Oral carbohydrate sensing: Beyond sweet taste

Physiology & Behavior 202 (2019) 14–25

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Review

Oral carbohydrate sensing: Beyond sweet taste ⁎

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Juyun Lim , Alexa J. Pullicin Department of Food Science and Technology, Oregon State University, Corvallis, OR 97331, United States

A R T I C LE I N FO

A B S T R A C T

Keywords: Amylase Maltooligosaccharides Oral Digestion Saliva Starch Taste

Carbohydrates encompass a wide range of molecules, which can be classified into three groups: mono−/disaccharides (sugars), oligosaccharides, and polysaccharides. Despite all three classes of saccharides being naturally present in foods, research on the human gustatory responses to carbohydrates has focused almost exclusively on sugars, which elicit sweet taste. This review is intended to share recent knowledge regarding possible additional gustatory pathways, other than the known T1R2/T1R3 sweet receptor, involved in carbohydrate sensing. The review begins by providing a brief overview of the chemistry and classification of carbohydrates, along with examples of carbohydrates in the diet, particularly those that can be digested by the human body (i.e., glycemic carbohydrates). Discussions on the oral digestion of glycemic carbohydrates and the enzymes relevant to the digestive process follow. Finally, we discuss sensory perception and possible transduction mechanisms underlying starch hydrolysis products.

1. Introduction Dietary carbohydrates are a diverse group of compounds with a range of chemical, physical, and physiological properties. While there are various ways to classify dietary carbohydrates, the system proposed by the Food and Agriculture Organization (FAO)/World Health Organization (WHO) Expert Consultation is based on chemical structure [1], dividing them into three main classes: sugars (mono/disaccharides), oligosaccharides, and polysaccharides (see Glossary). Within each of these classes, some carbohydrates are glycemic, which can be metabolized by the human body, while others are non-glycemic. Glycemic carbohydrates serve as a major source of energy to humans, accounting for an estimated 40 to 80% of total caloric intake worldwide [1,2]. Despite a significant increase in sugar consumption in the 20th century [3], starch-based polysaccharides (i.e., malto-polysaccharides) continue to be the largest source of calories across many cultures [1,2]. One of the primary functions of taste is to identify substances that provide energy and/or electrolyte balance, and distinguish those from substances that are toxic [4]. Given that glycemic carbohydrates are an important source of energy in the human diet, their gustatory detection would be highly beneficial. Historically, research has focused almost exclusively on the perception and mechanisms underlying the gustatory detection of sugars based on the T1R2/T1R3 sweet receptor (for reviews on sugars and sweet taste, see [5,6]). In contrast, the gustatory detection of maltooligo- and maltopolysaccharides was thought to be unlikely [7]. Accordingly, commercially available starch hydrolysis

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products (e.g., maltodextrin; mixtures of primarily maltooligo- and maltopolysaccharides) have been used as tasteless, caloric substances in studies of flavor-nutrient conditioning [8–10] and exercise performance [11,12]. Interestingly, numerous studies using rodent (reviewed in [13,14]) and nonhuman primate models [15,16] showed that these animals are attracted to the taste of maltooligo- and maltopolysaccharides. Recently, our research team also found evidence that humans can taste starch hydrolysis products of certain chain lengths and that such detection is independent of the human sweet taste receptor, hT1R2/hT1R3. This review is written to illustrate this new evidence and further to discuss the sensory perception and possible transduction mechanisms of starch hydrolysis products. Importantly, a full understanding of carbohydrate taste requires comprehension of basic carbohydrate chemistry and enzymatic actions on carbohydrates in the gustatory system, which should help readers follow the logic behind the experimental design and the implications of sensory data. Therefore, we first provide a brief overview of carbohydrate chemistry and classification, focusing primarily on glycemic carbohydrates, along with examples of these carbohydrates in the diet. This is followed by a discussion on the oral digestion of carbohydrates, and details on the enzymes relevant to the digestive process.

Corresponding author. E-mail address: [email protected] (J. Lim).

https://doi.org/10.1016/j.physbeh.2019.01.021 Received 14 November 2018; Received in revised form 15 January 2019; Accepted 23 January 2019 Available online 24 January 2019 0031-9384/ © 2019 Elsevier Inc. All rights reserved.

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can produce one of two anomers, which differ only by the configuration of the newly-formed hydroxyl (-OH) group on the anomeric carbon, classified as either α or ß (Fig. 1B) [18,19]. These α- and ß-anomers interconvert in solution in a process known as mutarotation; note that mutarotation is not limited to monosaccharides, but may occur whenever a carbohydrate has a free anomeric carbon [17]. As shown in Fig. 1B, glucose can exist in solution as a 5- or 6-membered ring as either an α- or β-anomer; these different forms approach equilibrium over time (minutes to hours), in a proportion based on their thermodynamic stability in solution at the specific temperature and pH [17]. Interestingly, the sensory properties of monosaccharides can differ depending on the form of the ring; for example, the 6-membered ring form of the monosaccharide fructose is sweeter than its 5-membered ring form [20]. 2.1.2. Degree of polymerization Monosaccharides typically link together to form longer-chain carbohydrate molecules. These can range from two monosaccharides units linked together (i.e., disaccharides) to those that are tens to hundreds of thousands of units in length [18,19]. The number of linked units in a saccharide is referred to as its degree of polymerization (DP). 2.1.3. Type of linkage The characteristic bonds that join monosaccharide residues are termed glycosidic linkages. The glycosidic linkages in saccharides are formed between the anomeric carbon of one monosaccharide and a hydroxyl group of another. These linkages are classified both by the configuration of the anomeric carbon(s) participating in the linkage (i.e., α or ß; Fig. 2A), and by the positions of the carbon atoms joined by the linkage (e.g., 1,4 vs. 1,6; Fig. 2B) [18]. If there is a free anomeric carbon at the end of a molecule, the saccharide is considered reducing (this is the case for maltooligo- and maltopolysaccharides); if all anomeric carbons are participating in the linkage(s), the saccharide is non-reducing (see Fig. 2B). When succeeding residues are linked at only two points, linear saccharides are formed; more than two linkages stemming from a single residue (at a separate carbon) leads to a branch point (Fig. 2C). The type of linkages that a saccharide possesses has structural consequences to the overall conformation of the molecule, which in turn governs the behavior of that molecule in the human body. For example, non-glycemic carbohydrates (e.g., fibers) have linkages that cannot be broken down in the upper digestive tract, and thus have a different physiological outcome compared to glycemic carbohydrates such as starch, which serve as a source of energy in the form of glucose [21].

Fig. 1. (A) The D- and L-isomers of glucose, defined by the position of the hydroxyl group (-OH; highlighted) at the chiral carbon atom farthest from the carbonyl group (C=O). (B) The tautomers of D-glucose in solution. Glucose exists in an equilibrium of 5-membered furanose (bottom) and 6-membered pyranose (top) rings, with low amounts in straight-chain form. The conformation of the anomeric carbon of cyclic forms dictates its α (right) or ß (left) distinction, indicated by the position of the highlighted hydroxyl group.

2. Chemistry, classification, and sources of glycemic carbohydrates 2.1. Chemistry of carbohydrates There are three defining characteristics in the chemistry of carbohydrates: the identity of component monomer unit(s), the number of monomer units linked together (i.e., degree of polymerization), and the type of the linkage(s) connecting these units. These chemical characteristics affect a carbohydrate's physical (e.g., soluble vs. insoluble) and physiological (e.g., glycemic vs. non-glycemic) properties.

2.2. Classification of carbohydrates The primary classification of dietary carbohydrates is by molecular size (as determined by DP), and divides dietary carbohydrates into three classes: sugars (mono−/disaccharides), oligosaccharides, and polysaccharides [1]. The distinction between oligo- and polysaccharides varies across fields of study [22]. For example, some consider those that contain 3–10 monomer units as oligosaccharides, whereas others count up to 20. In this review, carbohydrates with a DP of 3 to 20 are referred to as oligosaccharides, while longer-DP carbohydrates (DP > 20) are referred to as polysaccharides.

2.1.1. Monomer(s) Carbohydrates typically follow the general empirical formula (CH2O)n, signifying a carbon (C) atom plus two hydrogen (H) atoms and an oxygen (O) atom in the same proportion as water, hence the name carbohydrates, or ‘hydrates of carbon’ [17]. Monosaccharides are the simplest carbohydrates and serve as a base to all carbohydrate molecules. All monosaccharides exist as L- or D-isomers, defined by the position (left vs. right) of the hydroxyl group (-OH) farthest from the carbonyl group (C=O) when depicted in straight-chain form (see Fig. 1A); D-isomers are most common in nature, and will thus be the focus of this review. Many of the more abundant monosaccharides in nature, such as glucose, fructose, and galactose, contain 6 carbons [(CH2O)6] and tend to exist as 5- or 6-membered cyclic structures in aqueous solution (Fig. 1B) [18]. The intermolecular reaction that forms the cyclic molecule from a straight-chain molecule occurs between the carbon of the carbonyl group, termed the anomeric carbon, and the oxygen of a hydroxyl group within the chain. This reversible reaction

2.3. Dietary sources of glycemic carbohydrates The typical human diet contains a broad range of carbohydrates, which includes those found naturally in foods and those as added ingredients. Glycemic carbohydrates exist in the diet as sugars, starch, and starch hydrolysis products (e.g., maltodextrins, glucose syrups). For review on the dietary sources of non-glycemic carbohydrates, see [23,24]. 15

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Fig. 2. Glycosidic bonds of carbohydrates. (A) Bonds are classified as α or ß, determined by the conformation of the anomeric carbon participating in the linkage. (B) The standard procedure for numbering carbons (anomeric carbon = 1) is used to communicate which carbons the linkage connects. (C) Monosaccharide residues are linked in a linear fashion without or with branches.

preservation (e.g., jams), in addition to providing sweetness [17,19,31]. Lactose (galactose-ß-1,4-glucose) occurs naturally in mammalian milk and is common in unfermented dairy foods [17,19,31]. Trehalose (glucose-α-1,1-glucose) and maltose (glucose-α-1,4-glucose) are two glucose-based disaccharides found in foods, both naturally and as added ingredients. Trehalose is found in yeast, mushrooms, and some plants [22,31,33], and is used in the food industry as a replacement for sucrose to match its technological properties in foods where a lower sweetness is desired [33]. Maltose is not common in nature, but is found in sprouted wheat and barley, and is a component of malted grains [17,19]. The most common source of maltose in foods is maltodextrin, which is a mixture of starch hydrolysis products (see Section 2.3.3).

2.3.1. Sugars Glucose, fructose, and galactose are the principal monosaccharides in nature and are the building blocks of a majority of the naturally occurring di-, oligo-, and polysaccharides [22,25,26]. Glucose is the most abundant of these monosaccharides, and is found naturally in honey as well as in many fruits, vegetables, and legumes [25,27]. Fructose is considered to be the sweetest sugar on a molar basis, and is also naturally prevalent in fruits and honey [25,27,28]. Fructose and fructose-based sweeteners, including high-fructose corn syrup and sucrose, are the most common sweeteners added to foods [29,30]. Disaccharides are more common than monosaccharides in nature [19,25,31], with the two most prevalent disaccharides being sucrose and lactose [17,22]. Sucrose (glucose-α-1,4-fructose) is produced during photosynthesis as an energy source for all plant cells; accordingly, it is present to varying degrees in the edible portions of plants [32]. It also possesses several functional properties when added to foods; some applications include browning (caramelization) and food

2.3.2. Starch Digestible oligo- and polysaccharides include starch and its hydrolysis products (collectively termed α-glucans) [22]. Starch serves as the main energy store of plants, and is found in all green leaves, and in the 16

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amylose content of 50–70%, whereas potato, wheat, and tapioca starches have amylose contents near or below 20% [19,34,39]. Together, these components are stored in plants as granules. The ratio between amylose and amylopectin as well as other factors (e.g., non-starch components present in granules) contribute to differences in the physical behavior between various starches in food systems, including their viscosity, pasting properties, and retrogradation tendencies [19,38,41]. Native starch granules are insoluble in cold water, but can reversibly swell [19]. Upon heating in water, granules undergo a process termed gelatinization, which irreversibly disrupts order within the granules. This process makes starch components (i.e., amylose and amylopectin) more available for acid or enzyme hydrolysis [19]. 2.3.3. Starch hydrolysis products Starch hydrolysis products are used throughout the food industry for their desirable functional properties (e.g., solubility) over native starch [19,42,43]. These products, added to foods during processing, constitute a significant portion of the digestible carbohydrate in processed foods such as snacks, soups, and candies [19]. They have a number of uses in the food industry, including but not limited to flavoring, thickening, stabilizing, and moisture retention [42–44]. Some commercially available starch hydrolysis products include glucose syrups, corn syrup solids, and maltodextrins. These products are typically classified by their dextrose equivalent (DE), which is a quantitative measure of the average reducing power of the product (recall that all α-glucans have a free anomeric carbon and are thus reducing saccharides) [45]. Therefore, DE is inversely related to a product's average DP. Industrially, these derivatives are produced by acid or enzyme hydrolysis [19]. The extent of hydrolysis, in addition to the method of hydrolysis used results in products with diverse saccharide profiles (i.e., the DP makeup of the product) [19,34]. Glucose syrup and corn syrup solids are produced by extensive starch hydrolysis, and are largely composed of smaller saccharides such as glucose, maltose, and low-DP maltooligosaccharides. These products have DE values of ~20–60 [19]. Lesser hydrolysis of starch results in maltodextrins, which are defined as having DE values ≤20 (i.e., products possessing an average DP of 5 or above). Fig. 3. (A) The active site of human salivary α-amylase possesses multiple subsites for binding linear glucosyl residues at the interior part of an α-glucan chain. An initial cleavage takes place cutting the α-glucan into two chains. One of these chains remains complexed with the enzyme, and is pushed toward the catalytic site where it is successively cleaved, producing mainly maltose and maltotriose. (B) About three of these attacks occur on a single α-glucan chain before it dissociates and a new α-glucan chain associates with the enzyme. Numbers depict a hypothetical sequence of catalytic events of a single salivary α-amylase interacting with three successive α-glucan chains. (C) Acarbose, an α-amylase inhibitor, comprises an acarviosin moiety α-1,4-linked to a maltose moiety. The glycosidic nitrogen linkage of the acarviosin moiety is anchored at subsites II and III—the location of the catalytic site. Ø indicates the direction of the reducing end of the α-glucan. Adapted from Yoon & Robyt, 2003 [86].

3. Enzymatic actions on glycemic carbohydrates during oral digestion As food enters the mouth, the molecular structures of starch and its hydrolysis products are altered immediately. This structural modification occurs not only through mastication, but also as a result of the concurrent action of enzymatic hydrolysis. This section provides an overview of the enzymatic action of salivary α-amylase, the key enzyme responsible for the oral hydrolysis of long-chain glycemic carbohydrates, along with differences in its enzymatic activity between individuals. In addition, α-glucosidases, enzymes that hydrolyze shortchain glycemic carbohydrates, are briefly covered. Finally, compounds that can inhibit the catalytic action of these enzymes are discussed.

seeds, stems, roots, tubers, and fruit of most plants [34–36]. Starchy foods, including cereal grains, tubers, root vegetables, and legumes, serve as dietary staples across the world [2,36,37]. Depending on the plant source, starch content on a dry basis can range from ~40% (beans) to ~90% (rice, yam, cassava) [38]. Commercial starches are obtained from a variety of sources, commonly including cereal grains such as corn, wheat, and rice, along with tubers and roots, such as potato and cassava (tapioca) [19,39,40]. Starches are composed of two types of glucose polymers: amylose and amylopectin. Whereas amylose is predominately linear (α-1,4), about 5% of the linkages in amylopectin are branch points (α-1,6) (see Fig. 2C) [34]. The ratio of amylose to amylopectin differs depending on the source of starch; for example, high-amylose corn starch has an

3.1. Salivary α-amylase α-Amylase is the most predominant enzyme in human saliva [46]. Although it comprises only a small portion of the total amylase produced by the body (the principal α-amylase being pancreatic, secreted to the small intestine) [47], salivary α-amylase appears to serve an important role in initiating the enzymatic oral digestion of starch and starch hydrolysis products (i.e., α-glucans). Notably, recent evidence suggests that the resulting hydrolysates, maltooligosaccharides, could elicit taste perception (see Section 4 below). 3.1.1. Enzymatic action of salivary α-amylase Salivary α-amylase is an endo-acting enzyme that catalyzes the 17

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hydrolysis of α-1,4 glycosidic linkages at the interior parts of α-glucans. The active center of α-amylase comprises multiple substrate binding subsites and a catalytic site [48]. The number of subsites within the active site of this enzyme has been reported to be at least 5, and possibly up to 7 [49–51]. When contiguous α-1,4-linked glucosyl residues of an α-glucan substrate bind with these subsites, hydrolysis occurs at the catalytic site located between binding subsites II and III (see Fig. 3A) [52,53]. After an initial catalytic cleavage at a random interior glycosidic linkage, one half of the α-glucan chain remains associated with the enzyme. The chain is repositioned to fill the empty subsites, and the amylase catalyzes about two additional cleavages on the αglucan chain before dissociating, whereby it binds with another substrate and repeats the process (see Fig. 3B) [54]. This ‘multiple attack’ mechanism [54] leads to the rapid fragmentation of α-glucans to smaller maltooligo- and maltopolysaccharides along with the smaller final products of maltose (DP 2), maltotriose (DP 3), and α-limit dextrins (i.e., saccharides containing one or two α-1,6 branch points; the α1,6 linkages themselves, as well as linear glucosyl residues adjacent to these branches are resistant to the hydrolysis by α-amylase) [52,55,56]. In vivo studies have shown that considerable hydrolysis takes place in the oral cavity through the action of salivary α-amylase, despite relatively short oral processing time [57–59]. A study implementing in vitro rheological measurements has supported this observation [57]. Recently, our research team performed an in vitro study in an effort to understand how rapidly starch degradation products are produced by salivary α-amylase. In that study [60], stimulated saliva collected from five subjects with low and high amylase activities (see section 3.1.2 below) was reacted with 8% raw and cooked starch for 2, 15, and 30 s. Hydrolysis products ranging from DP 1–8 were quantified using a high performance liquid chromatography (HPLC). The results showed that the status of starch and reaction time influenced the extent of in vitro starch digestion. More importantly, the study demonstrated that roughly 16% (12.4 in 80 mg/mL) of a cooked corn starch preparation was hydrolyzed to saccharides of DP 2–8 at 2 s (see Table 1) and reached nearly 25% after 30 s. Note that DP 1–8 were the only saccharides that could be measured since there are no commercially available standards for DP ≥ 9. Notably, the major products generated beyond the 2 s time point were maltose and maltotriose, with a minimum increase in maltotetraose (DP 4); differences in the total amounts of DP 5–8 produced were negligible over the time points tested.

3.1.2. Variability in salivary amylase activity The quantity and enzymatic activity of salivary α-amylase shows significant variation between individuals [47,57]. That is, in addition to considerable differences in the concentration of salivary amylase produced by individuals, its enzymatic efficiency at a set amount also varies. Values reported from a few studies have shown that the quantity of salivary α-amylase can range from 0 to 7.5 mg/mL of saliva [57], and its enzyme activity ranges from 1 to 371 U/mL of saliva [57,61,62]. Furthermore, salivary flow rate can also differ between individuals. Our research team previously reported about a 20-fold difference in stimulated salivary flow rates between subjects; importantly, salivary flow rate and salivary α-amylase activity did not appear to be correlated [63]. A number of factors have been suggested to explain the variability of α-amylase quantity and activity, most of which relate to an individual's genetics, diet, or environment [57]. Salivary α-amylase is encoded by the gene AMY1 [64,65], which is one of the most variable genes within the human genome in terms of individual copy number variation, with a reported ranges of 1 to 27 copies among various human populations [66]. Importantly, there is a strong positive correlation between AMY1 copy number and the quantity and enzymatic activity of α-amylase in saliva [57,67–69]. It has been suggested that the starch content of diets in humans is associated with AMY1 copy number, with evidence showing that individuals from populations with high-starch diets have more AMY1 copies on average compared to those with historically lower-starch diets [69]. Nevertheless, copy number does not fully explain the variations of α-amylase quantity and activity [70]. Environmental factors such as stress [71–73] and circadian rhythm [72,74] as well as physical activity [75–77] have also been found to contribute to the variations. 3.2. α-Glucosidases in the oral cavity The final α-amylase hydrolysis products of α-glucans (i.e., maltose, maltotriose, and limit dextrins) as well as disaccharides (e.g., sucrose) inherent to the food are further digested by α-glucosidases to their component monosaccharides at the brush border of the small intestine before those components can be absorbed and enter the bloodstream [78,79]. These membrane-bound α-glucosidases include maltase-glucoamylase (MGAM), sucrase-isomaltase (SI), trehalase, and lactase [79,80], each of which possess different specificities for certain disaccharides, small maltooligosaccharides, and/or limit dextrins (e.g., MGAM cleaves α-1,4-linkages, SI cleaves α-1,2 and α-1,6 linkages). Recently, it has been reported that these α-glucosidases are also expressed in sweet-responsive taste cells in the oral cavity of mice [81]. It is currently unknown whether these enzymes exist in human taste cells. If they do, it is possible that salivary α-amylase end products as well as sugars in foods could be broken down to absorbable monosaccharides in the oral cavity. This has important implications for metabolic pathways that recognize monosaccharides in the gustatory system; one such pathway has been identified in the taste cells of some rodents (see section 4.3.2) [82,83], and has been proposed to exist in human taste cells [84].

Table 1 Mean ( ± SE) quantity (mg/mL) of hydrolysis products generated through in vitro salivary α-amylase hydrolysis of 8% (w/v) cooked starch at 2, 15, and 30 s. Adapted from Lapis et al., 2017 [60]. Hydrolysis productsa

2s

15 s

30 s

DP 1 DP 2 DP 3 DP 4 DP 5 DP 6 DP 7 DP 8 Total DP 2–8 Total DP ≥ 9b

ND 2.0 ± 0.3 2.1 ± 0.2 1.9 ± 0.1 1.7 ± 0.0 1.3 ± 0.3 1.5 ± 0.1 1.8 ± 0.1 12.4 ± 0.3 ~67.6

ND 3.6 ± 1.1 3.6 ± 0.8 2.6 ± 0.3 1.7 ± 0.1 1.6 ± 0.1 1.6 ± 0.1 1.8 ± 0.1 16.5 ± 1.8 ~63.5

ND 5.1 ± 1.8 4.8 ± 1.0 2.9 ± 0.3 1.7 ± 0.1 1.6 ± 0.1 1.6 ± 0.1 1.8 ± 0.1 19.6 ± 2.4 ~60.4

3.3. Inhibition of α-amylase and α-glucosidases Critical to controlling the enzymatic breakdown of carbohydrates in research is the utilization of enzyme inhibitors. One of the most wellknown inhibitors of α-amylase and α-glucosidases is acarbose [85,86]. Acarbose is a natural saccharide analog consisting of an acarviosin moiety α-1,4-linked to a maltose (see Fig. 3C); the unique chemistry of the acarviosin moiety mimics the transition state for the enzymatic cleavage of glycosidic linkages, thus making it a competitive inhibitor of those enzymes [86]. The efficacy of acarbose in taste research has been tested in vitro by our research team [87]. Stimulated saliva collected from individuals with low, medium, and high amylase activities

Values are averaged from five subjects, having both low (N = 3) and high (N = 2) α-amylase activity; each 8% w/v sample was reacted with a constant volume of saliva for the specified time periods. ND = none detected by high performance liquid chromatography (limit of detection values for standards ≤0.006 mg/mL as determined in Balto et al., 2016 [101]). a Saccharides DP 1–8 were not detected in samples void of saliva. b Theoretical values obtained by subtracting total DP 2–8 from 80 mg/mL. 18

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maltodextrin and that the responsiveness to maltodextrin is independent of that to simple sugars.

was mixed with 10% w/v maltodextrin preparations without and with 5 mM acarbose. In the presence of acarbose, no substantial hydrolysis of the maltodextrin was observed regardless of the amylase activity status, indicating salivary α-amylase was sufficiently inhibited [87]. Importantly, acarbose at 5 mM has been reported to impart no detectable taste quality [78]. Our more recent work [88] suggests, however, that acarbose can elicit sweet taste at higher concentrations (> 18 mM). The efficacy of acarbose on α-glucosidases has been discussed elsewhere [89]. In addition to acarbose, other compounds such as acarbose derivatives (e.g., isoacarbose, acarviosin-glucose) [52,85], voglibose [90], and miglitol [91] have been found to be effective inhibitors of αamylase and α-glucosidases.

4.2. Target ligands responsible for the detection of starch hydrolysis products There are several proposed criteria for a taste to be considered unique. One of the key criteria specifies that the sensation should be elicited by a distinctive class of chemicals [99]. In the case of welldefined tastes, certain target chemicals are known to be responsible for eliciting the specific taste of interest, independent of any other sensorial cues (e.g., smell, texture). While the results from the studies discussed in section 4.1 provide strong evidence that humans can detect maltodextrins, it is unclear whether textural cues play a role in their detection. In addition, it is unclear which components of maltodextrins are responsible for its detection. DP profiles of commercially available maltodextrins are often diverse; they possess a wide DP-range of maltooligosaccharides and maltopolysaccharides. Further, maltodextrins may contain appreciable amounts of glucose and maltose. Two maltodextrin products can also differ markedly in DP profile, despite having an equivalent DE value [100]. The use of unspecified mixtures as test stimuli hinders understanding of what components of the mixture are responsible for eliciting a percept, as these components have the potential to target separate perception mechanisms and possess different degrees of detectability. Our initial step to produce more narrow carbohydrate stimuli took advantage of the differential solubility of α-glucans in ethanol-water mixtures [101]. That is, α-glucans decrease in solubility with increasing ethanol concentrations, and their solubility in an ethanol-water mixture at a given concentration is inversely related to their DP. These solubility properties were used to produce three maltooligo- and maltopolysaccharide preparations by repeatedly mixing a commercial maltodextrin with different ethanol-water solutions and recovering the soluble and/or insoluble fractions. These preparations possessed more narrow DP profiles than the starting maltodextrin (see profiles in Fig. 4) and had differing distributions of maltooligo- and maltopolysaccharides (average DP 7, 14,and 44). Note the preparations were effectively sugar-free (< 0.01 mg/mL DP 1 or 2). Analysis of the preparations using proton nuclear magnetic resonance (NMR) revealed that the ratio of α-1,4 (linear) to α-1,6 (branched) linkages decreased as the average DP of the preparation increased, from ~25:1 in the average DP 7 preparation to ~6:1 in the average DP 44 preparation [101]. The three resulting preparations were used for a psychophysical study [87]. In one experiment, subjects were asked to discriminate the stimuli at 6% and 8% w/v from water blanks while wearing nose clips. Importantly, the DP profiles of the stimuli were maintained by using 5 mM acarbose (see section 3.3). The results showed that subjects could significantly discriminate the average DP 7 and 14 preparations at both concentrations from water blanks (p < .05; 82% and 95% correct response rates at 6 and 8% w/v for the average DP 7 preparation; 55% and 59% correct response rates at 6 and 8% w/v for the average DP 14 preparation). In contrast, subjects could not discriminate the average DP 44 stimulus at a significant degree under the same conditions (32% and 27% correct response rates, corresponding to chance level discrimination). It was further noted that the detectability of the average DP 7 stimulus was higher than that of the average DP 14 stimulus at both concentrations [87]. While these results provided some insight on potential target ligands, it was recognized that comparisons across target stimuli with differing DP-distributions may not be equitable at equivalent w/v%. For example, the two stimuli with lower average DPs have considerably higher molar concentrations at the same w/v% compare to the high-average DP preparation. In a separate experiment, the three stimuli were prepared on an equivalent molar basis, which corresponds to that fact that a single saccharide chain contains one reducing end (RE); recall that all α-glucans are reducing saccharides. At a concentrations of 75 mM RE, the

4. Oral detection of starch hydrolysis products Numerous lines of research have shown that rodents have mechanisms for sensing starch and its hydrolysis products in the oral cavity that are independent to that of sweet taste sensing (see [13,14]). Earlier studies aiming to find a comparable response and/or mechanism in humans concluded that these stimuli did not represent a unique taste [7,92]. The possibility of an unidentified carbohydrate taste perception mechanism(s) in humans has been revisited in recent years. This section is intended to review this important and evolving topic. 4.1. Evidence that humans can detect starch hydrolysis products While our research team was investigating the role of nutrients in flavor learning, we recognized that some subjects could consistently taste maltodextrin—commonly used as a tasteless, nutritive substance in nutrient conditioning [8–10]—in the absence of odor cues. The possibility that humans can orally detect maltodextrin has been raised by several exercise scientists. Numerous studies in this area have reported that oral exposure to maltodextrin solutions significantly improves physical performance for certain types of exercise (e.g., highintensity exercise) compared to water or sweet, non-caloric solutions [11,12,93] and that the improvement in exercise performance may be due to the activation of brain regions believed to be involved in reward and motor control [94]. This has led some in that field to propose that there may be a class of unidentified oral receptors that respond to carbohydrates independently of those for sweetness, though the impact of perceptible taste has been questioned [94,95]. In order to investigate the possibility of a perceptible oral detection mechanism for maltodextrins, we conducted a formal psychophysical study [63]. In that study, subjects were asked to rate the perceived intensities of three commercial maltodextrin preparations with varying saccharide compositions [DE (dextrose equivalency) 5, 10, and 20; see [63] for details], along with glucose and sucrose, while their noses were clamped. The results showed that the ratings for the three maltodextrin preparations were highly correlated with one another (r = 0.69–0.82, p < .001). Notably, responses to the DE 5 and 10 preparations were not correlated to the responses to glucose and sucrose (r = 0.07–0.27, p > .05). On the other hand, responses to DE 20 were moderately correlated to that of the sugars (r = 0.43–0.51, p < .01). The latter finding was likely due to the considerable presence of sweet-tasting saccharides (i.e., DP 1–3, see section 4.3.2) in the preparation, accounting for ~20% of its contents by weight (the content of DP 1–3 in the other two preparations were lower: 2.8% and 7.8% for DE 5 and DE 10, respectively). Interestingly, the results also showed that the responsiveness to the maltodextrins tested did not significantly differ between individuals with high and low α-amylase activity [63]. The claim that maltodextrins can be orally detected by humans has since been supported by others [96–98]. Those studies investigated oral sensitivities to maltodextrin as well as other prototypical tastants using two separate psychophysical measures, i.e., perceived intensity and threshold. These data together, along with reports on exercise performance [93,95], provide strong evidence that humans can orally detect 19

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Fig. 4. Representative chromatograms from high performance anion-exchange chromato-graphy with pulsed amperometric detection (HPAEC-PAD) depicting the degree of polymerization (DP) profiles of (A) the starting maltodextrin and the three new preparations (B-D) produced by repeatedly mixing the maltodextrin with different ethanol-water solutions and recovering the soluble and/or insoluble phases. (B) average DP of 7, (C) average DP of 14, and (D) average DP of 44. Figures taken from Balto et al., 2016 [101].

sucrose, sucralose, and the maltooligosaccharide preparation with an average DP of 14 described above. Recall that this preparation contained no appreciable amount of sugars (i.e., DP 1, 2) and only 4% maltotriose (a sweet-tasting oligosaccharide, see Section 4.4.2) by weight [101]. Subjects described the taste quality of sucrose and sucralose as “sweet” like sugar and “sweet” like an artificial sweetener, respectively [87]. The group mutually described the maltooligosaccharide preparation as having a taste quality similar to that of a root vegetable, corn, bread, or pasta (i.e., starchy foods). The term “starchy” was selected as a collective definition for this taste quality [87]. Importantly, subjects wore nose clips to eliminate olfactory input, and swabbed the stimuli on the tongue to attenuate texture cues; thus, these quality descriptors were a result of gustatory perception. When a psychophysical function was considered, the same maltooligosaccharide preparation was found to have a function indistinguishable from that of glucose at 45, 100, and 224 mM (Fig. 5A) [87]. In contrast, when the results were re-plotted on a w/v% basis (Fig. 5B), the psychophysical function for the maltooligosaccharide preparation was shifted to the right along the x-axis. This distinction highlights the amount of maltooligosaccharide needed on a weight basis to achieve the same level of perceived intensity compared to its monosaccharide counterpart, glucose [87]. Understandably, comparisons of the relative taste intensity of saccharides based on molarity provide more accurate information regarding the binding process between molecules and the mechanism(s) that leads to a taste response. This result further offered potential support as to why our earlier study [63] found maltodextrins to have about “weak” taste intensity, while glucose and sucrose at the same concentration (10% w/v) were found to have “moderate” taste intensity. Nevertheless, it is clear that the taste sensation elicited by maltooligosaccharides is weaker than that of sugars on a w/v% basis. Thus, it is unlikely that the taste of maltooligosaccharides contributes greatly to the flavor of foods in humans. This generally weak taste sensation can be viewed as an indication that the gustatory-based detection of maltooligosaccharides is less robust than that of other tastes (e.g., sweetness). Alternatively, the relatively weaker taste intensity of maltooligosaccharides may be considered as a manifestation of its unique nutritional and digestive capacity in human

average DP 7, 14, and 44 preparations had w/v% equivalents to 8%, 17%, and 54% w/v, respectively. Because the stimuli, particularly the latter two, were perceptibly viscous, the tasteless, viscogenic agent methylcellulose was used to match the viscosity of blank stimuli to the target stimuli [87]. The results from this study confirmed that those preparations with high contents of maltooligosaccharides (i.e., the average DP 7 and DP 14 preparations) could be significantly discriminated from viscosity-matched water blanks at a similar degree (p < .01; 62% and 58% correct response rate, respectively). Conversely, the average DP 44 stimulus, containing mostly maltopolysaccharides, could not be significantly discriminated (response rate of 38%, corresponding to chance level). This latter result suggests that texture cues do not fully explain the detection of α-glucans, but that taste is more likely responsible for their detection [87]. Regarding the ranges of detectable α-glucans, our findings are mostly consistent with those obtained in rats, where well-defined stimuli were used [102]; the study reported that rats could not only detect a maltooligosaccharide preparation (average DP 6), but preferred it over maltotriose, maltose, and glucose. Their findings showed, however, that the rats could also detect a maltopolysaccharide preparation with an average DP of 43, which is in disagreement with our results. While this may indicate potential differences in the abilities to taste α-glucans between species, it is worth recognizing that the study did not control for salivary α-amylase activity, which could have produced detectable levels of hydrolysis products [102]. Overall, our results suggest that there is an upper limit of molecular size that allows for α-glucan taste perception in humans, and that taste is elicited by maltooligosaccharides with an average DP of at least up to 14, but below DP 44 [87]. It is currently unknown what the upper-limit of DP that humans can detect is, as well as how the presence of branching impacts detection. 4.3. Sensory properties: quality and intensity In order to establish a taste quality descriptor of maltooligosaccharides, a focus group study was conducted [87]. Subjects were asked to describe taste qualities of equi-intense solutions of 20

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Fig. 5. Psychophysical functions of sucrose, glucose, and maltooligosaccharide preparation (average degree of polymerization of 14) based on (A) molar and (B) w/v % concentrations. Symbols represent the log means of intensity of the stimuli with standard error whiskers. The x-axis represents the log concentration tested. The molar concentrations tested were 45, 100, and 224 mM for all three stimuli; equivalent of 1.5, 3.4, and 7.7% for sucrose, 0.8, 1.8, and 4% for glucose, and 10.3, 22.8, and 51.1% for the maltooligosaccharide preparation. The y-axes represent log perceived overall intensity (left), and semantic labels of the general labeled magnitude scale: BD = barely detectable (dashed line), W = weak, M = moderate. Subjects wore nose clips while performing the task, and all stimuli were prepared with 5 mM acarbose to keep saccharide profiles intact. Figures taken from Lapis et al., 2016 [87].

4.4.2. Sensory mechanisms underlying the detection of starch hydrolysis products As discussed above, our data provide strong evidence that humans can taste maltooligosaccharides. The transduction mechanism responsible for their detection is currently unknown. Given that maltooligosaccharides are composed of glucose, which elicits sweet taste, it was of interest to investigate whether the detection of maltooligosaccharides is mediated through hT1R2/hT1R3. Two studies have been conducted by our group to explore this possibility using the sweetness inhibitor lactisole, which binds to a pocket in the transmembrane region of T1R3 and effectively inhibits sweet taste [117]. The first study [87] showed that the gustatory detection of maltooligosaccharides was independent of hT1R2/hT1R3. In that study, subjects were asked to discriminate two maltooligosaccharide preparations (average DP 7 and 14) as well as typical sweet tasting stimuli (glucose, maltose, sucralose) in the presence of lactisole. Note that acarbose, the amylase inhibitor described in Section 3.3 above, was added to the test stimuli described here and in the next study in order to preserve the DP profile of the preparations. The results showed that when lactisole was present, subjects could not detect the three sweet substances (all 24% correct response rates with a chance rate of 33%; p > .05), but could still detect maltooligosaccharide preparations at a statistically significant level (52% and 44% correct response rates for average DP 7 and 14 preparations, respectively; p < .05). In an effort to further understand the lower DP-limit of the hT1R2/ hT1R3-independent detection of maltooligosaccharides, our research team conducted a follow-up study [118]. We first prepared a series of narrow, well-defined groups of maltooligosaccharides of DP 3, 3–4, 5–6, and 6–7 through the combined processes of ethanol-water solubility fractionation and cellulose-based column chromatography [118]. The four maltooligosaccharide groups, along with glucose and maltose were prepared at 75 mM with or without lactisole. In the absence of lactisole, subjects were able to discriminate glucose, maltose, and the four maltooligosaccharide preparations to a significant degree (p < .001; see Fig. 6, light bars). Interestingly, the differences in the discriminability between all six stimuli under this condition was statistically insignificant, suggesting the stimuli had a similar stimulatory impact on the mode of perception when considered on an equimolar basis. In the presence of lactisole (Fig. 6, dark bars), the paired maltooligosaccharide stimuli, i.e., DP 3–4, 5–6, and 6–7, were still detected; in fact, the discriminability of these three maltooligosaccharide stimuli between the two lactisole conditions were statistically indifferent (p < .05). Conversely, glucose, maltose, and maltotriose were

diet [103]; because starches are more slowly digested and absorbed, and hence cause a lower and slower rise in blood glucose than sugars, the human body may accommodate a higher concentration of starches than sugars with a smaller impact on blood glucose and therefore insulin levels.

4.4. Gustatory mechanisms for detecting carbohydrates 4.4.1. Known carbohydrate sensing mechanisms The most well-known gustatory mechanism to detect carbohydrates is the sweet taste receptor, T1R2/T1R3. It is a heteromeric complex composed of two subunits, T1R2 and T1R3, both members of class C G protein-coupled receptors [104–107]. T1R2/T1R3 recognizes a variety of chemical substances including sugars, artificial sweeteners (e.g., sucralose, aspartame, saccharin), amino acids (e.g., D-tryptophan, glycine), and sweet proteins (e.g., brazzein, monellin, thaumatin) [104,108–110], all of which can bind to one or more of the multiple ligand-binding sites (reviewed in [5]) and lead to the perception of sweetness. Recently, it was reported that mice lacking T1R3 showed no preference for artificial sweeteners, but still had (somewhat diminished) behavioral and nerve responses to sugars (i.e., sucrose, glucose) [111–113]. These findings suggested the possible presence of T1R-independent sugar-sensing mechanism in taste cells [111]. Accordingly, recent studies have reported that glucosensors, namely, glucose transporters (GLUTs), sodium-glucose cotransporter 1 (SGLT1), and the ATPgated K+ (KATP) channel are present in T1R3-expressing taste cells of mice, and function as metabolic sensors triggered by glucose [81–83,114]. α-Glucosidases (see section 3.2), recently found to be expressed in those taste cells, appear to hydrolyze maltose and smaller α-glucans to supply glucose for the aforementioned pathway [81]. This T1R-independent pathway has been shown to stimulate gustatory nerves and to play an important role in cephalic phase insulin release (CPIR), which enhance glucose tolerance [115,116]. In the work of Glendinning and colleagues [116], both wild-type and T1r3 knockout (KO) mice exhibited a CPIR following oral administration of glucose and sucrose, but not water alone. Interestingly, when behavioral attraction to the solutions was assessed, T1r3 KO mice did not exhibit preference between the sugar solutions and water, while wild type mice preferred the sugar solutions. The latter finding implies that the T1Rindependent pathway may not be involved in generating a salient taste. It is currently unknown whether this T1R-independent glucose sensing pathway exists in human taste cells. 21

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mechanism, originally hypothesized by Nissenbaum and Sclafani [123] to exist in rodents. This mechanism would be responsible for recognizing maltooligosaccharides four units in length or greater, although the upper limit is currently unknown. One report shows that the ability for rodents to display normal preferences for Polycose depends on the presence of the TRPM5 or α-gustducin signaling proteins, which are critical components in some taste receptor cell signaling [126]. Such a finding implicates the importance of the gustatory system in maintaining responsiveness to maltooligosaccharides. 5. Conclusions The psychophysical studies described herein provide evidence that humans can taste maltooligo-saccharides and potentially short chain maltopolysaccharides, independent of the sweet taste receptor, hT1R2/ hT1R3. These saccharides appear to have a taste quality different than that of sugars, and are described as “starchy”. Importantly, the oral detection of these saccharides is independent of odor and texture cues. Although smaller α-glucans themselves are not prevalent in nature, they are rapidly produced in the mouth (within seconds) during the oral digestion of starch by salivary α-amylase. An oral mechanism for detecting these saccharides would presumably function to signal the body of incoming starch, which is a major component of staple foods worldwide. Further work is required to fully understand the mechanisms underlying the detection of starch hydrolysis products. Additional information regarding the relationship between structural characteristics of oligosaccharides (e.g., branching) and their oral detectability will further provide insight regarding such mechanisms.

Fig. 6. Discriminability of glucose (DP 1), maltose (DP 2), maltotriose (DP 3), and additional maltooligosaccharide preparations (DP 3–4, 5–6, and 6–7) at 75 mM in the absence (light bars) and presence (dark bars) of the sweetness inhibitor lactisole. Subjects performed discrimination tests. The proportion correct responses (right y-axis) was used to obtain the discriminability (i.e., d’; left y-axis [127]). The dashed horizontal line indicates significant discriminability based on d’ analysis at p < .05. Graphed from Table 2 in Pullicin et al., 2017 [118].

not detected in the presence of lactisole. It was concluded from these results that the taste detection of maltooligosaccharides > 3 units in length is not mediated by hT1R2/hT1R3. The results from the two studies discussed above are supported by numerous rodent studies. Combined genetic and behavioral work has shown that the deletion of the T1R2 or T1R3 subunit in mice has only minor effects on the responses to Polycose (a maltodextrin), but severely disrupts responses to sucrose [119–121]. Electrophysiological studies have also shown that rats can differentiate between the tastes of Polycose and sucrose, as different neural responses are produced in the nucleus of the solitary tract in response to the stimuli [122]. Further, aversions conditioned to sugars or Polycose are only weakly crossgeneralized [123,124]. In terms of the specific ligands that are recognized by the T1R2/T1R3-independent mechanism, one study [121] reported that mice lacking the T1R2 and/or T1R3 component of the sweet taste receptor had severely impaired responses to not only maltose and glucose, but also to maltotriose, suggesting maltotriose may be a ligand of the mouse sweet receptor. Conversely, Polycose was still detectable to the single and double knockouts in that study [121], suggesting that, similar to our report [118], the maltooligosaccharidesensing mechanism responds to oligomers > 3 units. One possible alternative mechanism for the gustatory detection of maltooligosaccharides is the T1R-independent sugar sensing pathway. Recall, however, that the glucosensors involved in this pathway are only sensitive to glucose [125], and would thus require maltooligosaccharide stimuli to be hydrolyzed to their glucose counterparts before recognition could take place. Importantly, acarbose was used in all stimuli, which is an inhibitor of both α-amylase and α-glucosidases; as a result, detectable amounts of glucose were not likely to be produced from these stimuli. Nevertheless, if these glucosensors were responsible for conscious taste perception, we would expect to see similar responses to glucose as we would with the maltooligosaccharides, when they are discriminated against water with hT1R2/hT1R3 blocked. The results from the above mentioned two experiments, however, do not support this possibility; rather, the ability to discriminate glucose solutions from water was found to be greatly diminished in the absence of normal hT1R2/hT1R3 function (see Fig. 6, DP1). This supports the recent work suggesting the T1R-independent pathway may not lead to conscious, salient taste perception in mice [116]. Another possibility to explain the conscious perception of maltooligosaccharides is the presence of a novel taste transduction

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Term: Definition Degree of Polymerization (DP): The number of monomer units linked together. α-Glucan: A collective term for maltooligosaccharides and maltopolysaccharides. Glycemic Carbohydrates: Carbohydrates that can be digested by the human body to provide energy. Those includes most sugars as well as maltooligosaccharides and maltopolysaccharides. Malto-: Prefix indicating the carbohydrate consists of a linear α-1,4-linked glucose backbone. α-1,6 branch points connecting additional α-1,4-linked glucose residues may be present. Maltodextrin: A commercially produced starch hydrolysis product. It primarily consists of maltooligosaccharides and maltopolysaccharides. Can also contain glucose and maltose. Monomer: A molecule that can be bonded to other molecules to form a polymer. In the context of this review, a molecule refers to a monosaccharide. Oligosaccharide: Carbohydrate with a DP of 3–20. Polysaccharide: Carbohydrate with a DP of 21 or greater. Saccharide: A synonym of carbohydrate. Starch: A carbohydrate consisting of a large number of glucose units linked by α-1,4- and α-1,6 bonds. It occurs widely in plant tissues and is obtained in staple foods like potatoes, wheat, corn, rice, and cassava. Starch Hydrolysis Products: Saccharide products consisting of enzymatically or chemically hydrolyzed starch. Sugar: Carbohydrate with a DP of 1–2.

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