Available via license: CC BY 4.0
Content may be subject to copyright.
The Journal of Nutrition
Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions
The Role of D-allulose and Erythritol on the
Activity of the Gut Sweet Taste Receptor and
Gastrointestinal Satiation Hormone Release in
Humans: A Randomized, Controlled Trial
Fabienne Teysseire,1,2Valentine Bordier,1,2Aleksandra Budzinska,3,4Nathalie Weltens,3,4Jens F Rehfeld,5
Jens J Holst,6Bolette Hartmann,6Christoph Beglinger,1Lukas Van Oudenhove,3,4,7
Bettina K Wölnerhanssen,1,2and Anne Christin Meyer-Gerspach1,2
1St. Clara Research Ltd at St. Claraspital, Basel, Switzerland; 2Faculty of Medicine, University of Basel, Basel, Switzerland; 3Laboratory for
Brain-Gut Axis Studies, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism,
KU Leuven, Leuven, Belgium; 4Leuven Brain Institute, KU Leuven, Leuven, Belgium; 5Department of Clinical Biochemistry, Rigshospitalet,
University of Copenhagen, Copenhagen, Denmark; 6Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic
Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; and 7Cognitive and
Affective Neuroscience Lab, Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, USA
ABSTRACT
Background: Glucose induces the release of gastrointestinal (GI) satiation hormones, such as glucagon-like peptide 1
(GLP-1) and peptide tyrosine tyrosine (PYY), in part via the activation of the gut sweet taste receptor (T1R2/T1R3).
Objectives: The primary objective was to investigate the importance of T1R2/T1R3 for the release of cholecystokinin
(CCK), GLP-1, and PYY in response to D-allulose and erythritol by assessing the effect of the T1R2/T1R3 antagonist
lactisole on these responses and as secondary objectives to study the effect of the T1R2/T1R3 blockade on gastric
emptying, appetite-related sensations, and GI symptoms.
Methods: In this randomized, controlled, double-blind, crossover study, 18 participants (5 men) with a mean ±SD BMI
(in kg/m2)of21.9±1.7 and aged 24 ±4 y received an intragastric administration of 25 g D-allulose, 50 g erythritol, or tap
water, with or without 450 parts per million (ppm) lactisole, respectively, in 6 different sessions. 13 C-sodium acetate was
added to all solutions to determine gastric emptying. At xed time intervals, blood and breath samples were collected,
and appetite-related sensations and GI symptoms were assessed. Data were analyzed with linear mixed-model analysis.
Results: D-allulose and erythritol induced a signicant release of CCK, GLP-1, and PYY compared with tap water (all
PHolm <0.0001, dz>1). Lactisole did not affect the D-allulose– and erythritol-induced release of CCK, GLP-1, and PYY
(all PHolm >0.1). Erythritol signicantly delayed gastric emptying, increased fullness, and decreased prospective food
consumption compared with tap water (PHolm =0.0002, dz=–1.05; PHolm =0.0190, dz=0.69; and PHolm =0.0442, dz
=–0.62, respectively).
Conclusions: D-allulose and erythritol stimulate the secretion of GI satiation hormones in humans. Lactisole had no
effect on CCK, GLP-1, and PYY release, indicating that D-allulose– and erythritol-induced GI satiation hormone release
is not mediated via T1R2/T1R3 in the gut. J Nutr 2022;152:1228–1238.
Keywords: D-allulose, erythritol, gut sweet taste receptor, lactisole, gastrointestinal satiation hormones, gastric
emptying, appetite-related sensations
Introduction
The increasing prevalence of obesity and diabetes mellitus
type 2 (T2DM) and associated metabolic and cardiovascular
disorders creates serious health problems worldwide (1). Sugar
consumption has been shown to have harmful effects on
the development of these diseases (2,3). The WHO strongly
recommends to reduce free sugar intake to <10% of total
energy intake, preferably <5% (4). Partial substitution of
sugar with natural, low-caloric sweeteners such as D-allulose
and erythritol is one possible way to achieve the WHO
recommendations.
Enteroendocrine cells (EECs) form the largest endocrine
organ in the body, although they represent only 1% of the
epithelial cells in the gut (5). Scattered along the gastrointestinal
(GI) tract, they are responsible for nutrient sensing, resulting in
the release of GI satiation hormones such as cholecystokinin
C
The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition. This is an Open Access article distributed under the
terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and
reproduction in any medium, provided the original work is properly cited.
Manuscript received October 29, 2021. Initial review completed November 29, 2021. Revision accepted February 1, 2022.
First published online February 4, 2022; doi: https://doi.org/10.1093/jn/nxac026.
1228
(CCK), glucagon-like peptide 1 (GLP-1), and peptide tyrosine
tyrosine (PYY) (6). These hormones signal retardation of gastric
emptying, increases in satiety and fullness, and reduction in food
intake (7–12). In humans, glucose can induce the release of GI
satiation hormones via the activation of the sweet taste receptor
(T1R2/T1R3) located on EECs (13), whereas this is not the
case for articial sweeteners, such as sucralose, acesulfame K,
or cyclamate (14–16). Lactisole, a competitive inhibitor of the
T1R3 subunit, attenuates glucose-stimulated release of GLP-1
and PYY in humans (13,17).
D-allulose (C-3 epimer of D-fructose), also known as
D-psicose, is a natural sugar with zero calories (18)and
70% of the sweetness of sucrose. In nature, it occurs
only in small amounts, but it is industrially produced by
enzymes catalyzing the conversion of D-fructose into D-allulose
(19). Moreover, D-allulose seems to have benecial effects
regarding fat and glucose metabolism in humans (20–23).
Animal studies have indicated GLP-1 release upon D-allulose
administration (24,25). The effect of D-allulose on GI satiation
hormone release and on gastric emptying is not yet known in
humans.
Erythritol is a naturally occurring sugar-alcohol without
calories and 70% of the sweetness of sucrose, which can
be commercially produced by yeast fermentation of glucose.
Besides the preventive effect on caries (26), erythritol has a
glycemic index of zero (27). Recently, we demonstrated that
intragastric administration of erythritol induced the release of
CCK, GLP-1, and PYY similar to glucose in healthy participants.
Furthermore, erythritol leads to a signicant retardation of
gastric emptying (28,29). Whether D-allulose induces the
release of GI satiation hormones and, if yes, whether their
secretion is mediated via T1R2/T1R3 has not been studied
in humans. Also, whether the erythritol-induced GI satiation
hormone secretion is mediated via the gut sweet taste receptor
is not yet known.
The primary objective of this study was therefore to inves-
tigate the importance of T1R2/T1R3 for the release of CCK,
GLP-1, and PYY in response to intragastric administration of
D-allulose and erythritol in healthy humans by assessing the
effect of lactisole on these responses. The secondary objectives
aimed to study the effect of the T1R2/T1R3 blockade on gastric
emptying, appetite-related sensations, and GI symptoms. More
specically, we hypothesize that CCK, GLP-1, and PYY will
be released in response to D-allulose and erythritol compared
with tap water. We also hypothesize that GLP-1 and PYY but
not CCK release will be reduced by lactisole. Gastric emptying
rates will be reduced in response to D-allulose and erythritol
compared with tap water, without an effect of lactisole.
Satiety/fullness and hunger/prospective food consumption will
be increased and reduced, respectively, in response to D-allulose
and erythritol compared with tap water, without an effect of
lactisole.
Supported by the Swiss National Science Foundation and the Research
Foundation Flanders (grant 320030E_189329) to ACM-G, BKW, and LVO.
Author disclosures: The authors report no conicts of interest.
BKW and ACM contributed equally to this work.
Address correspondence to ACM-G (e-mail: annechristin.meyergerspach@
unibas.ch).
Abbreviations used: CCK, cholecystokinin; EEC, enteroendocrine cell; GI,
gastrointestinal; GLP-1, glucagon-like peptide 1; ppm, parts per million; PYY,
peptide tyrosine tyrosine; SGLT-1, sodium-glucose transporter 1; T2DM, type
2 diabetes mellitus; VAS, visual analog scale.
Methods
Participants
A total of 18 normal-weight, healthy participants (5 men and
13 women) with a mean ±SD BMI (in kg/m2)of21.9±1.7 (range:
19.1–24.3) and aged 24 ±4 y (range: 19–39 y) completed the study.
See participant owchart in Figure 1.
Overall study design
The study was conducted as a randomized (counterbalanced), placebo-
controlled, double-blind, crossover trial. The protocol was approved by
the Ethics Committee of Basel, Switzerland (Ethikkomission Nordwest-
und Zentralschweiz: 2019–01,111) and conducted in accordance with
the principles of the Declaration of Helsinki (version October 2013),
the International Conference on Harmonisation for Good Clinical
Practice (ICH-GCP), and national legal and regulatory requirements.
Recruitment of participants and follow-up took place over a period
of 12 mo (September 2019 to September 2020). Each participant
gave written informed consent for the study. The study was registered
at clinicaltrials.gov as NCT04027283. Exclusion criteria included
substance and alcohol abuse, acute infections, chronic medical illness,
or illnesses affecting the GI system. None of the participants had a
history of food allergies, dietary restrictions, or preexisting consumption
of D-allulose and/or erythritol more than once a week. Weight,
height, BMI, heart rate, and blood pressure were recorded for all
participants. On 6 separate test sessions, at least 3 d apart and after
a 10-h overnight fast, participants were admitted to the St. Clara
Research Ltd at ∼08:30 h. An antecubital catheter was inserted
into a forearm vein for blood collection. Participants swallowed a
polyvinyl feeding tube (external diameter 8 French). The tube was
introduced via an anesthetized nostril. The rationale for intragastric
administration of the test solutions was to bypass orosensory cues
to provide information on the isolated postoral effects, which is
crucial to increase the understanding of the role of the GI tract in
the short-term control of appetite without confounding effects of
cephalic and oral phases of ingestion, triggering hedonic responses and
cognitions.
Experimental procedure
After taking blood samples (t =–10 and –1 min) and breath samples (t
=–10 min) in the fasting state, as well as recording of appetite-related
sensations and GI symptoms, participants received one of the following
test solutions (at t =0 min) directly into the stomach over 2 min in a
randomized order:
• 50 g erythritol dissolved in 300 mL tap water
• 50 g erythritol and 450 parts per million (ppm) lactisole dissolved in
300 mL tap water
• 25 g D-allulose dissolved in 300 mL tap water
• 25 g D-allulose and 450 ppm lactisole dissolved in 300 mL tap
water
• 300 mL tap water (placebo)
• 300 mL tap water and 450 ppm lactisole (placebo)
Concentrations were chosen based on the following considerations:
50 g erythritol induces GI satiation hormone release reliably without GI
side effects and corresponds to ∼33.5 g sucrose typically found in sweet
beverages (28). The effect of D-allulose on GI satiation hormones has
not been investigated so far. The recommended maximal single dose—
where no GI side effects are observed—is 25 g (30). In a previous
study design, 450 ppm lactisole reliably induces a blockade of the
gut sweet taste receptor (13). The effectiveness of lactisole has been
tested before in a pretest oral taste experiment. Lactisole was able
to block the D-allulose– and erythritol-induced sweet taste on the
tongue. The results are in line with previous observations of other
sweeteners (31). To determine gastric emptying rates, 50 mg 13 C-
sodium acetate was added to the different test solutions. The intragastric
test solutions were freshly prepared each morning of the study and
were at room temperature when administered. The participants and
the personnel involved in performing the study days and blood
The role of D-allulose and erythritol on T1R2/T1R3 1229
(n = 26)
(n = 5)
(n = 3)
(n = 2)
(n = 21)
(n = 21)
(n = 21)
(n = 0)
(n = 0)
(n = 3)
(n = 1)
(n = 2)
(n = 18)
(n = 0)
FIGURE 1 CONSORT ow diagram.
analysis were blinded regarding the content of administered test
solutions.
After the administration of the test solution, blood samples (at
t=15, 30, 45, 60, 90, 120, and 180 min), for analysis of plasma CCK,
GLP-1, and PYY, and end-expiratory breath samples (at t =15, 30, 45,
60, 75, 90, 105, 120, 150, 180, 210, and 240 min), for analysis of gastric
emptying rates, were taken.
Appetite-related sensations (hunger, prospective food consumption,
satiety, and fullness) were assessed at t =15, 30, 45, 60, 90, 120, and
180 min using visual analog scales (VASs) as previously described (32,
33). The ratings were recorded to 1 decimal point (e.g., 2.1).
Participants were also asked to rate GI symptoms [no symptoms (0
points), mild (1 point), or severe symptoms (2 points)] at t =30, 60, 90,
120, 150, 180, and 240 min after the administration of the test solutions.
The list included the following symptoms: abdominal pain, nausea,
vomiting, diarrhea, borborygmus, abdominal bloating, eructation, and
atulence.
Vital signs (blood pressure, heart rate) were measured at the
beginning and at the end of each study day.
Materials
Erythritol was purchased from Mithana GmbH and 13C-sodium acetate
from ReseaChem. D-allulose was purchased from Tate&Lyle. Lactisole
was a friendly gift of Domino Sugar Corporation.
Blood sample collection and processing
CCK, GLP-1, and PYY blood samples were collected on ice into
tubes containing EDTA (6 μmol/L blood), a protease inhibitor
cocktail (Complete, EDTA free, 1 tablet/50 mL blood; Roche), and a
dipeptidyl peptidase IV inhibitor (10 μL/mL blood; Millipore). After
centrifugation (4◦C at 1409 ×gfor 10 min), plasma samples were
immediately processed into different aliquots and stored at –80◦C until
analysis.
Assessment of gastric emptying
The gastric emptying rate was determined using a 13C-sodium
acetate test, an accurate, noninvasive method for measuring gastric
emptying, without radiation exposure, and a reliable alternative to
scintigraphy, the current “gold standard” (34). Test solutions were
enriched with 50 mg 13C-sodium acetate, a compound readily absorbed
in the proximal small intestine and transported to the liver, where
it is metabolized to 13CO2, which is then exhaled rapidly (34). At
t=–10, 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, and
240 min, end-expiratory breath samples were taken into a 100-mL
foil bag. The 13 C-exhalation was determined by nondispersive infrared
spectroscopy using an isotope ratio mass spectrophotometer (Kibion
Dynamic Pro; Kibion GmbH) and expressed as the relative difference
(δ‰) from the universal reference standard (carbon from Pee Dee
Belemnite limestone). 13 C-enrichment was dened as the difference
between preprandial 13C-exhalation and postprandial 13 C-exhalation
at dened time points, δover basal (‰). Delta values were converted
1230 Teysseire et al.
into atom percent excess and then into percentage of administered dose
of 13C excreted per hour [% dose/h (%)].
Laboratory analysis
Plasma CCK was measured with a sensitive radioimmunoassay using a
highly specic antiserum (No. 92,128) (35). The intra- and interassay
variability is <15%, respectively. The appropriate range of this assay
is 0.1 to 20 pmol/L. Plasma GLP-1 samples were extracted in a nal
concentration of 70% ethanol before GLP-1 analysis. Total GLP-1 was
measured as described by Ørskov et al. (36) using a radioimmunoassay
(antibody code No. 89,390) specic for the C-terminal part of the GLP-1
molecule and reacting equally with intact GLP-1 and the primary (N-
terminally truncated) metabolite. The intra-assay variability is <10%,
and the sensitivity of this assay is <1 pmol/L. Plasma PYY was
measured using Millipore human total PYY ELISA (cat.EZHPYYT66K;
Millipore). The intra- and interassay variability is <5.78% and 16.5%,
respectively.The dynamic range of this assay is 14 pg/mL to 1800 pg/mL
when using a 20-μL sample size.
Statistical analysis
In previous data on GI satiation hormone responses to intragastric
infusion of 50 g erythritol compared with tap water (29), the smallest
proposed sample size (N=18) yields 100% power to detect the
hypothesized difference in the CCK, GLP-1, and PYY response between
erythritol and tap water in linear mixed-model analyses. Based on
previous data on lactisole inhibition of glucose-induced hormone
secretion (13), N=18 yields >80% power to detect the hypothesized
inhibitory effect of lactisole on GLP-1 and PYY secretion. Data were
analyzed in SAS 9.4 (SAS Institute) and shown as mean ±SEM unless
otherwise stated. A 2-tailed Pvalue ≤0.05 was considered signicant
and Cohen’s dzfor paired ttests was reported as a measure of effect size.
For all analyses, if the assumption of normally distributed residuals
was violated (based on a signicant Pvalue of the Shapiro–Wilk
test), natural logarithmic transformations of the dependent variables
were used to normalize this distribution. Analysis was performed
on transformed data. Logarithmic transformation of the dependent
variables adequately normalized the residual distribution. Visit number
was included to control for putative order effects in all models. All
outcome variables were analyzed using (generalized) linear mixed
models on changes from baseline [average of preinfusion time
point(s)]. “Test solution”(intragastric D-allulose, D-allulose +lactisole,
erythritol, erythritol +lactisole, tap water, and tap water +lactisole)
and “time” were included as within-subject independent variables in
the models (including their main effects and the interaction). All the
models were controlled for baseline values. To follow up on signicant
main or interaction effects, planned contrast analyses were performed
to test our specic hypotheses, with stepdown Bonferroni (Holm)
correction for multiple testing. To test the hypothesis that D-allulose
or erythritol induces an increase in GI satiation hormones and retards
gastric emptying compared with tap water, we compared postinfusion
GI satiation hormone concentrations and gastric emptying (change
from baseline) between tap water, on one hand, and D-allulose or
erythritol, on the other hand. To test the hypothesis that D-allulose
or erythritol increases satiety/fullness and decreases hunger/prospective
food consumption compared with tap water, respectively, we compared
postinfusion appetite-related sensations between tap water, on one
hand, and D-allulose or erythritol, on the other hand. To test
the hypothesis that addition of lactisole does (not) decrease GI
satiation hormones, retard gastric emptying, or change appetite-related
sensations in response to D-allulose or erythritol, we compared
postinfusion GI satiation hormone concentrations and gastric emptying
(change from baseline) to each of the substances with and without added
lactisole.
For the associations, the difference between the test solutions of the
signicant planned contrasts at each time point was calculated and used
as a dependent variable in the model with the same difference at each
time point for the GI satiation hormones as an independent variable in
addition to time.
Results
Twenty-one participants were recruited for the study. There
were 3 dropouts (1 participant had to withdraw due to a
knee surgery and 2 withdrew for personal reasons). Therefore,
18 participants completed the 6 treatments. Complete data from
all 18 participants were available for analysis.
GI satiation hormones
Plasma CCK, GLP-1, and PYY.
CCK, GLP-1, and PYY secretion in response to D-allulose and
erythritol is depicted in Figure 2 and Table 1 . Both D-allulose
and erythritol induced a signicant increase in GI satiation
hormones compared with tap water. Adding lactisole had no
effect on the secretion.
Planned contrast analyses showed that the increase of CCK,
GLP-1, and PYY was greater for D-allulose and erythritol
compared with tap water (comparisons of the changes from
baseline, all PHolm <0.0001, dz>1), with no signicant
difference for D-allulose +lactisole and erythritol +lactisole
compared with the test solutions without lactisole (all PHolm
>0.1). The main effect of test solution was signicant for
CCK, GLP-1, and PYY [F(5, 65) =14.08, P<0.0001; F(5,
60) =12.85, P<0.0001; and F(5, 54) =28.68, P<0.0001,
respectively], indicating a difference in GI satiation hormone
concentrations between the 6 test solutions over all time points.
Furthermore, the test solution-by-time interaction effect was
signicant for CCK, GLP-1, and PYY [F(30, 264) =7.73,
P<0.0001; F(30, 267) =1.66, P=0.0203; and F(30, 271)
=5.26, P<0.0001, respectively], indicating that the difference
between test solutions differs between time points.
Gastric emptying
Changes in gastric emptying in response to D-allulose and
erythritol are depicted in Figure 3 and Tabl e 1 . Erythritol
induced a signicant retardation of gastric emptying compared
with tap water, whereas D-allulose had no effect. Adding
lactisole did not retard gastric emptying. Planned contrast anal-
yses showed that gastric emptying was retarded for erythritol
compared with tap water but not for D-allulose compared
with tap water (comparisons of the changes from baseline,
PHolm =0.0002, dz=–1.05 and PHolm =1, respectively),
with no signicant difference for D-allulose +lactisole and
erythritol +lactisole compared with the test solutions without
lactisole (all PHolm =1). The main effect of test solution was
signicant [F(5, 39) =6.13, P=0.0003], indicating a difference
in gastric emptying between the 6 test solutions over all time
points. Furthermore, the test solution-by-time interaction effect
was signicant [F(15, 102) =10.43, P<0.0001], indicating
that the difference between test solutions differs between time
points.
Appetite-related sensations
Hunger.
Sensations of hunger in response to D-allulose and erythritol
are depicted in Figure 4AandTab l e 1 . Neither D-allulose
nor erythritol affected the sensations of hunger compared
with tap water. Adding lactisole had no effect. None of
the planned contrast analyses were signicant. The main
effect of test solution was not signicant [F(5, 57) =1.51,
P=0.2020], indicating no difference in hunger between the
6 test solutions over all time points. Furthermore, the test
solution-by-time interaction effect was signicant [F(30, 277)
=1.54, P=0.0400].
The role of D-allulose and erythritol on T1R2/T1R3 1231
0 30 60 90 120 150 180
0
2
4
6
8
Time (min)
CCK (pmol/L)
A
tap water + 450ppm lactisole
25g D-allulose + 450ppm lactisole
50g Erythritol + 450ppm lactisole
25g D-allulose
50g Erythritol
tap water
0 30 60 90 120 150 180
0
10
20
30
40
Time (min)
GLP-1 (pmol/L)
B
0 30 60 90 120 150 180
0
50
100
150
200
250
Time (min)
PYY (pg/mL)
C
FIGURE 2 (A) CCK, (B) GLP-1, and (C) PYY release after intragastric administration of solutions containing 25 g D-allulose, 25 g D-allulose +450
ppm lactisole, 50 g erythritol, 50 g erythritol +450 ppm lactisole, tap water, and tap water +450 ppm lactisole to 18 healthy adults. Data
are expressed as mean ±SEM; absolute values are reported. N=18 (5 men, 13 women). Statistical tests: linear mixed-effects modeling
followed by planned contrasts with Holm correction for multiple testing. The increase of CCK, GLP-1, and PYY was greater for D-allulose and
erythritol compared with tap water (comparisons of the changes from baseline, all PHolm <0.0001, dz>1), with no signicant difference for
D-allulose +lactisole and erythritol +lactisole compared with the test solutions without lactisole (all PHolm >0.1). CCK, cholecystokinin; GLP-1,
glucagon-like peptide-1; ppm, parts per million; PYY, peptide tyrosine tyrosine.
1232 Teysseire et al.
TAB L E 1 Estimates from linear mixed models, results from planned contrast analyses, and effect sizes in response to intragastric
administration of solutions containing 25 g D-allulose, 25 g D-allulose +450 ppm lactisole, 50 g erythritol, 50 g erythritol +450
ppm lactisole, tap water, and tap water +450 ppm lactisole to 18 healthy adults1
Test solutions Pvalues
Characteristic
D-allulose
vs. tap
water
D-allulose vs.
D-allulose +
lactisole
Erythritol
vs. tap
water
Erythritol vs.
erythritol +
lactisole
Main
effect of
test solution
Tes t
solution-by-time
interaction
CCK, pmol/L 0.77 ±0.12 –0.29 ±0.16 1.58 ±0.19 0.03 ±0.23 <0.0001 <0.0001
PHolm <0.0001 0.1703 <0.0001 0.8800
dz1.48 1.94
GLP-1, pmol/L 4.08 ±0.76 0.55 ±1.09 7.41 ±0.96 2.40 ±1.34 <0.0001 0.0203
PHolm <0.0001 0.6136 <0.0001 0.1594
dz1.27 1.83
PYY, pg/mL 64.4 ±6.15 9.48 ±6.35 104 ±9.21 13.5 ±8.68 <0.0001 <0.0001
PHolm <0.0001 0.2502 <0.0001 0.2502
dz2.47 2.67
Gastric emptying, dose/h(%13C) 0.10 ±0.16 –0.22 ±0.28 –0.37 ±0.08 0.08 ±0.17 0.0003 <0.0001
PHolm 1 1 0.0002 1
dz–1.05
Hunger, cm –0.14 ±0.24 0.56 ±0.31 –0.49 ±0.25 0.16 ±0.28 0.2020 0.0400
PHolm 0.2283 1 0.2283 1
Pfc, cm 0.06 ±0.21 0.39 ±0.32 –0.61 ±0.24 –0.08 ±0.27 0.0615 0.1784
PHolm 0.6811 1 0.0442 1
dz–0.62
Satiety, cm –0.23 ±0.26 0.18 ±0.27 0.47 ±0.29 0.41 ±0.36 0.1206 0.1521
PHolm 0.7695 0.7695 0.4533 0.7695
Fullness, cm –0.18 ±0.22 0.16 ±0.33 0.71 ±0.24 0.62 ±0.33 0.0011 0.3473
PHolm 0.8714 0.8714 0.0190 0.2071
dz0.69
1N=18 (5 men, 13 women). Estimates are expressed as mean ±SE and represent the changes from baseline for D-allulose and erythritol compared with tap water and the
changes from baseline for lactisole within D-allulose and erythritol. Statistical tests: linear mixed-effects modeling followed by planned contrasts with Holm correction for
multiple testing and Cohen’s dzfor pa ired ttests is reported as a measure of effect size. CCK, cholecystokinin; GLP-1, glucagon-like peptide 1; Pfc, prospective food
consumption; ppm, parts per million; PYY, peptide tyrosine tyrosine.
Prospective food consumption.
Sensations of prospective food consumption in response to
D-allulose and erythritol are depicted in Figure 4Band
Tabl e 1 . Erythritol decreased the sensations of prospective
food consumption compared with tap water, whereas D-
allulose had no effect. Adding lactisole had no effect. Planned
contrast analyses showed that prospective food consumption
was lower for erythritol compared with tap water but not
0 30 60 90 120 150 180 210 240
0
5
10
15
20
Time (min)
Dose/h (%13C)
25g D-allulose
25g D-allulose + 450ppm lactisole
50g Erythritol
50g Erythritol + 450ppm lactisole
tap water
tap water + 450ppm lactisole
FIGURE 3 Gastric emptying after intragastric administration of solutions containing 25 g D-allulose, 25 g D-allulose +450 ppm lactisole, 50
g erythritol, 50 g erythritol +450 ppm lactisole, tap water, and tap water +450 ppm lactisole to 18 healthy adults. Data are expressed as
mean ±SEM. Change from baseline values is reported. N=18 (5 men and 13 women). Statistical tests: linear mixed-effects modeling followed
by planned contrasts with Holm correction for multiple testing. Gastric emptying was retarded for erythritol compared with tap water but not for
D-allulose compared with tap water (comparisons of the changes from baseline, PHolm =0.0002, dz=–1.05 and PHolm =1, respectively), with
no signicant difference for D-allulose +lactisole and erythritol +lactisole compared with the test solutions without lactisole (all PHolm =1).
CCK, cholecystokinin; GLP-1, glucagon-like peptide-1; ppm, parts per million; PYY, peptide tyrosine tyrosine.
The role of D-allulose and erythritol on T1R2/T1R3 1233
0 30 60 90 120 150 180
0
2
4
6
8
Time (min)
Hunger (cm)
25g D-allulose
25g D-allulose + 450ppm lactisole
50g Erythritol
50g Erythritol + 450ppm lactisole
tap water
tap water + 450ppm lactisole
A
0 30 60 90 120 150 180
0
2
4
6
8
Time (min)
Pfc (cm)
B
0 30 60 90 120 150 180
0
2
4
6
8
Time (min)
Satiety (cm)
C
0 30 60 90 120 150 180
0
2
4
6
8
Time (min)
Fullness (cm)
D
FIGURE 4 (A) Hunger, (B) Pfc, (C) satiety, and (D) fullness after
intragastric administration of solutions containing 25 g D-allulose,
25 g D-allulose +450 ppm lactisole, 50 g erythritol, 50 g erythri-
tol +450 ppm lactisole, tap water, and tap water +450 ppm lactisole
to 18 healthy adults. Data are expressed as mean ±SEM; absolute
values are reported. N=18 (5 men and 13 women). Statistical
tests: linear mixed-effects modeling followed by planned contrasts
with Holm correction for multiple testing. Pfc was lower for erythritol
compared with tap water but not for D-allulose compared with tap
water (comparisons of the changes from baseline, PHolm =0.0442,
dz=–0.60 and PHolm =0.6811, respectively), with no signicant
difference for D-allulose +lactisole and er ythritol +lactisole compared
with the test solutions without lactisole (both PHolm =1). Fullness
was greater for erythritol compared with tap water but not for
D-allulose compared with tap water (comparisons of the changes
from baseline, PHolm =0.0190, dz=0.69 and PHolm =0.8714,
respectively), with no signicant difference for D-allulose +lactisole,
and erythritol +lactisole compared with the test solutions without
lactisole (PHolm =0.9814 and PHolm =0.2071, respectively). No
signicant results for hunger and satiety. Pfc, prospective food
consumption; ppm, parts per million.
for D-allulose compared with tap water (comparisons of the
changes from baseline, PHolm =0.0442, dz=–0.62 and
PHolm =0.6811, respectively), with no signicant difference for
D-allulose +lactisole and erythritol +lactisole compared with
the test solutions without lactisole (both PHolm =1). Neither the
main effect of test solution [F(5, 61) =2.24, P=0.0615] nor
the test solution-by-time interaction effect [F(30, 278) =1.25,
P=0.1784] was signicant.
Satiety.
Sensations of satiety in response to D-allulose and erythritol
are depicted in Figure 4CandTable 1 . Neither D-allulose nor
erythritol affected the sensations of satiety compared with tap
water. Adding lactisole had no effect. None of the planned
contrast analyses were signicant.
Neither the main effect of test solution [F(5, 51) =1.84,
P=0.1206] nor the test solution-by-time interaction effect
[F(30, 283) =1.29, P=0.1521] was signicant.
Fullness.
Sensations of fullness in response to D-allulose and erythritol
are depicted in Figure 4DandTabl e 1 . Erythritol increased
the sensations of fullness compared with tap water, whereas D-
allulose had no effect. Adding lactisole had no effect. Planned
contrast analyses showed that fullness was greater for erythritol
compared with tap water but not for D-allulose compared
with tap water (comparisons of the changes from baseline,
PHolm =0.0190, dz=0.69 and PHolm =0.8714, respectively),
with no signicant difference for D-allulose +lactisole and
erythritol +lactisole compared with the test solutions without
lactisole (PHolm =0.9814 and PHolm =0.2071, respectively). The
main effect of test solution was signicant [F(5, 55) =4.76,
P=0.0011], indicating a difference in fullness between the 6 test
solutions over all time points. Furthermore, the test solution-by-
time interaction effect was not signicant [F(30, 280) =1.09,
P=0.3473].
Associations between GI satiation hormones and
gastric emptying
The difference in GLP-1 concentrations between erythritol
and tap water was signicantly associated with the respective
difference in gastric emptying [β±SE: 0.05 ±0.02; F(1, 101)
=7.33, P=0.0080 dz=0.64]. The differences in CCK and
PYY concentrations between erythritol and tap water were not
associated with the respective difference in gastric emptying
[0.04 ±0.06, F(1, 101) =0.4, P=0.5301 and 0.001 ±0.003,
F(1, 101) =0.59, P=0.4449, respectively].
Associations between GI satiation hormones and
appetite-related sensations
The difference in GLP-1 concentrations between erythritol
and tap water was signicantly associated with the respective
difference in prospective food consumption [–0.06 ±0.02,
F(1, 101) =5.60, P=0.0199, dz=–0.64]. The differences
in CCK and PYY concentrations between erythritol and tap
water were not associated with the respective difference in
prospective food consumption [–0.06 ±0.07, F(1, 101) =
0.88, P=0.3501 and 0.00002 ±0.004, F(1, 101) =0.00,
P=0.9956, respectively]. The differences in CCK, GLP-1, and
PYY concentrations between erythritol and tap water were not
associated with the respective difference in fullness [0.07 ±0.06,
F(1, 101) =1.08, P=0.3009; 0.008 ±0.02, F(1, 101) =0.11,
P=0.7458; and 0.003 ±0.004, F(1, 101) =0.85, P=0.3597,
respectively].
1234 Teysseire et al.
Gastrointestinal symptoms
All participants tolerated the study well. None of the par-
ticipants had to withdraw from the study due to GI-related
symptoms. The symptoms were mild and short-lasting. Details
are listed in Table 2 .
Discussion
The results of the current study can be summarized as follows:
D-allulose and erythritol induced a statistically signicant
release of CCK, GLP-1, and PYY compared with tap water.
Lactisole did not affect the D-allulose– and erythritol-induced
release of CCK, GLP-1, and PYY. Erythritol led to a statistically
signicant retardation of gastric emptying, an increase in
fullness, and a decrease in prospective food consumption
compared with tap water. Doses of 25 g of D-allulose and 50 g
of erythritol were well tolerated.
The increase in obesity and T2DM is related to sugar
consumption, especially in the form of sugar-sweetened bev-
erages (2,3). WHO and other national health institutions
have formulated guidelines encouraging consumers to limit
their sugar intake (37,38). A possible way to achieve such
reductions in sugar consumption is substitution of sugar
with natural, low-caloric sweeteners such as D-allulose and
erythritol. Both D-allulose and erythritol may have benecial
effects on glucose metabolism; in addition, both have been
shown to stimulate the release of GI satiation hormones (24,
25,28,29). Of particular interest are CCK, GLP-1, and PYY,
which induce a retardation of gastric emptying, an increase
in satiety and fullness, and a reduction in food intake (7–
12).
In humans, glucose can induce the release of CCK, GLP-
1, and PYY (13), whereas this is not the case for articial
sweeteners, such as sucralose, acesulfame K, or cyclamate (14–
16). Here we have shown that intragastric administration
of the naturally occurring, low-caloric sweetener D-allulose
induces the release of CCK, GLP-1, and PYY in healthy
humans, translating rodent studies to humans (24,25). The
previously demonstrated effect of erythritol on the secretion
of CCK, GLP-1, and PYY was conrmed in the present study:
intragastric administration of 75 g erythritol solution stimulated
the secretion of CCK and GLP-1 in healthy participants (28).
The ndings are in line with the results of Overduin et al.
(39), in which the partial replacement of sucrose by erythritol
in a test breakfast lead to equal secretion of GLP-1 and
PYY.
In humans, glucose has been reported to induce release
of GI satiation hormones in part via the activation of
T1R2/T1R3; lactisole, a competitive inhibitor of the T1R3
subunit, attenuated the glucose-stimulated release of GLP-1 and
PYY, whereas CCK release was unaffected (13). The inhibitory
effect of lactisole is specic to humans and other primates
(17). We therefore hypothesized that GLP-1 and PYY but not
CCK release would be reduced by lactisole in response to D-
allulose and erythritol. However, lactisole had no effect on
the D-allulose– and erythritol-induced GI satiation hormone
release in the current study. The knowledge about the T1R3
blockade in this study is based on the observations made by
Schiffman et al. (31) for the sweet taste receptor on the tongue.
The sweet intensity of different sweeteners (including sucrose
and glucose) was signicantly blocked at concentrations of
250 and 500 ppm lactisole. The inhibition was observed only
TAB L E 2 Assessment of gastrointestinal symptoms after
intragastric administration of solutions containing
25 g D-allulose, 25 g D-allulose +450 ppm lactisole, 50
g erythritol, 50 g erythritol +450 ppm lactisole, tap water, and
tap water +450 ppm lactisole to 18 healthy adults1
Symptom
Participants with
symptom, n2
Reported
severity3
Abdominal pain
D-allulose 3 1.0
D-allulose +lactisole 4 1.0
Erythritol 6 1.0
Erythritol +lactisole 7 1.0
Tap water 2 1.0
Tap water +lactisole 3 1.0
Nausea
D-allulose 3 1.0
D-allulose +lactisole 3 1.0
Erythritol 9 1.0
Erythritol +lactisole 10 1.1
Tap water 1 1.0
Tap water +lactisole 3 1.3
Vomiting
D-allulose 0 0
D-allulose +lactisole 0 0
Erythritol 2 1.5
Erythritol +lactisole 0 0
Tap water 0 0
Tap water +lactisole 0 0
Diarrhea
D-allulose 2 1.0
D-allulose +lactisole 0 0.0
Erythritol 5 1.0
Erythritol +lactisole 3 1.3
Tap water 0 0
Tap water +lactisole 0 0
Bowel sounds
D-allulose 11 1.1
D-allulose +lactisole 13 1.1
Erythritol 14 1.0
Erythritol +lactisole 14 1.1
Tap water 11 1.0
Tap water +lactisole 8 1.0
Bloating
D-allulose 3 1.0
D-allulose +lactisole 3 1.0
Erythritol 5 1.0
Erythritol +lactisole 4 1.0
Tap water 2 1.0
Tap water +lactisole 0 1.0
Eructation
D-allulose 4 1.0
D-allulose +lactisole 4 1.0
Erythritol 4 1.0
Erythritol +lactisole 7 1.3
Tap water 2 1.0
Tap water +lactisole 3 1.0
Flatulence
D-allulose 3 1.0
D-allulose +lactisole 2 1.0
Erythritol 5 1.0
Erythritol +lactisole 3 1.0
(Continued)
The role of D-allulose and erythritol on T1R2/T1R3 1235
TAB L E 2 (Continued)
Symptom
Participants with
symptom, n2
Reported
severity3
Tap water 0 0
Tap water +lactisole 0 0
1N=18 (5 men, 13 women). ppm, parts per million.
2Gastrointestinal symptoms were assessed by the use of a list. Participants were
asked to choose between “no symptom” (0 points), “mild symptoms” (1 point), and
“severe symptoms” (2 points) for each item.
3Reported severity was calculated by the sum of the points divided by the
participants with symptom.
when sweeteners and lactisole were mixed prior to tasting and
not when lactisole was introduced prior to these respective
substances (31). Therefore, a lack of effect based on mixing the
sweeteners with lactisole prior to the intragastric administration
can be excluded. Moreover, the use of 450 ppm lactisole is based
on previous intragastric studies in which glucose-stimulated
secretion of GLP-1 and PYY was signicantly reduced (13,
40). In both studies, glucose and lactisole were mixed prior
to the intragastric administration. Apart from these studies
with lactisole, Karimian Azari et al. (41) used a comparable
study design to evaluate the metabolic effects with lactisole in
response to an oral glucose load in healthy lean participants
with a comparable outcome. Another potential factor that could
have interfered with the effectiveness of lactisole inhibition
is the relative absorption rates of the test solutions used. D-
allulose and erythritol are absorbed with ∼80% and 90%
efciency, respectively, whereas lactisole is rapidly absorbed
(42–44). Based on this, lactisole could have effectively blocked
the natural sweeteners at the proximal intestine but not at
the distal intestine, which may have contributed to the lack
of inhibition. However, the distribution and density of GLP-
1 cells, although largely distributed in the terminal ileum, is
also present in the duodenum (45). Therefore, lactisole should
have effectively blocked the sweeteners at the proximal GLP-1
secreting cells, which was not the case.
The lack of effect of lactisole suggests that D-allulose and
erythritol induce the release of GI satiation hormones via other
receptor/transporter mechanisms. There is evidence suggesting
that sodium-dependent glucose cotransporter 1 (SGLT-1) is
the main driver of glucose-induced GLP-1 secretion (46). The
pharmacologic SGLT-1 inhibitor phlorizin or the comparison
between wild-type and Sglt1–/– mice reduced glucose-induced
GLP-1 release (47–49). However, mice lacking SGLT-1 have
an increase in the later phase of GLP-1 secretion after glucose
administration alone, suggesting that in the absence of SGLT-
1, other pathways are active (50). One hypothesis is that the
increased delivery of glucose into the distal intestine possibly
involves its fermentation into short-chain fatty acids, which
in turn may trigger GLP-1 release (50). Although up to
20% of erythritol is unabsorbed and available for colonic
fermentation (42), it is unlikely that this might be a reason
for the erythritol-induced GLP-1 release because we have an
increase in GLP-1 after 30 min in this study. Furthermore,
phlorizin did not reduce D-allulose–induced GLP-1 release in
rats, which also contradicts the hypothesis that SGLT-1 plays
a role in the GI satiation hormone release (25). In the same
study, the authors also used xanthohumol—an inhibitor of the
glucose/fructose transporter 5 (GLUT5)—which inhibited D-
allulose–induced GLP-1 secretion, suggesting that the secretion
might be stimulated via GLUT5. The authors explain this by
the fact that D-allulose and fructose are epimers and that a
possible mechanism for GLP-1 secretion via GLUT5 has been
suggested for fructose (46,51). Data in humans are lacking
so far.
Gastric emptying is regulated by several feedback mecha-
nisms, including GI satiation hormone release such as CCK,
GLP-1, and PYY (7,52). Here erythritol retarded gastric
emptying, conrming our previous ndings (28,29). Lactisole
had no effect on the erythritol-induced retardation of gastric
emptying. The latter ndings extend our previous results:
Gerspach et al. (13) showed that the retardation of gastric
emptying was not affected by lactisole after glucose or after
mixed liquid meal administration. We had anticipated that D-
allulose would retard gastric emptying—especially in view of
the observed effect on the GI satiation hormones—but we were
unable to conrm our hypothesis.
Both increased concentrations of GI satiation hormones
and prolonged gastric emptying are associated with feelings
of fullness and satiation (53,54). In this trial, erythritol
induced an increase in fullness and a decrease in prospective
food consumption. The ndings are most likely related to the
observed release of GI satiation hormones and the retardation
of gastric emptying. In contrast to erythritol, D-allulose did not
affect appetite-related sensations despite the marked increase
in GI satiation hormones. As discussed above, changes in
gastric emptying play an important role in the regulation
of hunger and satiety feelings. The missing effect on gastric
emptying observed in response to D-allulose is in line with this
observation.
The mild and short-lasting symptoms of the present study
for D-allulose are in line with a previous GI tolerance study
(30). There was a slight increase in symptoms after the
erythritol-containing solutions compared with our most recent
study (29). However, participants familiarized to erythritol
intake show a higher GI tolerance (55). The participants in
this trial were not used to these substances, and the test
solutions were rapidly applied (over 2 min) immediately into
the stomach, which probably causes the greatest stress for the
GI tract.
Some limitations of our study require consideration: rst,
we studied acute effects of single-bolus doses of D-allulose and
erythritol with and without lactisole applied in a liquid solution
to participants with a BMI between 19.0 and 24.9 who were
not used to these substances. Differential effects of long-term
exposure on the secretion of GI satiation hormones and gastric
emptying rates need to be investigated, as adaptive processes
cannot be ruled out. Second, we measured total GLP-1, which
may imply less sensitivity toward detecting a small size effect
for the gut sweet taste receptor inhibition than active GLP-1.
Third, the substances used in this trial may behave differently
when included in a food matrix with other nutrients rather than
administered in isolation. Moreover, effects on subsequent food
intake were not measured. Fourth, appetite-related sensations
could have been affected by the presence of the feeding tube,
although in the present study, it was used for only a short period
of time and immediately removed after the administration of the
test solutions.
In conclusion, D-allulose and erythritol stimulate the
secretion of GI satiation hormones in humans. Lactisole had
no effect on CCK, GLP-1, and PYY release, indicating that D-
allulose– and erythritol-induced GI satiation hormone release is
not mediated via the gut sweet taste receptor (T1R2/T1R3). The
mechanism remains to be determined.
1236 Teysseire et al.
Acknowledgments
We thank A. Atlass (study coordinator) and R. Nadermann, S.
Pfammatter, and M. Dean (master students).
The authors’ responsibilities were as follows—ACM-G,
BKW, LVO, NW, and CB: designed research; FT and VB:
conducted research; FT, ACM-G, JFR, JJH, BH, LVO, NW,
AB, and BKW: analyzed data; FT, ACM-G, and BKW: wrote
paper; FT, ACM-G, and BKW: had primary responsibility for
nal content; and all authors: have read and approved the nal
manuscript.
Data Availability
Data described in the manuscript and code book will be made
publicly and freely available at https://github.com/labgas/proj_e
rythritol_1.
References
1. DiNicolantonio JJ, O’Keefe JH, Lucan SC. Added fructose: a principal
driver of type 2 diabetes mellitus and its consequences. Mayo Clin Proc
2015;90(3):372–81.
2. Malik VS, Popkin BM, Bray GA, Després JP, Willett WC, Hu FB.
Sugar-sweetened beverages and risk of metabolic syndrome and type
2 diabetes: a meta-analysis. Diabetes Care 2010;33(11):2477–83.
3. Sigala DM, Hieronimus B, Medici V, Lee V, Nunez MV, Bremer
AA, Cox CL, Price CA, Benyam Y, Chaudhari AJ, et al. Consuming
sucrose- or HFCS-sweetened beverages increases hepatic lipid and
decreases insulin sensitivity in adults. J Clin Endocrinol Metab
2021;106(11):3248–64.
4. WHO. Sugars intake for adults and children: guideline. Geneva
(Switzerland): WHO; 2015.
5. Furness JB, Rivera LR, Cho HJ, Bravo DM, Callaghan B. The gut as a
sensory organ. Nat Rev Gastroenterol Hepatol 2013;10(12):729–40.
6. Lee AA, Owyang C. Sugars, sweet taste receptors, and brain responses.
Nutrients 2017;9(7):653.
7. Steinert RE, Feinle-Bisset C, Asarian L, Horowitz M, Beglinger C,
Geary N. Ghrelin, CCK, GLP-1, and PYY(3–36): secretory controls and
physiological roles in eating and glycemia in health, obesity, and after
RYGB. Physiol Rev 2017;97(1):411–63.
8. Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Ørskov C, Ritzel R,
Schmiegel WH. Glucagon-like peptide 1 inhibition of gastric emptying
outweighs its insulinotropic effects in healthy humans. Am J Physiol
1997;273(5):E981–8.
9. Deane AM, Nguyen NQ, Stevens JE, Fraser RJ, Holloway RH,
Besanko LK, Burgstad C, Jones KL, Chapman MJ, Rayner CK, et al.
Endogenous glucagon-like peptide-1 slows gastric emptying in healthy
subjects, attenuating postprandial glycemia. J Clin Endocrinol Metab
2010;95(1):215–21.
10. Savage AP, Adrian TE, Carolan G, Chatterjee VK, Bloom SR. Effects
of peptide YY (PYY) on mouth to caecum intestinal transit time and
on the rate of gastric emptying in healthy volunteers. Gut 1987;28(2):
166–70.
11. Witte AB, Grybäck P, Holst JJ, Hilsted L, Hellström PM, Jacobsson H,
Schmidt PT. Differential effect of PYY1–36 and PYY3–36 on gastric
emptying in man. Regul Pept 2009;158(1–3):57–62.
12. Muurahainen N, Kissileff HR, Derogatis AJ, Pi-Sunyer FX. Effects
of cholecystokinin-octapeptide (CCK-8) on food intake and gastric
emptying in man. Physiol Behav 1988;44(4–5):645–9.
13. Gerspach AC, Steinert RE, Schonenberger L, Graber-Maier A, Beglinger
C. The role of the gut sweet taste receptor in regulating GLP-1,
PYY, and CCK release in humans. Am J Physiol Endocrinol Metab
2011;301(2):E317–25.
14. Steinert RE, Frey F, Töpfer A, Drewe J, Beglinger C. Effects
of carbohydrate sugars and articial sweeteners on appetite
and the secretion of gastrointestinal satiety peptides. Br J Nutr
2011;105(9):1320–8.
15. Wu T, Bound MJ, Standeld SD, Bellon M, Young RL, Jones KL,
Horowitz M, Rayner CK. Articial sweeteners have no effect on gastric
emptying, glucagon-like peptide-1, or glycemia after oral glucose in
healthy humans. Diabetes Care 2013;36(12):e202–e3.
16. Ma J, Bellon M, Wishart JM, Young R, Blackshaw LA, Jones KL,
Horowitz M, Rayner CK. Effect of the articial sweetener, sucralose,
on gastric emptying and incretin hormone release in healthy subjects.
Am J Physiol Gastrointest Liver Physiol 2009;296(4):G735–9.
17. Jiang P, Cui M, Zhao B, Liu Z, Snyder LA, Benard LM, Osman R,
Margolskee RF, Max M. Lactisole interacts with the transmembrane
domains of human T1R3 to inhibit sweet taste. J Biol Chem
2005;280(15):15238–46.
18. Matsuo T, Suzuki H, Hashiguchi M, Izumori K. D-psicose is a rare sugar
that provides no energy to growing rats. J Nutr Sci Vitaminol (Tokyo)
2002;48(1):77–80.
19. Jiang S, Xiao W, Zhu X, Yang P, Zheng Z, Lu S, Jiang S, Zhang G,
Liu J. Review on D-allulose: in vivo metabolism, catalytic mechanism,
engineering strain construction, bio-production technology. Front
Bioeng Biotechnol 2020;8:26.
20. Han Y, Kwon EY, Yu MK, Lee SJ, Kim HJ, Kim SB, Kim YH, Choi
MS. A preliminary study for evaluating the dose-dependent effect of D-
allulose for fat mass reduction in adult humans: a randomized, double-
blind, placebo-controlled trial. Nutrients 2018;10(2):160.
21. Franchi F, Yaranov DM, Rollini F, Rivas A, Rivas Rios J, Been L, Tani
Y, Tokuda M, Iida T, Hayashi N, et al. Effects of D-allulose on glucose
tolerance and insulin response to a standard oral sucrose load: results
of a prospective, randomized, crossover study. BMJ Open Diabetes Res
Care 2021;9(1):e001939.
22. Iida T, Kishimoto Y, Yoshikawa Y, Hayashi N, Okuma K, Tohi M,
Yagi K,Matsuo T, Izumori K. Acute D-psicose administration decreases
the glycemic responses to an oral maltodextrin tolerance test in normal
adults. J Nutr Sci Vitaminol (Tokyo) 2008;54(6):511–4.
23. Noronha JC, Braunstein CR, Glenn AJ, Khan TA, Viguiliouk E,
Noseworthy R, Blanco Mejia S, Kendall CWC, Wolever TMS, Leiter
LA, et al. The effect of small doses of fructose and allulose on
postprandial glucose metabolism in type 2 diabetes: a double-blind,
randomized, controlled, acute feeding, equivalence trial. Diabetes Obes
Metab 2018;20(10):2361–70.
24. Iwasaki Y, Sendo M, Dezaki K, Hira T, Sato T, Nakata M, Goswami
C, Aoki R, Arai T, Kumari P, et al. GLP-1 release and vagal afferent
activation mediate the benecial metabolic and chronotherapeutic
effects of D-allulose. Nat Commun 2018;9(1):113.
25. Hayakawa M, Hira T, Nakamura M, Iida T, Kishimoto Y, Hara
H. Secretion of GLP-1 but not GIP is potently stimulated by
luminal D-allulose (D-psicose) in rats. Biochem Biophys Res Commun
2018;2:S0006–291X(18)30143-8.
26. Honkala S, Runnel R, Saag M, Olak J, Nõmmela R, Russak S,
Mäkinen PL, Vahlberg T, Falony G, Mäkinen K, et al. Effect of
erythritol and xylitol on dental caries prevention in children. Caries Res
2014;48(5):482–90.
27. Livesey G. Health potential of polyols as sugar replacers, with emphasis
on low glycaemic properties. Nutr Res Rev 2003;16(2):163–91.
28. Wölnerhanssen BK, Cajacob L, Keller N, Doody A, Rehfeld JF,
Drewe J, Peterli R, Beglinger C, Meyer-Gerspach AC. Gut hormone
secretion, gastric emptying, and glycemic responses to erythritol and
xylitol in lean and obese subjects. Am J Physiol Endocrinol Metab
2016;310(11):E1053–61.
29. Wölnerhanssen BK, Drewe J, Verbeure W, le Roux CW, Dellatorre-
Teixeira L, Rehfeld JF, Holst JJ, Hartmann B, Tack J, Peterli R,
et al. Gastric emptying of solutions containing the natural sweetener
erythritol and effects on gut hormone secretion in humans: a pilot dose-
ranging study. Diabetes Obes Metab 2021;23(6):1311–21.
30. Han Y, Choi BR, Kim SY, Kim SB, Kim YH, Kwon EY, Choi MS.
Gastrointestinal tolerance of D-allulose in healthy and young adults:
a non-randomized controlled trial. Nutrients 2018;10(12):2010.
31. Schiffman SS, Booth BJ, Sattely-Miller EA, Graham BG, Gibes
KM. Selective inhibition of sweetness by the sodium salt of
±2-(4-methoxyphenoxy)propanoic acid. Chem Senses 1999;24(4):
439–47.
32. Blundell J, de Graaf C, Hulshof T, Jebb S, Livingstone B, Lluch
A, Mela D, Salah S, Schuring E, van der Knaap H, et al. Appetite
control: methodological aspects of the evaluation of foods. Obes Rev
2010;11(3):251–70.
The role of D-allulose and erythritol on T1R2/T1R3 1237
33. Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and
validity of visual analogue scales in assessment of appetite sensations in
single test meal studies. Int J Obes 2000;24(1):38–48.
34. Ghoos YF, Maes BD, Geypens BJ, Mys G, Hiele MI, Rutgeerts PJ,
Vantrappen G. Measurement of gastric emptying rate of solids by
means of a carbon-labeled octanoic acid breath test. Gastroenterology
1993;104(6):1640–7.
35. Rehfeld JF. Accurate measurement of cholecystokinin in plasma. Clin
Chem 1998;44(5):991–1001.
36. Ørskov C, Rabenhøj L, Wettergren A, Kofod H, Holst JJ. Tissue and
plasma concentrations of amidated and glycine-extended glucagon-like
peptide I in humans. Diabetes 1994;43(4):535–9.
37. Institute of Medicine. Dietary reference intakes for energy,
carbohydrate, ber, fat, fatty acids, cholesterol, protein, and amino
acids. Washington (DC): The National Academies Press; 2005.
38. US Department of Health and Human Services and US Department
of Agriculture. 2015–2020 Dietary Guidelines for Americans
[Internet]. December 2015 [cited 2021 Aug 18]. Available from:
https://health.gov/our-work/nutrition- physical-activity/dietary-guidel
ines/previous-dietary- guidelines/2015.
39. Overduin J, Collet TH, Medic N, Henning E, Keogh JM, Forsyth F,
Stephenson C, Kanning MW, Ruijschop R, Farooqi IS, et al. Failure of
sucrose replacement with the non-nutritive sweetener erythritol to alter
GLP-1 or PYY release or test meal size in lean or obese people. Appetite
2016;107:596–603.
40. Steinert RE, Gerspach AC, Gutmann H, Asarian L, Drewe J, Beglinger
C. The functional involvement of gut-expressed sweet taste receptors
in glucose-stimulated secretion of glucagon-like peptide-1 (GLP-1) and
peptide YY (PYY). Clin Nutr 2011;30(4):524–32.
41. Karimian Azari E, Smith KR, Yi F, Osborne TF, Bizzotto R,
Mari A, Pratley RE, Kyriazis GA. Inhibition of sweet chemosensory
receptors alters insulin responses during glucose ingestion in healthy
adults: a randomized crossover interventional study. Am J Clin Nutr
2017;105(4):1001–9.
42. Bornet FR, Blayo A, Dauchy F, Slama G. Plasma and urine kinetics of
erythritol after oral ingestion by healthy humans. Regul Toxicol Pharm
1996;24(2):S280–5.
43. Kishida K, Martinez G, Iida T, Yamada T, Ferraris RP, Toyoda Y. d-
Allulose is a substrate of glucose transporter type 5 (GLUT5) in the
small intestine. Food Chem 2019;277:604–8.
44. Adams TB, Cohen SM, Doull J, Feron VJ, Goodman JI, Marnett LJ,
Munro IC, Portoghese PS, Smith RL, Waddell WJ, et al. The FEMA
GRAS assessment of phenethyl alcohol, aldehyde, acid, and related
acetals and esters used as avor ingredients. Food Chem Toxicol
2005;43(8):1179–206.
45. Wölnerhanssen BK, Moran AW, Burdyga G, Meyer-Gerspach AC,
Peterli R, Manz M, Thumshirn M, Daly K, Beglinger C, Shirazi-Beechey
SP. Deregulation of transcription factors controlling intestinal epithelial
cell differentiation; a predisposing factor for reduced enteroendocrine
cell number in morbidly obese individuals. Sci Rep 2017;7(1):8174.
46. Kuhre RE, Frost CR, Svendsen B, Holst JJ. Molecular mechanisms of
glucose-stimulated GLP-1 secretion from perfused rat small intestine.
Diabetes. 2015;64(2):370–82.
47. Gorboulev V, Schürmann A, Vallon V, Kipp H, Jaschke A, Klessen D,
Friedrich A, Scherneck S, Rieg T, Cunard R, et al. Na(+)-D-glucose
cotransporter SGLT1 is pivotal for intestinal glucose absorption and
glucose-dependent incretin secretion. Diabetes 2012;61(1):187–96.
48. Parker HE, Adriaenssens A, Rogers G, Richards P, Koepsell H,
Reimann F, Gribble FM. Predominant role of active versus facilitative
glucose transport for glucagon-like peptide-1 secretion. Diabetologia
2012;55(9):2445–55.
49. Sun EW, de Fontgalland D, Rabbitt P,Hollington P, Sposato L, Due SL,
Wattchow DA, Rayner CK, Deane AM, Young RL, et al. Mechanisms
controlling glucose-induced GLP-1 secretion in human small intestine.
Diabetes 2017;66(8):2144–9.
50. Powell DR, Smith M, Greer J, Harris A, Zhao S, DaCosta
C, Mseeh F, Shadoan MK, Sands A, Zambrowicz B, et al.
LX4211 increases serum glucagon-like peptide 1 and peptide YY
levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated
absorption of intestinal glucose. J Pharmacol Exp Ther 2013;345(2):
250–9.
51. Kuhre RE, Gribble FM, Hartmann B, Reimann F, Windeløv JA,
Rehfeld JF, Holst JJ. Fructose stimulates GLP-1 but not GIP secretion
in mice, rats, and humans. Am J Physiol Gastrointest Liver Physiol
2014;306(7):G622–30.
52. Hellström PM, Grybäck P, Jacobsson H. The physiology of
gastric emptying. Best Pract Res Clin Anaesthesiol 2006;20(3):
397–407.
53. Halawi H, Camilleri M, Acosta A, Vazquez-Roque M, Oduyebo I,
Burton D, Busciglio I, Zinsmeister AR. Relationship of gastric emptying
or accommodation with satiation, satiety, and postprandial symptoms
in health. Am J Physiol Gastrointest Liver Physiol 2017;313(5):
G442–7.
54. Z Zanchi D, Depoorter A, Egloff L, Haller S, Mählmann L, Lang UE,
Drewe J, Beglinger C, Schmidt A, Borgwardt S. The impact of gut
hormones on the neural circuit of appetite and satiety: a systematic
review. Neurosci Biobehav Rev 2017;80:457–75.
55. Tetzloff W, Dauchy F, Medimagh S, Carr D, Bär A. Tolerance to
subchronic, high-dose ingestion of erythritol in human volunteers. Regul
Toxicol Pharm 1996;24(2):S286–95.
1238 Teysseire et al.
