Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : June 8, 2016
Accepted : July 9, 2016
Published online : September 30, 2016

Original article

The effects of water chestnut (Trapa bispinosa Roxb.) on the inhibition of
glycometabolism and the improvement in postprandial blood glucose levels
in humans
Shouko Takeshita 1), Yoshika Ishioka 2), Masayuki Yagi 2), Tomohiro Uemura 1),
Michio Yamada 1), Yoshikazu Yonei 2)1) Hayashikane Sangyo Co.,Ltd. Yamaguchi, Japan2) Anti-Aging Medical Research Center and Glycation Stress Research Center, Graduate School of Life and Medical Sciences,
Doshisha University, Kyoto, Japan

Abstract

Objective: In the search for functional foods to reduce glycation stress, we evaluated the effects of the water chestnut peel
extract (TBE) on glycometabolism-related enzymes α-amylase and α-glucosidase. Moreover, we assessed the impact of theextract on postprandial blood glucose levels in a human ingestion test and examined the possibility of using the extract as ananti-glycation stress food.
Method: TBE’s inhibitory effect on glycometabolism-related enzymes was evaluated as follows: in the presence of the test
extract, we caused a reaction in each of the two pairs – α-amylase and starch, α-glucosidase and disaccharides – then evaluatedthe measured amount of resulting glucose using an in vitro test system. In addition, we tested 7 Japanese, healthy male andfemale subjects (3 male, 4 female, average age 23.1 ± 1.1 years) and 4 Japanese subjects (1 male, 3 female, average age 28.7
± 2.3 years). The subjects ingested bread or rice after TBE intake, and we evaluated the subsequent swing in blood glucose
levels to assess the impact of TBE on postprandial blood glucose levels on a comparative basis.
Results: TBE showed concentration-dependent inhibitory activity on α-amylase and α-glucosidase. In humans, if the test
extract was ingested before meals, the elevation in blood glucose levels 45, 60, and 90 minutes after bread intake and 15
minutes after rice intake was significantly lower ( p < 0.05) than when the test extract was not ingested. In addition, the blood
glucose area under the curve, AUC, was significantly lower ( bread: p = 0.012, rice: p < 0.01) in the test extract group forboth high-glycemic index foods.
Conclusion: TBE showed an inhibitory effect on α-amylase and α-glucosidase. Further, trials of TBE ingestion in humans
suggested its ability to suppress elevation of postprandial blood glucose levels. TBE is expected to become a functional food
item that can have composite effects in countering glycation stress by controlling blood glucose levels.

KEY WORDS: postprandial blood glucose levels, glycative stress, water chestnut (Trapa bispinosa)
Introduction

In diabetic patients with persistently high blood glucose
levels, glycation reactions are accelerated compared to healthy
subjects, causing early onset of diabetic nephropathy andeye disease 1), arteriosclerosis 2), osteoporosis 3), Alzheimer’s
disease 4), infertility 5), and skin hardening 6). In addition, evenin healthy subjects, an excessive increase in postprandial
blood glucose levels and insulin secretion promotes theaccumulation of visceral fat, elevating risks of lifestyle diseases
such as dyslipidemia, hypertension, and arteriosclerosis 7, 8).
Therefore, proper management of blood glucose levels is
important in reducing glycation stress and diabetes-related

complications, as well as lifestyle diseases. In addition, it isbelieved that the suppression of glycation reactions (as partof glycation stress management) and the promotion of thedecomposition and metabolism of existing saccharides will
not only prevent diseases, but will also prolong life expectancy
and improve quality of life (QOL). In light of this, the authorsof this paper discovered strong anti-glycation and saccharide
decomposition effects of water chestnut (Trapa bispinosaRoxb.) peel extract, and have researched and reported thepossibilities around glycation stress reduction 9). As part ofthe main experiment, this paper studies the inhibitory effectof the water chestnut hot water extract on glycometabolism-

Contact Address: Shouko Takeshita
Hayashikane Sangyo Co., Ltd.
2-4-8 Yamato-machi, Shimonoseki, Yamaguchi, 750-8608, Japan
Phone: +81-83-267-0094 FAX: +81-083-267-0192 E-mail: stakesita@hayashikane.co.jp
Co-authors: Ishioka Y, ishiyoshi.2.13@gmail.com ; Yagi M, myagi@mail.doshisha.ac.jp ;Uemura T, tuemura@hayashikane.co.jp ; Yamada M, myamada@hayashikane.co.jp ;Yonei Y, yyonei@mail.doshisha.ac.jp_ 12 4 _Glycative Stress Research 2016; 3 (3): 12 4 - 132(c) Society for Glycative Stress ResearchGlycative Stress Research

related enzymes and its ability to control blood glucose
levels when ingested by humans.

Materials and Methods

Preparation of Water chestnut (T.bispinosa)
Peel Extract (TBE)

Water chestnut peel was dried, sterilized, and crushed,
and then extracted using hot water (approximately six-foldthe weight of the water chestnut peel). Dextrin was added
to this solution at a ratio of 67 : 33 of dry weight, and theresulting solution was spray-dried to obtain TBE. Sample
solutions for subsequent measurements were prepared bydissolving the TBE in distilled water.

Measurement of α-glucosidase and α-amylase
inhibition

TBE’s inhibitory activity on α-glucosidase was measured
according to the standards of prior research 10), and evaluatedby measuring the amount of glucose produced after
disaccharide decomposition. The α-glucosidase enzyme
solution was obtained by dissolving intestinal acetone powder
from rat (Sigma-Aldrich, Missouri, USA) in 0.1 mol / Lphosphate buffer solution (pH 7.0), then applying ultrasonictreatment while cooling on ice, and finally fractionating
the supernatant by applying centrifugation at 800 x g
over 10 minutes. We mixed 500 μL of TBE solution, eachconcentration of which was dissolved in distilled water, 2
mL of 250 mmol/L maltose or sucrose solution, and 2.4 mLof distilled water in a test tube, then pre-incubated at 37 °C
for 5 minutes, before adding 100 μL of the above-mentioned
α-glucosidase enzyme solution and causing a reaction
during a 37 °C incubation for 40 minutes. After the reaction,
5 mL of 0. 2 mol/L sodium carbonate was added to stop thereaction and a measurement sample was removed. The Glucose
CⅡ-Test Wako (Wako Pure Chemical Industries, Ltd., Osaka,
Japan) kit was used to determine the amount of glucose
contained in the sample in accordance with the manufacturer’s
instructions. A mixture of 3 mL of the color former includedin the kit and 0.02 mL of the measurement sample wasincubated at 37 °C for 5 minutes, and the absorbance wasmeasured at 505 nm using a microplate reader (Tecan,
Salzburg, Austria). The inhibitory activity of TBE on
glucosidase was then calculated using the following equation.
The treatment group described above is [S], the control
test group [C] used distilled 0.02 mL of water instead of
TBE, and a third test group [SB] in which the solution withthe halted chemical reaction was added in the presence of
TBE and then mixed with enzyme solution. For each test
case we obtained the value of absorbance and calculated
the inhibitory activity of TBE on the α-glucosidase enzyme
using the following equation.
α-glucosidase inhibitory activity (%) =100 - 100 × ([S] - [SB])/[C]We evaluated the inhibitory activity of TBE on α-amylase
using a positive control amount of glucose produced byenzymatic degradation of soluble starch, as cited in previous
research 11). In a microtube, 0.4% soluble starch was added to
50 μL TBE solution dissolved in distilled water and 300 μL
of 25 mmol/L PIPES buffer containing 5 mmol/L calcium

chloride (pH 6.0), and mixed thoroughly to create a reaction
composition solution. To this reaction composition solution
we added 150 μL of enzyme solution, obtained by dissolving
porcine pancreatic α-amylase (Sigma-Aldrich, Missouri,
USA) in 25 mmol/L PIPES buffer solution to form 2 units/mL.
The reaction was carried out over a 10 minute incubation
period at 37 °C. The enzymatic reaction was stopped byheating in boiling water for 10 minutes. After cooling, 100
μL of 2 mol/L sodium hydroxide aqueous solution and 200
μL of 0.5% dinitrosalicylic acid were added to the reacted
solution and heated in boiling water for 10 minutes. Aftercooling, the absorbance was measured at 540 nm using
a microplate reader. We labeled the test group describedabove as [S], a control test group [C] in which distilled water
was added instead of TBE, a third test group [B] in which
distilled water was added instead of TBE and enzyme solution,and the final test group [SB] in which distilled water wasadded instead of the enzyme solution. For each test case
we obtained the value of absorbance and calculated theinhibitory activity of TBE on the α-amylase enzyme using
the following equation.
α-amylase inhibitory activity (%) =100 - 100 × ([S] - [C] /([B] - [C])As a comparison, in place of TBE, we simultaneously
carried out tests using acarbose, an oral hypoglycemic drugwith an inhibitory effect on α-amylase and α-glucosidase,and the leaf extract of mulberry (Morus alba Linn.)which is reported to have similar inhibitory effects 12) on
glycometabolism-related enzymes.

Human Clinical Study
Subjects

The subjects were selected from healthy Japanese men
and women of ages 20 years or older, for whom the following
exclusion criteria did not apply:
Exclusion criteria: patients with diabetes, anyone taking
medication, smokers, anyone with food or drug allergies,
women who are pregnant or nursing, anyone with a pasthistory of severe symptoms or surgery of the digestive tract,
anyone taking daily supplements.
7 subjects were tested with bread (3 males, 4 females,
average age 23.1 ± 1.1 years of age), and 4 subjects were
tested with rice (1 male, 3 females, average age 29.0 ± 2.4
years).

Study Design

Referencing the methodology of prior research 13), we
tested as outlined below. The subjects finished dinner by 10
pm on the night before the experiment, skipped breakfast,and drank only water until the test. In addition, the subjects
abstained from alcohol the day before the test.
Measurements of blood glucose levels were carriedout in the following manner. The subject’s fingertip was
disinfected with rubbing alcohol and then a lancing device
was used to test a small amount of blood using a blood
glucose meter (Medisafe Mini by Terumo, Tokyo, Japanor Glucocard MyDia by Arkray, Kyoto, Japan). Two blood
glucose levels were simultaneously measured and theaveraged value was used. If the difference between the two
measurements was more than 10% of the higher value, a_ 125 _

Effect of Water Chestnut on Blood Glucose Levels
third measurement was taken and the average value of two
measurements with a smaller difference was used.
During the test the subject’s fasting blood sugar level wasmeasured, subjects were administered the test extract with
10 0 mL water, and the elimination food was ingested 5
minutes later. The ingestion time of the elimination foodwas 10 minutes, and the rate of ingestion was kept constant.
After ingesting the elimination food we measured blood
glucose levels after 15 minutes, 30 minutes, 4 5 minutes, 60
minutes, 90 minutes, and 120 minutes. Collected data wasused to evaluate the blood glucose levels, fluctuations in blood
glucose levels, and the blood glucose area under the curve(AUC). With regard to the elimination food, the tests werecarried out separately for bread and rice, and we performed
a comparison of the blood glucose levels when ingesting only
the elimination food and when ingesting the tes t extractand elimination food. In consideration of the lingering
effects of the ingested test extract, each test was carried out
at 1 week intervals.

The Characteristics of the Test Extract andElimination Food

The ingested test extract and elimination food is
outlined below. Table 1 & 2 show their composition andnutritional components.
Test extract: gelatin hard capsules containing 100 mg of TBE
Elimination Food 1: 170 g bread (Pasco Chojuku) (Shikishima
Corporation, Aichi, Japan)
Elimination Food 2: 200 g packaged rice (TableMark Co.,
Ltd., Tokyo, Japan) + 2.5 g seasoning (Nagatanien Co. Ltd.,Tokyo, Japan)

Ethical considerations

This study complies with the ethical principles and theprotection of personal information based on the Declarationof Helsinki (annotations added at the 2004 Tokyo meeting).
The experiment was carefully explained to the subjects inwriting, and consent to participate in the experiment wasalso obtained in writing. We also held an ethics committee
regarding Doshisha University’s ethical standards,“Experimentation Involving Human Subjects,” to deliberate
the ethics and validity of the test. The experiment wasapproved (Application Number: 1228-2).

Statistical Analysis

Test results are expressed as mean ± standard deviation.
A Student’s t-test was used to compare the test and control
groups. We set the significance level of the two-sided test
to 5% and considered values less than or equal to this to bestatistically significant.

Results

Measurement of α-glucosidase and α-amylase
inhibition

Figure 1 shows a graph that depicting the α-glucosidase
inhibitory activity of TBE, while the graph in Fig. 2 shows
the α-amylase inhibitory activity. Data in Fig. 1 confirms
the dose-dependent increase in the α-glucosidase (maltase,sucrase) inhibitory activity of TBE. The IC 50 value was 571
μg/mL for maltase and 548 μg/mL for sucrase. The IC 50

Table 1. Nutritional facts of the standard diet.

Serving weight(g)

Carbohydrate(g)Energy( kcal )Protein
(g)

Fat
(g)

170

79.4

448.8

15.8

7.5

Rice

200

69

299

4.4

0.6

Seasoning

2.5

1.2

9

0.7

0.13

(A) Bread
Bread(B) Rice and seasoning

Table 2. Composition and nutritional factor of the test diet.
Nutritional factor per serving

Composition per serving
TBE (mg)100

Carbohydrate ( g )0.25

Cornstarch (mg)

187

Energy ( kcal )1

Calcium stearate (mg)3

Protein ( g )0

Total (mg)290

Fat ( g )0

Test diet is served as a capsule which contains 100 mg TBE. TBE, water chestnut peel extract.

_ 12 6 _Glycative Stress Research

(a)

TBE

Mulberry Leaf ProductAcarbose

140

120

Inhibition ratio (%)

100

80

60

40

20

0
125

250

500

1000

Concentration (µg/mL)

(b)

TBE

Mulberry Leaf ProductAcarbose

120

100

Inhibition ratio (%)

80

60

40

20

0
125

250

500

1000

Concentration (µg/mL)

Fig. 1. Inhibitory activitiy of TBE, mulberry leaf product and acarbose on (a) sucrase, (b) maltase.
TBE, water chestnut peel extract.

_ 127 _

Effect of Water Chestnut on Blood Glucose Levels
TBE

Muberry Leaf ProductAcarbose

120

100

80

Inhibition ratio (%)

60

40

20

0
-- 20
-- 40
0

200

400

600

800

1000

1200

Concentration (µg/mL)

Fig. 2. Inhibitory activity of TBE, mulberry leaf product and acarbose on α-amylase.
TBE, water chestnut peel extract.

values of both acarbose and mulberry leaf extract, used ascomparative controls, were <125 mg/mL, with confirmed
high activity in comparison with TBE. Similarly, data in
Fig. 2 confirmed the dose-dependent increase of α-amylase
inhibitory activity of TBE; the IC 50 value was 67.3 μg/mL.
The IC 50 value of acarbose, which had been used as acomparative control, was found to be < 1 μg/mL, having
a higher activity in comparison with TBE. On the other

hand, α-amylase inhibitory activity was not observed in themulberry leaf extract.

Human Clinical Study

Table 3 shows blood glucose levels after the ingestion ofeach elimination food, the amount of change in blood glucose
levels, and the AUC value. Figure 3 depicts a graph of theTable 3. Effects of TBE on blood glucose and area under the glucose curve (AUC) in human.
Group
Blood
glucoselevel
ΔBloodglucoselevel

B

B + TBER

R + TBEB

079.8 ± 7.5

93.8 ± 5.7
84.1 ± 4.3

85.6 ± 2.5

B + TBER

R + TBE15

92.9 ± 15.0

100.0 ± 10.0
133.0 ± 4.1
114.9 ± 2.9
13.1 ± 5.6

6.2 ± 4.3

48.9 ± 4.1
29.3 ± 4.8*

Time after intake (minutes)
30
45
131.1 ± 14.5

144.1 ± 20.2
137.0 ± 9.4

128.3 ± 7.4
51.3 ± 5.1

50.3 ± 8.6
52.9 ± 8.3
42.6 ± 7.1

144.6 ± 20.8
139.6 ± 12.5

60

90

120

142.9 ± 31.7 124.8 ± 31.7

118.9 ± 30.7

37.8 ± 6.4*

16.9 ± 7.2
7.6 ± 2.1

115.4 ± 5.5
114.8 ± 7.7

128.6 ± 15.7 113.4 ± 24.8 110.6 ± 19.5
102.1 ± 4.6 104.6 ± 2.7
91.8 ± 5.9
99.4 ± 8.0
90.8 ± 6.7
91.5 ± 3.1
63.1 ± 11.2 45.0 ± 11.0 39.1 ± 10.5

31.3 ± 2.9
29.1 ± 6.2

18.0 ± 5.6
13.8 ± 7.1

64.8 ± 6.8
45.8 ± 5.8*

19.6 ± 8.6*

20.5 ± 2.4
5.1 ± 7.1

5.9 ± 3.0

AUC
5298.2 ± 779.4
Area under B
the glucose B + TBE 3236.2 ± 570.0*
curve
3129.2 ± 623.4
R(AUC)
R + TBE 2167.5 ± 551.5*
Intook bread (n = 7); group B, intook bread after TBE; group B + TBE. Intook rice (n = 4); group R, intook rice after TBE; group R + TBE. Results are expressed
as mean ± standard deviation. * p < 0.05, group B vs group B + TBE and group R vs group R + TBE, by Student’ s t-test. TBE, water chestnut peel extract.

_ 12 8 _Glycative Stress Research

amount of change in blood glucose levels. Figure 4 shows agraph charting AUC. From Table 3 and Fig. 3, significantly
lower blood glucose levels (p < 0.05) were observed in thetest group that ingested TBE before bread intake (Group B+ TBE) compared to the test group with just bread intake(Group B) at 45, 60, and 90 minutes after ingestion. In
addition, significantly lower blood glucose levels (p < 0.05)
were observed for the test group that ingested TBE before(a)rice intake (Group R + TBE) in comparison to the groupwith just rice intake (Group R) 15 minutes after ingestion.
From Fig. 4, the AUC of Group B + TBE (3,236.2 ± 570)
is significantly lower (p = 0.012) compared to the AUC ofGroup B (5,298.2 ± 779.4). Likewise, the AUC of Group R+ TBE (2,167.5 ± 551.5) was significantly lower (p < 0.01)
compared to the AUC of Group R (3,129.3 ± 623.4).

Group B

Group B + TBE

80

Δblood glucose level (mg/dL)

70
60

*

50

*

40

*

30
20
10
0
0

15

30

45

60

90

120

Post-ingestive time (min)

(b)

70

Group B

Group B + TBE

Δblood glucose level (mg/dL)

60
50

*

40
30
20
10
0
-- 10
0

15

30

45

60

90

120

Post-ingestive time (min)Fig. 3. Effects of TBE on postprandial blood glucose level on subjects in (a) bread or (b) rice.

Test subjects were loaded (a) bread (n = 7) or (b) rice (n = 4). (a) Intook bread; group B, intook bread after TBE; group B + TBE. (b)Intook rice; group R, intook rice after TBE; group R + TBE. Results are expressed as mean ± standard deviation. * p<0.05, group B
vs group B + TBE and group R vs group R + TBE, by Student’s t-test. TBE, water chestnut peel extract.

_ 12 9 _Effect of Water Chestnut on Blood Glucose Levels

Area under the glucose curve (AUC)

(a)
7000
6000
5000

*

4000
3000
2000
1000
0
Group B

Group B + TBE

Area under the glucose curve (AUC)

(b)
4000
3500

*

3000
2500
2000
1500
1000
500
0
Group R

Group R + TBE

Fig. 4. Effects of TBE on area under the glucose curve (AUC) in (a) bread or (b) rice.

Test subjects were loaded (a) bread (n = 7) or (b) rice (n = 4). (a) Intook bread; group B, intook bread
after TBE; group B + TBE. (b) Intook rice; group R, intook rice after TBE; group R + TBE. Results
are expressed as mean ± standard deviation. * p < 0.05, group B vs group B + TBE and group R vsgroup R + TBE, by Student’s t-test. TBE, water chestnut peel extract.

_ 13 0 _Glycative Stress Research

Discussion

The water chestnut fruit used as the subject of this study
is a large fruit among plants in the Trapacese family 14). In
Japan, water chestnut has been in circulation since ancient
times in the Fukuoka and Saga prefectures, where the peelis dried and used as a specialty tea. However, the benefits ofwater chestnut intake are limited to oral tradition and folklore,
and there are few research reports. Therefore, to thoroughly
study the subject of glycation slowdown with respect toglycemic control, we focused on TBE’s strong anti-glycation
activity and evaluated its effects on glycometabolism-related
enzymes, and its impact on postprandial blood glucose levels
in humans.
TBE’s inhibitory activity was examined on theglycometabolism-related enzymes α-glucosidase andα-amylase, both of which regulate blood glucose levels.
We confirmed TBE to inhibit enzymatic activity in a dosedependent manner. When compared with the mulberry leaf
extract, a positive control group, the inhibitory activity of
TBE on α-glucosidase was weaker than the mulberry leaf
extract, but its inhibitory effect on α-amylase was higher
than the mulberry leaf extract.
The active ingredient in the α-glucosidase inhibitory
activity of the mulberry leaf extract has been found to be
1-deoxynojirimycin, which is an analog of glucose. Indeed,high inhibitory activity is reported when 1-deoxynojirimycinbinds specifically to α-glucosidase 12). On the other hand, it
has been reported that the mulberry leaf extract is poor in
α-amylase inhibitory activity, which is consistent with theresults of this study 15). Previous reports show that the pericarp
extract of plants in the Trapa genus contain polyphenols 16),and inhibitory activity on glycometabolism-related enzymes
has been confirmed in polyphenols such as eugeniin andtrapain contained in the pericarp extract of the Trapa
japonica 11). Thus the inhibitory activity of TBE on
glycometabolism-related enzymes has been partiallyattributed to polyphenols, and it is believed to be a different
mechanism than the mulberry leaf extract. α-glucosidase(maltase, sucrase) is a disaccharide-degrading enzyme
located in the intestinal tract, and α-amylase is a starchdegrading enzyme found in saliva and pancreatic fluid. It
is thought that, because TBE inhibits the activity of bothglycometabolism-related enzymes, it is able to suppress thedegradation of starch, sucrose, and maltose into glucose.
In the human clinical trials, we evaluated blood glucose
fluctuations after ingesting TBE and elimination foods.
Bread and rice, which were used as elimination foods, haveglycemic indices (GI values) of 70 or more. The GI values
represent an index of the swing in postprandial blood glucose
levels proposed by Jenkins DJ et al. 17). Bread and rice cause
a rapid rise in blood glucose levels, and are commonlymodeled to observe the swing in postprandial blood glucose
levels. The results of the TBE ingestion test show that theingestion of TBE before the elimination food caused theswing in blood glucose levels to be significantly lower incomparison to the test group that did not consume TBE, at 45,
60, and 90 minutes after bread consumption, and 15 minutes
after rice consumption. For both elimination foods, themaximum blood sugar value was lower with TBE intake
than without, and this is inferred to be due to TBE’s inhibitory
activity on glycometabolism-related enzymes as shown in
the in vitro test described above. The AUC value, the indicatorof total change in blood glucose level, was also significantly

lower during TBE intake in comparison to no intake. The
difference in the AUC values of bread and rice is thought
to be attributable to the differences in GI value andcarbohydrate content.
This study suggests that the ingestion of TBE eases therise of postprandial blood glucose levels. Its mechanism isthought to be a result of delayed absorption or suppression of
glucose in the intestines due to TBE’s inhibitory activity on
glycometabolism-related enzymes, α-glucosidase and αamylase. With regards to TBE’s ability to reduce glycationstress, we have already discovered and reported on its highinhibitory effect on glycation and saccharide decomposition 9).
It is presumed that our study on TBE’s potential to control
postprandial blood glucose levels may further contribute to
the reduction of glycation stress.
This study helped to gain knowledge on the impact of asingle ingestion of TBE on the control of postprandial blood
glucose levels. Since the long-term ingestion of TBE is
believed to lead to suppression of in vivo formation of AGEs,
we look to further continue our research.

Conclusion

TBE showed an inhibitory effect on α-amylase andα-glucosidase. Further, trials of TBE ingestion in humans
suggested its ability to suppress elevation of postprandial
blood glucose levels. TBE is expected to become a functional
food item that can have composite effects in countering
glycation stress by controlling blood glucose levels.

Conflicts of interest statement

Part of this work was supported by Hayashikane Sangyo
Co.,Ltd.

Acknowledgments.

This work was partially supported by the JapaneseCouncil for Science, Technology and Innovation, SIP(Project ID 14533567), “Technologies for creating nextgeneration agriculture, forestry and fisheries” (funding
agency: Bio-oriented Technology Research Advancement
Institution, NARO

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Effect of Water Chestnut on Blood Glucose Levels

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