Paul A. S. Breslin

Sensitivity to bitterness from Antidesma bunius fruit was previously reported to be inversely correlated with the ability to taste bitterness from phenylthiocarbamide (PTC). To replicate and extend these findings, we conducted psychophysical testing in a large single-family pedigree (n = 86) for PTC, propylthiouracil (PROP), and Antidesma bunius berries and genotyped participants for hTAS2R38. We found that PTC sensitivity was inversely related to Antidesma fruit bitterness ratings (p = 8.54 × 10–3). Participants who are PAV/PAV for TAS2R38 tend to find Antidesma berries less bitter than AVI/AVI participants (beta = −6.32, p = 0.069, R2 = 0.057). Perception of Antidesma bitterness was moderately heritable (h2 = 0.56), although this did not reach significance (p = 0.08). We conclude that TAS2R38-PAV prevents the detection of Antidesma bitterness, and hypothesize that an unknown receptor cofactor may be required to partner with TAS2R38-AVI and -AAV to enable tasting bitterness from Antidesma bunius berries.

Increasing acceptance of bitter stimuli is important for the health of pediatric patients who must consume bitter medicines or nutritional interventions. The aim of this study was to determine if children age 6 months to 5 years accept an amino acid (AA)‐supplemented oral rehydration therapy (ORT) that contains multiple bitter tasting AAs. These AAs can be clinically advantageous to the gastrointestinal tract, which could benefit children during acute diarrhea, but no research has shown that children will accept and ingest this novel formulation. Sodium gluconate, sucralose, strawberry flavor, and pink color were used to decrease bitterness and increase palatability. Participants were taught how to play “The Tasting Game” in which they gave the solutions they liked to a plush toy of Big Bird _TM and those they did not like to a plush toy of Oscar the Grouch _TM . Participants were filmed during the sessions and their facial expressions were analyzed. Participants were offered the solutions to drink and the volume consumed was also measured. The addition of sodium gluconate, color, or flavor as individual additives did not significantly increase acceptance of the AA‐based ORT. Sucralose increased acceptance in comparison to quinine but was still less accepted than sucrose. Sucralose in combination with strawberry flavor was significantly more liked than quinine and not significantly less than sucrose. Sucralose, strawberry flavor, and pink color in combination was the most liked solution. The most positive facial reactions were expressed in response to this solution as well. Participants drank and tolerated up to 80 mL of the sucralose‐sweetened, strawberry‐flavored, and pink‐colored amino acid‐based formulation in one 15 min sitting. This study demonstrates that pediatric participants will accept a novel bitter‐reduced AA‐based formulation of oral rehydration therapy with sucralose, strawberry flavor, and pink color added.

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.

Recent research has shown that KATP channels in mouse taste bud cells enhance glucose taste signaling by depolarizing the cell when ATP is present. Relatedly, estradiol has been shown to enhance glucose sensing in human pancreatic β cells via closure of KATP channels. Since taste tissue has estradiol receptors, we linked these 2 observations and tested whether elevated estradiol may also enhance taste sensitivity and liking for glucose in humans. We hypothesized that around the time of ovulation, when estrogen peaks during the menstrual cycle in female participants, oral taste detection thresholds for glucose (metabolizable monosaccharide) would decrease but would not for sucralose or the glucose analog methyl-D-glucopyranoside (MDG) (both nonmetabolizable sweeteners that do not close KATP channels). Fifteen healthy eumenorrheic females were asked to track their urinary estrogen metabolite estrone-3-glucuronide (E3G) via a fertility monitor. The participants were tested using oral detection thresholds for glucose, sucralose and MDG during the E3G nadir at menstruation and E3G peak (>100 ng/mL) at peri-ovulation. Seven male participants were also tested for glucose detection thresholds over the same 2-wk interval. Female participants were also asked to rate their liking for glucose solutions at mildly sweet (450 mM) and moderately sweet (900 mM) concentrations. Detection thresholds for glucose, but not sucralose or MDG, decreased peri-ovulation during estrogen peak (P < 0.05), indicating enhanced sensitivity to glucose specifically. Males showed no change in glucose threshold over the 2 wk. Liking ratings for 900 mM glucose tended to increase during ovulation (P = 0.06). These observations are consistent with the idea that estrogen and/or other co-modulating hormones, such as luteinizing hormone and progesterone, enhance a metabolic signaling pathway during the peri-ovulatory phase.

Amino acids are necessary for life, and many must be consumed because they cannot be endogenously synthesized. Typically, we eat them as proteins and peptides, which have little taste. However, we also directly ingest free amino acids, several of which are aversive because they elicit bitterness. This bitterness often prevents many patient populations from taking formulas and supplements containing free amino acids. Here, we characterize which amino acids are the most bitter, their concentration-intensity functions, and individual differences in bitterness perception, and we explore how sodium salts suppress the bitterness of amino acids. We found that the essential amino acids comprise the most bitter stimuli, with six of them conveying the most bitterness. Clustering and correlating amino acids by individual differences in bitterness perception show that there are approximately four groupings of amino acids and suggest that within these clusters, amino acids may be activating the same or overlapping TAS2Rs. We also show that bitterness can be largely suppressed by sodium salts for 5 of the 6 most bitter amino acids. These results hold promise for managing the bitter taste of nutritional supplements that contain amino acids and improving compliance.

The sweet taste receptor, TAS1R2-TAS1R3, is expressed in taste bud cells, where it conveys sweetness, and also in intestinal enteroendocrine cells, where it may facilitate glucose absorption and assimilation. In the present study, our objective was to determine whether TAS1R2-TAS1R3 influences glucose metabolism bidirectionally via hyperactivation with 5 mM sucralose (n = 12) and inhibition with 2 mM sodium lactisole (n = 10) in mixture with 75 g glucose loads during oral glucose tolerance tests (OGTTs) in healthy humans. Plasma glucose, insulin, and glucagon were measured before, during, and after OGTTs up to 120 minutes post-prandially. We also assessed individual participants’ sweet taste responses to sucralose and their sensitivities to lactisole sweetness inhibition. The addition of sucralose to glucose elevated plasma insulin responses to the OGTT (F(1, 11) = 4.55, p = 0.056). Sucralose sweetness ratings were correlated with early increases in plasma glucose (R² = 0.41, p2 = 0.38, p2 = 0.84, p<0.01) when lactisole was added to the OGTT over the whole test (120 minute AUC). In summary, stimulation and inhibition of the TAS1R2-TAS1R3 receptor demonstrates that TAS1R2-TAS1R3 helps regulate glucose metabolism in humans and may have translational implications for metabolic disease risk.

The savory or umami taste of the amino acid glutamate is synergistically enhanced by the addition of the purines inosine 5ʹ-monophosphate (IMP) and guanosine 5ʹ-monophosphate (GMP) disodium salt. We hypothesized that the addition of purinergic ribonucleotides, along with the pyrimidine ribonucleotides, would decrease the absolute detection threshold of (increase sensitivity to) l-glutamic acid potassium salt (MPG). To test this, we measured both the absolute detection threshold of MPG alone and with a background level (3 mM) of 5 different 5ʹ-ribonucleotides. The addition of the 3 purines IMP, GMP, and adenosine 5ʹ-monophosphate (AMP) lowered the MPG threshold in all participants (P < 0.001), indicating they are positive modulators or enhancers of glutamate taste. The average detection threshold of MPG was 2.08 mM, and with the addition of IMP, the threshold was decreased by approximately 1.5 orders of magnitude to 0.046 mM. In contrast to the purines, the pyrimidines uridine 5ʹ-monophosphate (UMP) and cytidine 5ʹ-monophosphate (CMP) yielded different results. CMP reliably raised glutamate thresholds in 10 of 17 subjects, suggesting it is a negative modulator or diminisher of glutamate taste for them. The rank order of effects on increasing sensitivity to glutamate was IMP > GMP> AMP >> UMP// CMP. These data confirm that ribonucleotides are modulators of glutamate taste, with purines enhancing sensitivity and pyrimidines displaying variable and even negative modulatory effects. Our ability to detect the co-occurrence of glutamate and purines is meaningful as both are relatively high in evolutionarily important sources of nutrition, such as insects and fermented foods.

The taste stimulus glucose comprises approximately half of the commercial sugar sweeteners used today, whether in the form of the di-saccharide sucrose (glucose-fructose) or half of high-fructose corn syrup (HFCS). Therefore, oral glucose has been presumed to contribute to the sweet taste of foods when combined with fructose. In light of recent rodent data on the role of oral metabolic glucose signaling, we examined psychopharmacologically whether oral glucose detection may also involve an additional pathway in humans to the traditional sweet taste transduction via the class 1 taste receptors T1R2/T1R3. In a series of experiments, we first compared oral glucose detection thresholds to sucralose thresholds without and with addition of the T1R receptor inhibitor Na-lactisole. Next, we compared oral detection thresholds of glucose to sucralose and to the non-metabolizable glucose analog, α-methyl-D-glucopyranoside (MDG) without and with the addition of the glucose co-transport component sodium (NaCl). Finally, we compared oral detection thresholds for glucose, MDG, fructose, and sucralose without and with the sodium-glucose co-transporter (SGLT) inhibitor phlorizin. In each experiment, psychopharmacological data were consistent with glucose engaging an additional signaling pathway to the sweet taste receptor T1R2/T1R3 pathway. Na-lactisole addition impaired detection of the non-caloric sweetener sucralose much more than it did glucose, consistent with glucose using an additional signaling pathway. The addition of NaCl had a beneficial impact on the detection of glucose and its analog MDG and impaired sucralose detection, consistent with glucose utilizing a sodium-glucose co-transporter. The addition of the SGLT inhibitor phlorizin impaired detection of glucose and MDG more than it did sucralose, and had no effect on fructose, further evidence consistent with glucose utilizing a sodium-glucose co-transporter. Together, these results support the idea that oral detection of glucose engages two signaling pathways: one that is comprised of the T1R2/T1R3 sweet taste receptor and the other that utilizes an SGLT glucose transporter.