typical doses of 2–3 tablets (400–600 mg), would inhibit low sugar concentrations in vitro using cells that stably express hTAS1R2–TAS1R3. Then we asked if these low plasma concentrations of ibuprofen affect sweet taste perception in humans. Furthermore, we also wanted to know if these plasma concentrations of ibuprofen would alter perception of low oral glucose levels, which we measured with absolute glucose detection thresholds. If ibuprofen at physiologically relevant levels inhibits TAS1R2–TAS1R3 in vivo, then there could be translational implications for regular use of ibuprofen, 2–3 (200 mg) tablets, to modulate whole-body glucose metabolism. In support of this idea, 600-mg ibuprofen three times per day reduced plasma glucose by 20 mg·dl−1 in hyperglycaemic patients with Type 2 diabetes (Mork & Robertson, 1983). We are not recommending that ibuprofen be used by all patients to help regulate blood sugar, because regular use of ibuprofen carries the risk of gastrointestinal and vascular events (Bhala et al., 2013).

Nevertheless, ibuprofen is the second most commonly used drug. An estimated 17% of the US population uses ibuprofen more than once a week, and 3.5% of the population uses naproxen weekly (Kaufman et al., 2002), with a high prevalence of overuse (excess of the recommended dose) (Cryer et al., 2016; Kaufman et al., 2018). The main use of ibuprofen and naproxen is to reduce pain and inflammation by decreasing the biosynthesis of prostaglandins and other proinflammatory agents (Vane, 1971). If ibuprofen also inhibits TAS1R2–TAS1R3 systemically, it may have off-target metabolic effects.

2 |. METHODS

2.1 |. Participants

Participants provided written, informed consent on forms approved by the Rutgers University Institutional Review Board (IRB). The research protocol complied with the Declaration of Helsinki for Medical Research involving human subjects and was approved by the Rutgers University IRB (Pro2019001483). The study is registered through ClinicalTrials.gov as Protocol Number NCT06291337. A total of 32 healthy adults (15 males and 17 females) ranging in age from 18 to 58 years participated in these studies and were paid for their time. In any given experiment, between 9 and 14 subjects participated.

2.2 |. Experiment 1: Effect of ibuprofen and naproxen on sweet taste intensity

Fourteen healthy adults (seven males and seven females) in total, participated in the sweet taste intensity testing, with 9–11 participants completing each stimuli test. Participants were asked not to eat, drink or smoke 1 h prior to testing.

2.2.1 |. Study design

Participants rinsed their mouths with a pre-treatment of sodium ibuprofen (Sigma-Aldrich, l1892) or sodium naproxen (Thermo Fisher, 436710050) at three concentrations (0, 13.5 and 57.0 mM). These concentrations were selected from a 1/8 log step series, 13.5 mM is the 3/8 log step and 57.0 mM is the full log step, in order to show dose response. The highest concentration of ibuprofen was pre-screened so that it reduced the sweetness intensity of sweeteners from moderately strong to weak overall on a labelled magnitude scale. The concentrations of naproxen were linked to those selected for ibuprofen. We also tested ibuprofen and naproxen for sweetness reduction in admixture with the sweeteners, but pre-rinsing was more effective for reducing sweetness. Participants then rated the sweetness intensity of sucrose (Sigma-Aldrich, S9378), sucralose (Thermo Fisher, J66736.18) and fructose (Sigma-Aldrich, F0127) solutions. The sweet taste stimuli were sucrose (ranging in concentration from 30.0 to 646.3 mM), fructose (from 43.8 to 944.4 mM) and sucralose (from 43.0 to 927.3 μM). Concentrations increased in one-third logarithmic increments. Sweet stimuli concentrations were chosen to provide a comparable range of sweetness intensity throughout each stimulus. Testing was done in duplicate.

For ibuprofen testing, 11 participants completed the sucrose inhibition testing, 10 completed the sucralose inhibition testing, and 9 completed the fructose inhibition testing. For naproxen testing, 10 participants completed the sucrose and fructose inhibition testing, and 9 participants completed the sucralose inhibition testing. The difference in group size is attributable to the dropout of participants.

Subjects were trained in the use of a general labelled magnitude scale (gLMS) following standard published procedures (Green et al., 1993). The top of the scale was described as the strongest imaginable sensation of any kind (Bartoshuk et al., 2004). This gLMS required participants to rate the perceived intensity along a vertical axis lined with the following adjectives: barely detectable, weak, moderate, strong, very strong and strongest imaginable. The adjectives are spaced semi-logarithmically, based upon experimentally determined intervals to yield ratio quality data. The subjects were shown both adjectives and numbers on the scale.

2.3 |. Stimulus delivery

Aqueous solutions were prepared every other day with Millipore-filtered water and stored in amber glass at 4°C. All solutions were removed from the refrigerator and allowed to rise to room temperature for at least 1 h prior to tasting. All solutions were fully dissolved, and there were no visible signs of undissolved solids or precipitation from solutions.

The sample presentation was randomized using a random integer generator (random.org), and 20 ml of each solution was presented in 30-ml polyethylene medicine cups (Dynarex) on a numbered tray. Each session consisted of six trials with a 60-s interval between trials. For each sample, subjects held 20 ml of the treatment solution in the mouth for 30 s. After expectorating, subjects rinsed with Millipore water two times, then held the testing solution for 5 s, and then rated the taste intensity on a gLMS before expectorating. After expectorating, subjects rinsed with Millipore water four times during the interstimulus interval.

2.4 |. Experiment 2: Effect of ibuprofen on other major taste stimuli

Ten healthy participants (five males and five females) completed testing.

2.4.1 |. Design

Participants rinsed with a treatment of water or 57-mM ibuprofen and then rated taste intensity on a gLMS for salty (NaCl), bitter (quinine hydrochloride [QHCl]), savoury (mono potassium glutamate [MPG]) or sour (citric acid) stimuli at concentrations. The following concentrations of the four control taste stimuli were chosen to provide a ‘moderate’ taste intensity for each taste quality: 237-mM NaCl, 0.178-mM QHCl, 10-mM citric acid and 356-mM MPG. Testing was done in duplicate.

2.5 |. Experiment 3: Effect of physiological levels of ibuprofen on sweet signalling in vitro

2.5.1 |. Design

Human embryonic kidney 293 (HEK293) cells stably expressing TAS1R2, TAS1R3 and chimeric G protein Gα16–gust44 constructs were cultured in Gibco Dulbecco’s modified Eagle’s medium (DMEM) (1×) + GlutaMAX™-I medium supplemented with the antibiotics hygromycin B, G418 and zeocin. The stable line was generated in the lab parental cell line HEK293 (source: this paper; identifier: N/A). Briefly, these cells were plated in 96-well plates at a density of 30,000 cells per well. The next day, cells were washed with Hank’s balanced salt solution (HBSS) (Gibco, 14025–092) supplemented with 10-mM HEPES (assay buffer) (Gibco, 15630–080) and loaded with Fluo-4 (Thermo Fisher Scientific, F14201); they were then assayed using a FlexStation III reader. Ibuprofen and sweeteners, sucrose and sucralose were prepared using assay buffer. Ibuprofen was added to cells with sweeteners in admixture. Ibuprofen was assessed for interference with the fluorescence assay at 1, 25 and 50 mM. The 25- and 50-mM ibuprofen concentrations interfered with the fluorescence assay; 1-mM ibuprofen did not interfere with the fluorescence assay. Ibuprofen was used in the assay at the 0.12- and 0.24-mM levels, reflecting the levels in the human perceptual studies in Experiment 5 below. Responses were calculated as percentage change of fluorescence. The results were shown as mean ± SE of five experiments (n = 5), with each datum representing the average of technical triplicates. Bar graphs, curve fitting and statistics were generated using GraphPad Prism 9.

2.6 |. Experiment 4: Effects of physiological levels of ibuprofen on glucose sweetness intensity

2.6.1 |. Design

Ten healthy participants (five males and five females) completed testing; 0.18, 0.57 and 5.7 mM of ibuprofen were used to test the effects of lower, physiological concentrations of ibuprofen on glucose sweet taste; 0.18-mM ibuprofen is the average of the peak serum concentration of a drug for a given dose (Cmax) resulting from 400- and 600-mg doses (Dewland et al., 2009; Janssen & Venema, 1985; Källström et al., 1988; Li et al., 2012); 0.57-mM ibuprofen is the Cmax resulting from an 800-mg dose if it is provided via an intravenous (IV) push in 5–7 min (Pavliv et al., 2011; Smith & Voss, 2012), as may be done in a hospital setting; 5.7-mM ibuprofen in plasma would be above toxicity limits, but this concentration was included to establish a dose-dependent relationship regarding glucose sweet taste. Participants were asked to rinse with the ibuprofen or control treatment and then evaluate the sweetness intensity of glucose at the following five concentrations: 0, 56, 74, 99 and 176 mM. Participants followed the training and testing protocols explained in the Experiment 1 methods above.

2.7 |. Experiment 5: Effect of physiological levels of ibuprofen on glucose detection thresholds

2.7.1 |. Design

Seventeen healthy adults in total participated in the sweet taste intensity testing. From earlier studies, 0.12-mM ibuprofen is approximately the plasma concentration at Cmax resulting from 400-mg ibuprofen (Dewland et al., 2009; Li et al., 2012), and 0.24-mM ibuprofen is approximately the Cmax plasma equivalent after taking a 600-mg dose of ibuprofen (Janssen & Venema, 1985; Källström et al., 1988). We tested the effect of these physiologically relevant concentrations of ibuprofen on taste detection of glucose with threshold testing. Our previously reported glucose threshold concentrations (~13 mM) (Breslin et al., 2021) match post-prandial plasma glucose levels documented in hyperglycaemia. Glucose detection thresholds can thus provide a translational tool to make inferences regarding TAS1R2-TAS1R3 signalling extra-orally, where similar glucose plasma concentrations appear, particularly in diabetic disease states.

Twelve participants (six females and six males) completed the 0.24-mM ibuprofen versus water detection threshold testing. Fourteen participants (eight females and six males; note that five additional females replaced participants who dropped out) completed the 0.12-mM ibuprofen versus water detection threshold testing. Eight participants completed both threshold studies. Testing was done in duplicate.

Threshold testing followed a modified staircase methodology involving two-alternative forced-choice (2-AFC) trials. The participants were asked to rinse for 3 min with water, 0.12-mM ibuprofen or 0.24-mM ibuprofen prior to beginning the test and to continue to rinse with the same treatment between each sample pair. The sample pairs were filtered water versus glucose neat. The subject’s task was to identify which sample was not water. If unsure, they were instructed to pick one. Testing followed a four-down, one-up approach, in which four correct responses would result in a step down the concentration series to a lower (more difficult) concentration of the stimulus, whereas one incorrect response would result in a step up to a higher (easier) concentration of the stimulus. Detection thresholds were measured using a modified staircase method with five reversals, with a reversal defined as a change in direction along the concentration series of the stimulus following the four-down, one-up approach.

2.8 |. Data and statistical analysis

For each of the four sweeteners studied, two-way repeated measures ANOVA was used to analyse the effects of the stimulus, the treatment and the interaction of the stimulus and treatment. If any data points were missing, a repeated measures mixed-effects analysis was performed. Experimental data were adjusted for normality, and lack of sphericity was adjusted with a Greenhouse–Geisser correction. Post hoc Dunnett’s or Šidák’s multiple comparison tests were used to analyse differences among responses. Student’s t tests were used to analyse pairwise comparisons. An alpha value of <0.05 was used for allowing Type I errors. All perceptual tests were done in duplicate, and all in vitro tests were done in triplicate. All analyses were conducted using GraphPad Prism software (Version 9.4.1). The data and statistical analysis comply with the recommendations of the British Journal of Pharmacology on experimental design and analysis in pharmacology (Curtis et al., 2022).

2.9 |. Materials

Ibuprofen, sucralose, glucose, fructose, quinine hydrochloride and mono-potassium glutamate were supplied by Sigma-Aldrich (St. Louis, MO, USA). Sucrose and naproxen were supplied by Thermo Fisher (Waltham, MA, USA), NaCl by MP Biomedicals (Solon, OH, USA) and citric acid by Macron Fine Chemicals (Radnor, PA, USA).

2.10 |. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24 (Alexander, Christopoulos, Davenport, Kelly, Mathie, Peters, Veale, Armstrong, Faccenda, Harding, Davies, et al., 2023; Alexander, Fabbro, Kelly, Mathie, Peters, Veale, Armstrong, Faccenda, Harding, Davies, Amarosi, et al., 2023; Alexander, Fabbro, Kelly, Mathie, Peters, Veale, Armstrong, Faccenda, Harding, Davies, Annett, et al., 2023).

3 |. RESULTS

3.1 |. Experiment 1: Both ibuprofen and naproxen inhibited sweet taste

Both ibuprofen (13.5 mM) and naproxen (57 mM) significantly reduced gLMS sweetness intensity ratings in a dose-dependent manner for sucrose, sucralose and fructose. Figure 2a–c shows the tests with ibuprofen, and Figure 2d–f shows tests with naproxen. Statistical analysis was performed with a two-way repeated measures ANOVA with a Greenhouse–Geisser correction and post hoc Dunnett’s multiple comparison tests. When data points were missing, a mixed-effects analysis was applied with a Greenhouse–Geisser correction.

FIGURE 2.

FIGURE 2

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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.

3.1.1 |. Sucrose

There was a significant inhibition of sucrose perceived sweetness by ibuprofen, as well as a significant effect on sucrose perceived sweetness by naproxen (Figure 2a,d). Ibuprofen inhibited sweetness differently depending on its concentration and the sucrose concentration with ibuprofen showing greater sweetness inhibition with higher concentrations; this was also true for naproxen. Post hoc Dunnett’s multiple comparison tests showed that 13.5 and 57 mM significantly reduced sweetness intensity compared to 0-mM NSAID in a dose-dependent manner for both ibuprofen and naproxen.

3.1.2 |. Sucralose

There was significant inhibition of sucralose perceived sweetness by ibuprofen, and naproxen also significantly inhibited perceived sweetness of sucralose (Figure 2b,e). Ibuprofen inhibited sweetness differently depending on its concentration and the concentration of sucralose with greater concentrations of ibuprofen showing greater inhibition, and naproxen had a similar effect. Post hoc Dunnett’s multiple comparison tests showed that 13.5 and 57 mM significantly reduced sweetness intensity compared to 0 mM in a dose-dependent manner for both ibuprofen and naproxen.

3.1.3 |. Fructose

There was significant inhibition of fructose perceived sweetness by ibuprofen, as well as a significant inhibition of fructose sweetness by naproxen (Figure 2c,f). Ibuprofen inhibited sweetness differently depending on its concentration and the concentration of fructose with greater concentrations of ibuprofen showing greater inhibition. A similar effect was seen with naproxen. Post hoc Dunnett’s multiple comparison tests showed that 13.5 and 57 mM significantly reduced sweetness intensity compared to 0-mM ibuprofen in a dose-dependent manner.

3.2 |. Experiment 2: Ibuprofen had no effect on other major taste stimuli

Ibuprofen (57 mM) oral rinses had no significant effects on gLMS taste intensity ratings for salty (NaCl), bitter (quinine), savoury (MPG) or sour (citric acid) stimuli at concentrations that provided ‘moderate’ taste intensities (Figure 3). Consistent with past observations using the TAS1R3 inhibitors lactisole and fibrate drugs, there was a trend to suppress the taste of MPG. Thus, ibuprofen’s effects on taste were sweetener-specific.

FIGURE 3.

FIGURE 3

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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).

3.3 |. Experiment 3: Physiological levels of ibuprofen reduced sweet signalling of sucrose and sucralose in vitro

From the pharmacological assessment, 0.12- and 0.24-mM ibuprofen is approximately the Cmax plasma equivalent after taking 400- and 600-mg doses of ibuprofen, respectively (2 or 3 × 200-mg tablet). This physiologically relevant concentration of ibuprofen was used to test sweet signalling of sucrose and sucralose in vitro.

Ibuprofen affected the change in fluorescence responses of HEK293 cells stably expressing TAS1R2, TAS1R3 and chimeric G protein Gα16–gust44 to sucrose (Figure 4a). Ibuprofen also affected the change in fluorescence responses to 0.1-mM sucralose (Figure 4b). Post hoc Šidák multiple comparison tests showed that both 0.12- and 0.24-mM ibuprofen significantly reduced the change in fluorescence responses to 25-, 50- and 75-mM sucrose and 0.1-mM sucralose.

FIGURE 4.

FIGURE 4

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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.

3.4 |. Experiment 4: Oral rinses with physiological plasma levels of ibuprofen reduced glucose sweetness intensity

Ibuprofen (0.18, 0.57 and 5.7 mM) was used to test the effects of lower ibuprofen concentrations on glucose sweet taste; 0.18 mM is equivalent to 37.5 μg·ml−1, which is the average plasma concentration at Cmax resulting from 400- and 600-mg oral doses (see Section 2) (Dewland et al., 2009; Janssen & Venema, 1985; Källström et al., 1988; Li et al., 2012); 0.57 mM is equivalent to 120 μg·ml−1, which is the plasma concentration Cmax resulting from an 800-mg dose if it is provided via an IV push in 5–7 min (Pavliv et al., 2011; Smith & Voss, 2012), as may be done in a hospital setting; 5.7 mM was used to establish a dose-dependent relationship regarding glucose sweet taste. Ibuprofen significantly inhibited the perceived sweetness intensity of glucose and was dependent on the ibuprofen and glucose concentration with higher ibuprofen concentrations showing greater inhibition (Figure 5).

FIGURE 5.

FIGURE 5

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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.

3.5 |. Experiment 5: Oral rinses with physiological plasma levels of ibuprofen reduced sensitivity to low glucose levels and elevated oral glucose detection thresholds

From earlier studies (Dewland et al., 2009; Li et al., 2012), 0.12-mM ibuprofen is approximately the plasma concentration at Cmax resulting from 400-mg ibuprofen (2 × 200-mg tablets). And 0.24-mM ibuprofen is approximately the Cmax plasma equivalent after taking a 600-mg dose of ibuprofen (Janssen & Venema, 1985; Källström et al., 1988). These physiologically relevant concentrations of ibuprofen were used to determine if they could inhibit detection of low concentrations of glucose at perceptual threshold levels (approximating diabetic post-prandial plasma glucose levels); 0.24-mM ibuprofen rinses reduced sensitivity and elevated glucose detection thresholds (37 mM) compared to water rinses (30 mM) (Figure 6a); 0.12-mM ibuprofen rinses tended to reduce sensitivity and elevated glucose detection thresholds (35 mM) compared to water rinses (31 mM) (Figure 6b).

FIGURE 6.

FIGURE 6

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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.

4 |. DISCUSSION

Our results show the NSAIDs ibuprofen and naproxen inhibit sweet taste perception in humans, in a dose-dependent manner, for both the caloric and non-nutritive sweeteners, sucrose, fructose and sucralose (Figure 2), but not the exemplar stimuli of other taste qualities, NaCl (salty), MPG (savoury), quinine HCl (bitter) and citric acid (sour) (Figure 3). Ibuprofen and naproxen are similar in size and structure to lactisole, and they share a phenylpropionic acid moiety, which has been shown to bind to the TAS1R3 component of the sweet taste receptor (Figure 1) (Jiang et al., 2005). A recent in vitro study by Nakagita et al. (2020) demonstrated that ibuprofen and naproxen are inhibitors of the TAS1R2–TAS1R3 sweetener receptor when stimulated with the non-nutritive sweetener aspartame. They also reported that ibuprofen and naproxen are more potent inhibitors of TAS1R2–TAS1R3 (IC50: (±)-ibuprofen: 12 μM; (S)-naproxen: 17 μM; and (R)-naproxen: 43 μM) than (±)-lactisole (IC50: 65 μM), the commonly employed sweet taste inhibitor (Nakagita et al., 2020). The present study extends this work by showing that oral rinsing with ibuprofen or naproxen inhibited human sweet taste perception in vivo when elicited by the sugars glucose and fructose, as well as by sucralose.

We further demonstrated, in vitro, that ibuprofen admixture treatments inhibited Fluo-4 calcium fluorescence responses of hTAS1R2–TAS1R3 expressing HEK293 cells to multiple concentrations of the common food sugar, sucrose (Figure 4a). We also showed that ibuprofen inhibited in vitro responses to the non-nutritive sweetener, sucralose (Figure 4b). In this experiment, we utilized concentrations of ibuprofen (0.12 and 0.24 mM) that are within the physiological plasma range after ingesting a dose of 400- or 600-mg ibuprofen (2–3 × 200-mg tablets) (Dewland et al., 2009; Janssen & Venema, 1985; Källström et al., 1988; Li et al., 2012).

Based on these in vitro results, we tested adult humans with a similar low range of ibuprofen concentrations for inhibition of sweetness perception following oral rinses. We found that ibuprofen as low as 0.18 mM inhibited perceived sweet taste intensity ratings of 99- and 176-mM glucose (Figure 5). We further wished to identify whether these low physiological plasma levels of ibuprofen could inhibit physiological plasma concentrations of glucose. Because very low levels of glucose are not perceived as sweet by most people, we switched methods to oral absolute glucose detection thresholds from sweetness intensity ratings. Thresholds are useful because the concentrations of glucose for oral detection are similar to post-prandial plasma hyperglycaemia. We assessed glucose detection with and without the 0.12- and 0.24-mM ibuprofen associated with plasma levels from ingestion of two or three 200-mg tablets and found that ibuprofen elevated glucose thresholds (decreased sensitivity to glucose) (Figure 6). This outcome suggests that these low physiological ibuprofen levels are effective inhibitors of TAS1R2–TAS1R3 responses to physiological post-prandial plasma levels of glucose.

4.1 |. Implications

If ibuprofen inhibits extra-oral TAS1R2–TAS1R3 sensitivity to glucose, this could affect glucose metabolism. Many studies have shown that TAS1R2–TAS1R3 signalling affects glucose absorption and metabolism, although more studies are needed. TAS1R2–TAS1R3 activation increases glucose absorption through translocation of the glucose transporter 2 (GLUT2), and up-regulation of the sodium–glucose cotransporter 1 (SGLT1) in the intestine (Mace et al., 2007; Margolskee et al., 2007; Smith et al., 2018), augments enteroendocrine release of glucagon-like peptide-1 (GLP-1) (Daly et al., 2012; Kokrashvili et al., 2009), and stimulates insulin release from the pancreas (Hamano et al., 2015; Kyriazis et al., 2012; Nakagawa et al., 2009). TAS1R2 expression increased during a glucose load in participants with Type 2 diabetes during post-prandial hyperglycaemia, which further increased glucose absorption (Young et al., 2013). Sweeteners stimulate insulin secretion in both mouse and human pancreatic beta cells in vitro, whereas lactisole and gurmarin, a mouse TAS1R2–TAS1R3 antagonist, inhibit insulin secretion (Hamano et al., 2015; Kyriazis et al., 2012; Nakagawa et al., 2009). The effects of lactisole on glucose tolerance in vivo are less clear: Studies have shown that lactisole increased plasma insulin (Karimian Azari et al., 2017) or had no effects on plasma insulin or glucose when added to an oral glucose tolerance test (OGTT) (Grüneis et al., 2021; Kochem et al., 2024). Inhibition of TAS1R2–TAS1R3 may have overall protective effects, but clinical studies are needed. In humans, lactisole tends to slightly delay absorption of glucose loads (Kochem et al., 2024). In mice, Tas1r2 knockout animals were partly protected from metabolic disturbances associated with diet-induced obesity, including hyperinsulinaemia (Smith et al., 2016).

We have shown here that ibuprofen inhibited TAS1R2–TAS1R3 activation by sugars in vitro and blocked sweet taste orally in vivo, at levels that represent physiological concentrations of both ibuprofen and plasma glucose. Because TAS1R2–TAS1R3 signalling may affect glucose metabolism, the observation here that ibuprofen inhibited TAS1R2–TAS1R3 sugar signalling indicates that ibuprofen could also affect carbohydrate absorption and metabolism. To this point, there is evidence that ibuprofen and naproxen can decrease plasma glucose, similar to the effects of lactisole on OGTTs (Kochem et al., 2024). Naproxen decreased plasma glucose and increased plasma insulin levels in normal and Type 2 diabetic mouse models (Motawi et al., 2013). Ibuprofen, but not naproxen, improved glucose tolerance and prevented weight gain in mice fed with a high-fat diet (Kendig et al., 2008). This observation is consistent with the observation that mice lacking TAS1R2 were resistant to diet-induced obesity (Smith et al., 2016). It should be noted, however, that we do not know if ibuprofen inhibits the mouse mTas1r2–Tas1r3 saccharide receptor. In hyperglycaemic patients with Type 2 diabetes, 600-mg ibuprofen three times per day reduced plasma glucose by 20 mg·dl−1 (Mork & Robertson, 1983). In addition, ibuprofen use has been associated with reduced incidence of certain metabolic disorders, including Alzheimer’s disease (McGeer et al., 2018; Miguel-Álvarez et al., 2015; Vlad et al., 2008; Wang et al., 2015), Parkinson’s disease (Gao et al., 2011; McSharry, 2011) and some cancers, including colorectal, breast, gastric and lung cancers (Ait Ouakrim et al., 2015; Becker et al., 2015; Kehm et al., 2019; Pennock et al., 2018; Schack et al., 2019). Certain cancers have been found to overexpress TAS1R3 (Carey et al., 2022) and thus inhibiting the TAS1R2–TAS1R3 with ibuprofen or naproxen may reverse the metabolic effects of its overexpression in tumours.

The ubiquity of ibuprofen and naproxen intake makes these off-target effects particularly relevant to public health. Regular use of ibuprofen and naproxen has increased over time globally (Davis et al., 2017), and overuse is common (Cryer et al., 2016). It is important to remember that NSAIDs also have additional mechanisms of action that may help prevent or improve metabolic disorders, including reducing inflammation via inhibition of cyclooxygenases and NFκB, with the resultant reduction of prostaglandins and inflammatory cytokines (Stuhlmeier et al., 1999). However, not all NSAIDs are associated with reduced incidence of the above metabolic disorders, which may indicate an additional protective mechanism specific to ibuprofen and naproxen and their action on TAS1R2–TAS1R3, as indicated in the present work.

4.2 |. Limitations and future directions

The previously mentioned in vitro study on ibuprofen used mutational analysis of receptors to show that ibuprofen and naproxen were likely to interact with the transmembrane domain of TAS1R3 (Nakagita et al., 2020) of the TAS1R2–TAS1R3 heterodimer. TAS1R3 is also part of the taste receptor TAS1R1–TAS1R3 that conveys savoury taste signalling from glutamate and ribonucleotides. It is thus surprising that we did not see inhibition of the savoury taste intensity from MPG (Figure 3). Our previous work on clofibrate inhibition of both sweet taste and savoury taste indicates an interaction with the TAS1R3 component of both heterodimers (TAS1R1–TAS1R3 and TAS1R2–TAS1R3) (Kochem & Breslin, 2017). Due to the scope of this study, we did not test the effects of ibuprofen on the savoury taste intensity of multiple concentrations of MPG or other savoury stimuli. Future studies should explore the possible inhibition of savoury taste by ibuprofen, by exploring higher concentrations of ibuprofen as well as an admixture of the two.

We were able to assess the effect of physiological concentrations of ibuprofen at near-physiological concentrations of plasma glucose, such as occur during post-prandial hyperglycaemia. Due to limitations in oral glucose taste detection capacity in humans, we were unable to assess glucose concentrations to match those found in normal fasting conditions (3- to 5-mM plasma glucose). We also tried to test glucose in the heterologous expression cellular assay (Figure 4). Glucose at 25- and 50-mM concentrations, however, is not a potent enough agonist to elicit a fluorescence response in this assay. Also, when higher concentrations are used, there are osmotic effects of the sugar on the cells that disrupt the assay. In future studies, we will test ibuprofen’s effect on TAS1R2–TAS1R3 activation in low glucose settings with an inositol monophosphate (IP 1) assay, which may be more sensitive to cellular activation (Dubovski et al., 2022). This experiment should also be conducted in vitro in pancreatic beta cells to explore ibuprofen’s effect on glucose detection and insulin secretion. Finally, a limitation to this study is that we did not directly test the metabolic effects of ibuprofen on glucose metabolism. Future clinical studies should further explore the effects of prolonged, systemic inhibition of TAS1R2–TAS1R3 on metabolic disorders via ibuprofen, naproxen, lactisole and other inhibitors. However, it should be noted that regular ibuprofen and naproxen use carries a risk of gastrointestinal and vascular events, which should be taken into consideration with any future clinical study (Bhala et al., 2013).

In conclusion, ibuprofen and naproxen are powerful sweet taste inhibitors for humans. They inhibit perceived sweetness from sugars in a dose-dependent manner. Ibuprofen also inhibits the response of the TAS1R2–TAS1R3 receptor to natural sugars in vitro. Furthermore, ibuprofen is an effective sweet taste inhibitor when tested at concentrations that represent plasma ibuprofen levels seen after ingestion of two or three 200-mg tablets (0.12 and 0.24 mM). The concentrations of ibuprofen we employed, which represent physiological plasma levels, interfered with oral glucose detection, which also occurs at physiological plasma levels following meals. Prior reports showed that ibuprofen appears to alter glucose metabolism and to reduce the risk of several metabolic diseases. These observations combined with the present findings suggest that inhibition of TAS1R2–TAS1R3 may have beneficial metabolic effects, though human clinical trials are required to test this hypothesis.

What is already known.

  • TAS1R2–TAS1R3, the human sweet taste receptor, conveys sweet taste.

  • Ibuprofen and naproxen are structurally similar to TAS1R2–TAS1R3 inhibitors.

What does this study add.

  • Ibuprofen and naproxen inhibit activation of human TAS1R2-TAS1R3 by sugar in vivo and in vitro.

What is the clinical significance.

  • TAS1R2–TAS1R3 inhibition by ibuprofen is a novel pathway that may convey metabolic benefits.

ACKNOWLEDGEMENTS

This work was sponsored by grants from the National Institutes of Health, National Institute on Deafness and Other Communication Disorders (NIDCD) R01 014286 (PASB) and R21 020365 (PASB) and from the New Jersey Hatch Project NJ14120 (PASB). We thank D. J. Polacik for administrative assistance with this project.

Funding information

NIH, Grant/Award Number: NJ14120; National Institute on Deafness and Other Communication Disorders, Grant/Award Numbers: R01 014286, R21 020365

Abbreviations:

2-AFC

two-alternative forced-choice

C max

peak serum concentration of a drug for a given dose

gLMS

general labelled magnitude scale

GLP-1

glucagon-like peptide-1

GLUT2

glucose transporter 2

hTAS1R2

human taste receptor class 1, receptor number 2

IRB

Institutional Review Board

MPG

monopotassium glutamate

NSAID

non-steroidal anti-inflammatory drug

OGTT

oral glucose tolerance test

QHCl

quinine hydrochloride

SGLT1

sodium–glucose cotransporter 1

Footnotes

CONFLICT OF INTEREST STATEMENT

All authors declare no conflicts of interest.

DECLARATION OF TRANSPARENCY AND SCIENTIFIC RIGOUR

This Declaration acknowledges that this paper adheres to the principles for transparent reporting and scientific rigour of preclinical research as stated in the BJP guidelines for Design & Analysis and as recommended by funding agencies, publishers and other organizations engaged with supporting research.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions.

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