Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : Feb. 7, 2014
Accepted : Apr. 28, 2014
Published online : Jun. 30, 2014

Original Artcle

Maltitol endows foods with lower 3-deoxyglucosone content and less
RAGE agonism as a sweetener against sucrose
Aya Kuretani 1), Ryosuke Kawaura 1), Seiichi Munesue 2), Yasuhiko Yamamoto 2),
Junya Honda 1), Hiroshi Yamamoto 2)
1) Ueno Fine Chemicals Industry, Ltd., 2-4-8 Koraibashi, Chuo-ku, Osaka 541-8543, Japan
2) Department of Biochemistry and Molecular Vascular Biology, Graduate School of Medical Sciences, Kanazawa University,
13-1 Takara-machi, Kanazawa 920-8640, Japan

Abstract

Objective: Sweeteners have the potential to promote the production of advanced glycation endproducts (AGE), which influence
human health and aging and have been implicated in diseases such as diabetic vascular complications, Alzheimer’s disease,and cancer. Maltitol is a polyol used as a sweetener in the food industry. In this study, we evaluated the effects of maltitol on theformation of a potent glycation intermediate, 3-deoxyglucosone (3-DG), and AGE and on receptor for AGE (RAGE) signaling invarious food models.
Methods: Biscuit, muffin, pudding, bean compote, doughnut, chicken dumpling, bread, and broiled sauce were used as model
foods prepared with or without sucrose/MS-17 (a mixture of sucrose and maltitol)/maltitol. The resultant materials were assayedfor 3-DG, AGE fluorescence, N ε-(carboxymethyl) lysine (CML), pentosidine, and RAGE agonism/antagonism.
Results: Biscuit, muffin, doughnut, and bread samples treated with maltitol contained significantly less 3-DG than samples treatedwith sucrose. Although the levels of AGE fluorescence, CML, and pentosidine did not differ significantly between sucrose andmaltitol treatments in the model foods, maltitol endowed significantly less agonistic effects on RAGE signaling in the 4 model
foods with lower 3-DG content.
Conclusion: Compared with sucrose, maltitol is a functional sweetener that may exhibit more beneficial effects on human health.

KEY WORDS: Maltitol, Advanced glycation endproducts, RAGE, 3-Deoxyglucosone, Sweetener
Introduction

Protein glycation via the Maillard reaction involves multistep, spontaneous reactions initiated by the non-enzymatic
reaction between carbonyl groups of sugars and free aminogroups of proteins. This is followed by the formation of
Schiff bases and then by Amadori rearrangement to generate
reactive intermediates, which undergo irreversible reactions,
eventually yielding structurally divergent products known
collectively as advanced glycation endproducts (AGE) 1), 2 ).
A variety of intermediates and AGE have been identified,including 3-deoxyglucosone (3-DG) 3), pentosidine, and Nε(carboxymethyl) lysine (CML). Glycation alters the structure ofproteins, leading to their dysfunction. AGE accumulation in the
body has been linked to several age-related diseases. Glycatedproteins induce cytotoxicity by binding to the receptor for AGE(RAGE), and AGE-RAGE interactions have been implicated invarious pathologic conditions such as diabetes, arteriosclerosis,
osteoporosis, and Alzheimer’s disease 4). Thus, numerous

researches have been directed to controlling AGE formation
and action for health promotion, anti-aging, and overcoming
lifestyle-related disease. AGE and their intermediates are also
formed in foods during heating and are then absorbed from theintestine 5- 8).
Maltitol is a hydrogenated carbohydrate used in the
production of sugar-free or sugarless confectionery, chewing
gum, and chocolate. It is considered by manufacturers offoods to be an interesting ingredient that does not induce
high postprandial increases in blood glucose. Accordingly,
maltitol can be used as an alternative to sucrose in sugar-freeor sugarless foodstuffs. It has low-energy 9), low-glycemic10), low-insulinemic 11), and non-cariogenic 12) properties andcan be produced from maltose via catalytic hydrogenation 1316). Maltitol is only partially hydrolyzed by intestinal brushborder disaccharidase and thus is poorly absorbed through theintestinal mucosa 17 - 21); the products of its partial hydrolysis in
the intestine are glucose and sorbitol 13). In addition, maltitol
may have inhibitory effects on glycation 22) and tumorigenesis 23)

Corresponding to: Aya Kuretani, M.Agr., Ueno Fine Chemicals Industry, Ltd.,
2-4-8 Koraibashi, Chuo-ku, Osaka 541- 8543, Japan.;Tel: +81 79 568 2202; Fax: +81 79 568 2216; Email: a_kuretani@ueno-fc.co.jp
Co-authors: Kawaura R, r_kawaura@ueno-fc.co.jp, Munesue S, smunesue@med.kanazawa-u.ac.jp,
Yamamoto Y, yasuyama@med.kanazawa-u.ac.jp, Honda J, j_honda@ueno-fc.co.jp, Yamamoto H,
yamamoto@med.kanazawa-u.ac.jp_ 25 _

Glycative Stress Research 2014; 1(2): 25-31(c) Society for Glycation Stress Research

Maltitol-derived glycated foods
and a beneficial effect on cognitive function 24). The maximum
no-effect level (NOEL) is reported to be 0.3 g / kg body weightfor both males and females, and the excessive consumption of
maltitol may produce laxative effects 25).
This study evaluated the effects of maltitol on theformation of 3-DG and AGE in various model foods throughcomparison with the effects of sucrose. The effect of maltitol
on RAGE signaling was also compared in with the sucrosetreated model foods.

17 was added at the given percentage; sugar was omitted in thecontrol without sweetener. Two grams of each food model washomogenized in 20 mL of 0.5 M phosphate buffer (pH 7.4),
passed through a VIVA SPIN 20 (Sartorius Stedim Biotech
S.A., Göttingen, Germany), and divided into a higher molecularweight (MW) fraction (≥10,000) and a lower MW fraction(<10,000). The higher MW fraction underwent hydrolysis in 2
mL of 6 M HCl for 16 hours at 110°C under nitrogen gas andwas neutralized with 5 M NaOH. The neutralized solutions
were filtered through a Minisart (Sartorius) and used for AGE
determination and RAGE signaling assay. The lower MW
fraction was used for 3-DG determination.

Materials and Methods

3-DG measurement

Chemicals

3-DG concentration was determined as described
elsewhere 26). 2,3-Pentanedione was added as an internal
standard. TSK-gel ODS-80Ts (46 × 150 mm, Tosoh
Corporation, Tokyo, Japan) was used in high-performanceliquid chromatography.

Sucrose (granulated sugar) was purchased from Mitsui
Sugar Co., Ltd. (Tokyo, Japan), and maltitol (“MALTITOLPOWDER WHOLE CRYSTALLINE MALTITOL - UENO60M”) and MS-17 (“MALTITOL - BASED SUGAR
PREPARATION: MS-17”: sugar: maltitol = 83%:17%) wereobtained from Ueno Fine Chemicals Industry, Ltd. (Osaka,
Japan).

Measurement of AGE fluorescence

Aliquots of the neutralized higher MW model food
fractions were placed in the wells of a 96-well black microplateand excited at 380 nm. Emission was scanned at 400-600
nm in a Varioskan Flash microplate reader (Thermo Fisher
Scientific Inc., MA, USA). Perylene was used as the standard,in which emission from 410 to 600 nm was recorded upon
excitation at 386 nm. Relative fluorescence was calculated
according to the following formula:
Sum of sample fluorescence at 400 -600 nm / sum ofperylene fluorescence at 410-600 nm.

Food models and treatment with sucrose, maltitol, or
MS-17

Eight food models were prepared with the following
commonly used cooking methods: biscuit (180°C, 15 min),muffin (170°C, 20 min), pudding (85°C, 20 min), bean compote(85°C, 15 min), doughnut (180°C, 30 sec), chicken dumpling(100°C, 20 min), bread (150°C, 35 min), and broiled sauce(63°C, 20 min). The ingredients in these model foods areshown in Table 1. In place of sugars, sucrose, maltitol, or MS-

Table 1. Ingredients in the model foods used in this study
Ingredients (%)
Model food

Egg

Milk

Flour

Bean

Soy sauce

Sugar

Other

Biscuit

―

7.0

27.0

―

―

―

27.0

15.0

24.0

Muffin

25.0

―

25.0

―

―

―

―

25.0

25.0

Pudding

36.0

50.0

―

―

―

―

―

13.0

1.0

Bean compote

―

―

―

62.9

0.4

―

―

36.7

0.0

Doughnut

14.0

15.0

46.0

―

―

―

―

15.0

10.0

Chicken dumpling

―

―

―

―

―

83.0

―

8.0

9.0

Bread

―

1.8

49.0

―

―

―

―

10.0

39.2

Broiled sauce

―

―

―

―

―

―

―

25.0

75.0

_ 26 _

Chicken Corn starchGlycative Stress Research

CML measurement

Statistical analysis

Statistical analysis was performed using the Student’s
t test. A p value smaller than 0.05 was considered significant.

CML was measured with a CML enzyme-linked
immunosorbent assay kit (CycLex Co., Ltd., Nagano, Japan)
according to the manufacturer’s instructions.

Pentosidine measurement

Results

Pentosidine was measured with an FSK pentosidine enzymelinked immunosorbent assay kit (Fushimi PharmaceuticalCo., Ltd., Kagawa, Japan) according to the manufacturer’s
instructions.

Maltitol lowers 3-DG contents in biscuit, muffin,
doughnut, and bread.

Eight model foods were prepared with sucrose or maltitol
and assayed for 3-DG. As shown in Fig. 1, biscuit, muffin,
doughnut, and bread prepared with maltitol had 3-DG contents
significantly lower than that of their counterparts preparedwith sucrose. In bread, the 3-DG lowering effect of MS-17, a
mixture of sucrose and maltitol, was between that of sucrose
and maltitol. No significant difference was found between
sucrose and maltitol in pudding, bean compote, or broiledsauce. 3-DG was not detected in chicken dumpling.

Luciferase reporter assay

Rat C6 glioma cells that had been stably transformed
with an expression plasmid containing full-length human
RAGE complementary DNA and a firefly luciferase reporter
gene under the control of the nuclear factor κB ( N F κB )promoter 27) were used. After a 24 -hour preincubation in
Dulbecco’s modified Eagle’s medium supplemented with
0.1% fetal bovine serum, the cells were stimulated with thealiquots of the higher MW model food fractions in the presenceor absence of glyceraldehyde-derived AGE-bovine serum
albumin (BSA) (glycer-AGEs) for 4 hours. Luciferase activity
was determined with a Luciferase Assay System (Promega Co.,
WI, USA) and measured in a luminometer (Fluoroskan Ascent
FL; Labotal Scientific Equipment Ltd., Abu Gosh, Israel).

＊＊
＊＊
＊＊

131 ± 8.0

31 ± 2.7

＊＊
＊＊

7.0
6.0
＊＊

3 -DG (nmol/ml)

5.0

＊＊

＊＊

＊＊

＊＊

4.0
3.0
2.0
1.0

BiscuitFig.1.

MuﬃnPudding

BeancompoteDoughnut

Chickendumpling

ー

17

itol
Malt

MS -

ー

ose
Sucr

itol

17

ー

se

Bread

Malt

MS -

Sucr
o

se

itol
Malt

ー

Sucr
o

se

itol
Malt

ー

Sucr
o

se

itol
Malt

ー

Sucr
o

itol
Malt

ー

ose
Sucr

itol

ー

ose

Malt

Sucr

itol
Malt

Sucr
o

se

0.0

Broiled Sauce

3-Deoxyglucosone (3-DG) levels in model foods treated with or without (-) sucrose/maltitol. The conditions of the treatments are described in the
Materials and Methods. Values are expressed as means ± standard error. The values of broiled sauce treated with sucrose, MS-17, and maltitol are related
to the value without sweetener, which is equivalent to 281 (nmol/g). -, treated without sweetener. **p < 0.01 (vs. the sucrose-treated food) (n = 3-9).

_ 27 _

Maltitol-derived glycated foods
activity that was approximately 3-fold that of control BSA.
Samples with higher luciferase activity than that of the BSA
control were considered agonistic, whereas in the coexistenceof glycer-AGEs, those that showed lower luciferase activity
compared with that of glycer-AGEs alone were consideredantagonistic. Biscuit (see Fig. 2A), muffin (see Fig. 2B ),pudding (see Fig. 2C ), bean compote (see Fig. 2D), doughnut(see Fig. 2E ), and bread (see Fig. 2G ) showed statisticallysignificant increases in luciferase activity compared with thatin the BSA control. Statistically significant increases werealso found in the coexistence of glycer-AGEs in these foods
compared with the value with glycer-AGEs alone, indicatingthat they had agonistic effects on RAGE signaling. Broiledsauce (see Fig. 2H ) had an agonistic effect when added alone
but not when coexisting with AGE. Sucrose- and maltitoltreated chicken dumpling (see Fig. 2F ) caused no significant
changes in the presence or the absence of AGE.
Maltitol had less agonistic effects than those of sucrose
in biscuit, muffin, and doughnut in the presence of AGE (seeFig. 2 A, B, and E ) and in bread with or without AGE (see Fig.
2G ). These 4 model foods were those that had lower 3-DG
content when prepared with maltitol. None of the 8 food models
exhibited cell toxicity at the doses tested (data not shown).

Evaluation of AGE formation in model foods

To know whether maltitol affected AGE formation
during food preparation, we examined the levels of AGE
fluorescence, CML, and pentosidine in the model foods.
As shown in Table 2, these values were essentially invariant
between sucrose- and maltitol-treated biscuit, muffin, pudding,bean compote, doughnut, and chicken dumpling, and among
sucrose-, maltitol- and MS-17-treated bread and broiled sauce.

Maltitol had a less agonistic effect on RAGE signaling
compared with that of sucrose.

We next examined whether sucrose and maltitol treatments
of model foods affected RAGE signaling using a reporter
system in which the firefly luciferase gene was placed
under the control of a N F κB promoter in C6 glioma cells.
Reporter activation in this system is dependent on ligandRAGE interaction, as evidenced by (1) induction by AGE, (2)inhibition by small interfering RNA against RAGE messenger
RNA, (3) inhibition by transfection of dominant-negative
RAGE, and (4) neutralization by soluble RAGE 27).
As shown in Fig. 2 A-H, glycer-AGEs induced luciferase

Table 2. Levels of advanced glycation endproducts (AGE) fluorescence, Nε-(carboxymethyl lysine (CML),
and pentosidine
Model food
Food

Sweetener

Biscuit

MaltitolMuffinSucrose

39

±

―

33

±

36

±

70

±

SucroseMaltitol―Pudding

SucroseMaltitol―

Bean compote

SucroseMaltitol―

Doughnut

SucroseMaltitol―

Chicken dumpling

SucroseMaltitol―

Sucrose
Bread

MS-17

Maltitol―

Broiled sauce

AGE fluorescence(nmol /g)
32

±

37

±

30

±

81

±

45

±

52

±

23

±

27

±

27

±

30

±

27

±

104* ±
65

±

23

±

30* ±
26

±

32

±

35

±

Sucrose0.034 ±

Maltitol

0.030 ±

MS-17―

0.030 ±
0.036 ±

CML
(nmol /g)

8.2

823

±

1.8

789

±

4.3
0.8
2.0
2.8
3.5
8.1
8.6
2.7
7.6
8.9
1.5
1.9
1.1
0.7
1.9
2.1
1.6
4.3
1.5
2.5

0.004
0.004
0.003
0.003

861
540
532
466
791
764
892
777
784
821
680
741

±
±
±
±
±
±
±
±
±
±
±
±

813* ±
977

±

941

±

950
553
527
576

±
±
±
±

489* ±
1.2

±

1.2

±

1.1
1.2

±
±

Pentosidine(nmol /g)

28

6.2

±

1.9

29

5.0

±

0.8

±

0.2

9

22
12
44
26
24
32
27
17
26
16
23
34
77
72
57
4

20
30
19

8.5
1.1
1.2
1.0
1.4
2.0
1.9
4.7
2.8
5.0
1.8
1.3
2.2
1.4
1.4

1.23
0.61
1.85
0.38
0.79

± 81.2
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±

0.05

0.00040.02

0.0002* ±

0.04
0.02

0.0004±0.0003** ±

0.2
0.2
0.4
0.5
0.5
1.3
0.5
0.4
0.3
0.1
0.7
0.1
0.3
0.3

0.11
0.91
0.09
0.12

0.00001
0.00004

0.000003
0.00004

Model foods were treated as described in Materials and Methods. AGE fluorescence was recorded at 400-600 nm upon excitation at 380
nm, related to the value with 10 μM perylene, and expressed in nanomoles per milliliter. CML and pentosidine levels were determinedwith enzyme-linked immunosorbent assay. Values are expressed as means ± standard error. -, t reated without sucrose/maltitol.
**p < 0.01 (vs. the sucrose-treated food), *p < 0.05 (vs. the sucrose-treated food) (n = 3-9).

_ 28 _Glycative Stress Research

A

BC
Muf fin

＊＊
＊
＊＊

＊＊

＊＊

25,000Luciferase activity (AU)

＊＊

＊

＊＊

＊

＊＊ ＊

＊

＊＊ ＊

Doughnut
＊

＊

＊＊
＊＊

＊＊

15,000
＊＊
＊ ＊＊

5,000
＊

G

H

Bread

＊

Luciferase activity (AU)15,000
＊＊

＊

7,500

＊

Gl
yc BS
er A
-A
GE
Su s
cr
o
M se
al
t
ito
AG
l
Es
+
AG S ̶
AG E uc
Es s + ros
w/ M eo alti
Sw to
ee l
tn
er

Broiled sauce＊

10,000

＊
＊＊

＊

0

Gl
yc BS
er A
-A
GE
Su s
cr
o
M se
al
tit
AG
ol
Es
AG + S ̶
AG E uc
Es s + ros
w/ M eo alti
Sw to
ee l
tn
er

0

Gl
yc BS
er A
-A
GE
Su s
cr
o
M se
al
t
ito
AG
l
Es
+
AG S ̶
AG E uc
Es s + ros
w/ M eo alti
Sw to
ee l
tn
er

0

Chicken dumpling
10,000Luciferase activity (AU)＊

Luciferase activity (AU)

＊

＊

Gl
yc BS
er A
-A
GE
Su s
cr
o
M se
al
t
ito
AG
l
Es
+
AG S ̶
AG E uc
Es s + ros
w/ M eo alti
Sw to
ee l
tn
er

Gl
yc BS
er A
-A
GE
Su s
cr
o
M se
al
tit
AG
ol
Es
AG + S ̶
AG E uc
Es s + ros
w/ M eo alti
Sw to
ee l
tn
er

Gl
yc BS
er A
-A
GE
Su s
cr
o
M se
al
t
ito
AG
l
Es
+
AG S ̶
AG E uc
Es s + ros
w/ M eo alti
Sw to
ee l
tn
er
＊

75,000F

30,000

＊ ＊＊

＊＊

0

E

Bean compote
15,000＊＊15,0000D
Luciferase activity (AU)30,00015,000

0

＊＊

＊＊

＊＊
＊

5,000
＊

＊＊

＊

＊＊

Gl
yc BS
er A
-A
GE
Su s
cr
os
e
M
S17
M
al
tit
ol
AG
Es
̶
+
AG Su
Es crose
AG +AG Es MS
+ -17
Es
w/ Ma
lt
o
Sw itol
ee
tn
er

0

Gl
yc BS
er A
-A
GE
Su s
cr
os
e
M
S1
M 7
al
tit
ol
AG
Es
̶
+
AG Su
Es crose
AG +AG Es MS
+ -17
Es
w/ Ma
lt
o
Sw itol
ee
tn
er

0

Fig.2.

＊＊＊

Luciferase activity (AU)

Luciferase activity (AU)＊＊＊＊Pudding

30,000Luciferase activity (AU)

Biscuit50,000Luciferase activity of the C6 glioma cells exposed to model foods prepared with or without (-) sweetener. The model foods tested were biscuit (A), muffin (B ),pudding (C ), bean compote (D), doughnut (E ), chicken dumpling (F ), bread (G ), and broiled sauce (H ). BSA, bovine serum albumin (50 μg/mL) used as anegative control; glycer-AGEs, glyceraldehyde-derived AGE-BSA (50 μg/ml) used as a positive control; AGE + sucrose, cells incubated with glycer-AGEs andfood prepared with sucrose; AGE + MS-17, cells incubated with glycer-AGEs and food prepared with MS-17; AGE + Maltitol, cells incubated with glycer-AGEs
and food prepared with maltitol; AGE w/o Sweetener, cells incubated with glycer-AGEs and food prepared without sweetener. Values are expressed as means ±standard error. **p < 0.01 (vs. food prepared with sucrose); *p < 0.05 (vs. food prepared with sucrose); **p < 0.01 (vs. BSA); *p < 0.05 (vs. BSA); **p < 0.01 (vs.
glycer-AGEs); *p < 0.05 (vs. glycer-AGEs) (n = 3-6).

_ 29 _

Maltitol-derived glycated foods

Discussion

This study was conducted to determine the effects ofmaltitol, a polyol sweetener, on 3-DG and AGE formation and
RAGE signaling in 8 food models. The results indicate thatmaltitol endowed 4 of the 8 foods with lower 3-DG content andless agonistic RAGE activity. The food models that consistently
displayed lower 3-DG levels and less RAGE agonism were
biscuit, muffin, doughnut, and bread. Their common features
were (1) inclusion of flour as the major ingredient (see Table 1),and (2) cooking temperature above 150°C. The food models
that lacked 3-DG-lowering and RAGE signal-lowering effects
contained no flour and were cooked at temperatures below
100°C. It is, therefore, reasonable to posit that the higher the
3-DG content of a food the greater the number of products
causing RAGE activation. When gliadin, a main componentof flour, underwent similar analysis, 3-DG content in maltitoltreated gliadin was lower than that in sucrose-treated gliadin,whereas RAGE-dependent reporter activity was not different
between the two (data not shown). This result suggests that the
3-DG-lowering and RAGE signal-lowering effects of maltitol
might be independent phenomena or that components of flour
other than gliadin might account for the maltitol effects inthe model foods. Nevertheless, maltitol can be regarded as asweetener that yields less noxious food products than those
produced by sucrose (see Fig. 2).
Koschinsky et al. 28) have estimated that the total amount oforally absorbed AGE found in blood is equal to approximately
10% of that estimated to be present in an ingested meal, andthat only 30% of circulating AGE is excreted in the urine overthe subsequent 48 hours. Recently, Munesue et al. 29) havedemonstrated that certain food-derived AGE exhibit agonistic/

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antagonistic effects on RAGE signaling. Accordingly, levels of
AGE fluorescence, CML, and pentosidine in the food models
were determined in the present study. However, no significant
differences were revealed by these assays among sucrose-,
maltitol- or MS-17-treated foods. The RAGE signal-lowering
effect of maltitol may be ascribed to currently unassayable orhitherto unidentified AGE structures or non-AGE ligands of
RAGE.
Bread seems to exemplify the effects of maltitol. The
3-DG content of maltitol-treated bread was approximately
10-fold and 43-fold lower than that in MS-17- and sucrosetreated breads, respectively (see Fig. 1). The capability ofmaltitol to induce RAGE signaling was potent in thefollowing order: bread prepared with sucrose > MS-17 >maltitol (see Fig. 2 ). Serum 3-DG levels are reportedly 0.20
± 0.05 nmol/mL in normal humans and 0.35 ± 0.11 nmol/mL
in diabetic patients 26). Assuming that the blood volume of theaverage adult is 4,500 mL and that a sliced of bread weighs 60
g, serum 3-DG level should reach the level of a diabetic patientwhen 1 slice of bread prepared with sucrose, 5 slices of breads
prepared with MS-17, or 54 slices of breads prepared withmaltitol are consumed.

Conclusion

In this study, we have shown that maltitol yields lower
3-DG content and has a less agonistic effect on RAGE
signaling, especially in flour-rich foods. We thus conclude thatcompared with sucrose, maltitol is a sweetener that provides
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