Evaluation of Sweetener Synergy in Humans by Isobole Analyses

Abstract

The chemical senses and pharmaceuticals fundamentally depend on similar biological processes, but novel molecule discovery has classically been approached from vastly different vantage points. From the perspective of ingredient and flavor companies, there are countless ingredients that act via largely unknown mechanisms, whereas the pharmaceutical industry has numerous mechanisms in search of novel compounds. Mixtures of agonists can result in synergistic (superadditive) responses, which can be quantified via isobole analysis, a well-proven clinical approach in pharmacology. For the food and beverage industries, bulk (caloric) sweeteners like sugars are a key ingredient in sweetened foods and beverages, but consumers also desire products with fewer calories, which has led to the development of sweet enhancers and sweetener blends intended to achieve synergy or superadditivity. Synergistic mixtures are highly attractive targets commercially as they enable lower usage levels and enhanced efficacy. Although the psychophysical literature contains numerous prior reports of sweetener synergy, others have also noted that classical additive models fail to account for nonlinear dose-response functions. To address this shortcoming, here we systematically apply the isobole method from pharmacology to quantify the presence or absence of psychophysical synergy for binary pairs of sweeteners in a series of 15 separate experiments, each with ~100 adult volunteers (total n = 1576). Generally, these data support the hypothesis that structurally similar sweeteners acting as agonists will not synergize, whereas structurally dissimilar sweeteners binding to overlapping or distal sites can act as allosteric agonists or agonist-antagonists, respectively.

Synergic Effects in the Activation of the Sweet Receptor GPCR Heterodimer for Various Sweeteners Predicted Using Molecular Metadynamics Simulations

“…Table summarizes our metaMD studies of the 10 sweetener combinations based on calculations from psychophysical ratings over the full set of different experiments, partitioned into three groups: full synergy ( I -value of <0.6), partial synergy ( I -values of 0.9–0.6), and •suppression ( I -values > 1.0) …”

“…Some blends of two or more sweeteners display greatly enhanced sweetness, but other sweetener combinations can suppress sweetness . The early research in sweetener blend development involved cross-adaptation studies.…”

“…In this study, we address the synergic effect of various sweetener combinations by performing molecular metadynamics (metaMD) simulations for four cases of artificial and natural sweeteners (SGs) , from isobole analysis, a well-proven clinical approach in pharmacology (Table ). These experimental data indicate that structurally similar sweeteners acting as agonists do not synergize, while structurally dissimilar sweeteners binding to overlapping or distal sites can act as allosteric agonists or agonist/antagonists . To study the sweetener-induced modulation of the free-energy landscape of TAS1R2/1R3 heterodimer, we used the distance between the Cα of E3.53 and the Cα of R6.33 at TMD3 as the collective variable (CV) that must open to couple to the G protein for activation.…”

Optimization of Sucrose Substitution in Lassi by Tagatose as a Sweetenerto Foliar Application of PGRs

“…The improvement obtained in overall acceptability score of Lassi upon use of fructose as an adjunct sweetener with tagatose as major sweetening agent might be attributed to its high relative sweetness (Shallenberger, 1993;Barclay et al, 2012). Another reason might be attributed to its synergistic effect of fructose, because synergistic effect of fructose in improving taste is very well documented in literature (Van Tornout et al, 1985;Schiffman et al, 1995;Barclaya et al, 2012;Reyes et al, 2019).…”

Perspective: Measuring Sweetness in Foods, Beverages, and Diets: Toward Understanding the Role of Sweetness in Health

“…This is the reason, for example, why people might underestimate the sugar content of tonic water containing bitter quinine ( Figure 1 ). Enhancement effects, including synergy between different sweeteners, also occur ( 65 ), and such effects are part of what shapes rated sweetness during the consumption of foods and beverages. Assuming that rated sweetness reflects sweetness sensation, food matrix and enhancement effects are not problematic for measuring the sweetness of the diet.…”