Accepted : May 20, 2020 Published online : June 30, 2020 doi:10.24659/gsr.7.2_174
Original article
1) Anti-Aging Medical Research Center and Glycative Stress Research Center, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan
2) Pokka Sapporo Food & Beverage Ltd., Nagoya, Aichi, Japan
KEY WORDS:
glycative stress, postprandial hyperglycemia, lemon, citric acidAbstract
Objective: Persistence of postprandial hyperglycemia causes elevation of glycative stress. The purpose of this study was to examine the suppressing effect of lemon juice on postprandial hyperglycemia when ingesting cooked rice, thereby, the changes in blood glucose (BG) levels were compared and verified, based on an intake of cooked rice alone as a standard, when lemon juice was ingested before cooked rice.
Methods: Subjects were 12 healthy males and females aged 20 to 30 years old who participated in a briefing session held in advance and provided written consent. The changes in BG level were verified between three test foods as follows: when the cooked rice was ingested alone (A), 15 g of lemon juice was ingested before the rice (B), and 30 g of lemon juice was ingested before the rice (C). Lemon juice was ingested after diluting it with 150 mL of water. FreeStyle Libre Pro was used for the test, and the measured glucose concentration in the interstitial fluid was taken as the BG level. The BG levels evaluated were collected before ingesting the test food (0 min), 15, 30, 45, 60, 90, and 120 min after the start of the test. The results were evaluated by the BG level, the maximum BG change (ΔCmax) and the incremental area under the curve of BG (iAUC).
Bonferroni multiple test was performed for statistical analysis.
Results: here were no adverse events and no subject met the exclusion criteria for analysis, therefore, all 12 subjects were included in the efficacy analysis. The blood glucose change (ΔBG) increased until 45 min after the start of the A to C intake test, and decreased until 120 min thereafter. After 30 min, ΔBG of test food C tended to be lower than that of A and B (p < 0.1).
The highest value was shown 45 min after ingestion of the test foods A to C, when ΔBG was significantly lower in C than in A (p < 0.05). ΔCmax was 20.3% lower in C than in A (p < 0.05). iAUC in C tended to be 24.8% lower than that of A (p < 0.1).
Conclusion: This study showed that a diet that ingest lemon juice prior to rice suppressed postprandial hyperglycemia that was observed when 30 g of lemon juice was taken. A dietary habit of ingesting a beverage containing lemon juice before meals may reduce glycative stress by suppressing postprandial hyperglycemia, and may contribute to the prevention of aging and disease progression.
Effect of the postprandial blood glucose on lemon juice and rice intake.
Contact Address: Professor Masayuki Yagi, PhD
Anti-Aging Medical Research Center, Graduate School of Life and Medical Sciences, Doshisha University
1-3 Tatara Miyakodani, Kyotanabe, Kyoto, 610-0321 Japan TEL/FAX: +81-774-65-6394 e-mail: [email protected] Co-authors: Uenaka S, [email protected];
Masayuki Yagi 1), Shiori Uenaka 1), Kaori Ishizaki 1), Chieko Sakiyama 1), Rika Takeda 2), Yoshikazu Yonei 1)
Introduction
Due to the acceleration of glycative stress, advanced glycation end products (AGEs) are produced and accumulated in our body. AGE-modification of tissue proteins involves cross-linking, inflammation, and browning. Therefore, glycative stress causes physical, physiological, and visual
damage to tissues and cells in vivo 1). Glycative stress is one of the risk factors for aging, and may be a cause of progression of skin aging, diabetic complications, osteoporosis, and dementia. One of the factors that elevates glycative stress is the persistent hyperglycemic state.
Even in healthy subjects, extreme postprandial hyperglycemic conditions cause glycative stress. The methods
23.1 161 54.9 21
1.2 9.8 10.7 2.2
±
±
±
± Number of subjects
Age Body heigt Body weight BMI
years cm kg Table 1. Subject’s profile.
Total
Unit Male Female
Results are expressed as mean ± standard deviation. BMI, body mass index.
12
23.8 172.1 65.1 21.8
0.5 5.5 13.4 3.4
±
±
±
± 4
22.8 155.5 49.8 20.6
1.4 5.6 3.8 1.6
±
±
±
± 8
80.3 5.3 5.8 186.3 74.3 67.4 104.7
6.3 0.2 2.2 19.7 31.4 13.5 17.9
±
±
±
±
±
±
± FBG
HbA1c IRI
Total cholesterol TG
HDL-C LDL-C
mg/dL
% μU/mL
mg/dL mg/dL mg/dL mg/dL
Table 2. Results of the blood chemistry test.
Measured value Unit
Test item Reference range
Results are expressed as mean ± standard deviation. FBG, fasting blood glucose; IRI, immunoreactive insulin; TG, triglyceride; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
70 4.6 1.7 120 30 40 65
109 6.2 10.4 219 149 85 139 - - - - - - - to reduce glycative stress include suppression of postprandial
hyperglycemia, suppression of AGE production/accumulation, and reduced intake of diet-derived AGEs 2, 3). Postprandial hyperglycemia can be suppressed by selecting low glycemic index (GI) foods and dietary modification. It has been reported that postprandial hyperglycemia can be suppressed by ingesting carbohydrates (i.e. rice, bread), a vegetable salad 4, 5), vinegar 6), vinegar beverage 7), grapefruit 8), or plain yogurt 9) before meals. Furthermore, the suppression of postprandial hyperglycemia is reported to be more effective than eating udon or cooked rice alone by eating them with side dishes such as eggs, vegetable salad, Mabo eggplant 10), or beef bowl 11). The food information and ingestion methods that suppress postprandial hyperglycemia may widen the variety of diets that reduce glycative stress and provide health information that can be reasonably and comfortably continued. In this study, for the purpose of verifying the effect of lemon juice on postprandial blood glucose (BG) when ingesting cooked rice, the BG changes were compared under two conditions, when the rice was ingested alone as a standard and when the lemon juice was ingested before rice.
Methods
Subject
Subject were 12 individuals who met the following selection criteria (Table 1): Men and women between the ages of 20 and 30 at the time of obtaining consent to participate in the study; A healthy person without chronic illness; A
person who has a sufficient explanation about the purpose and contents of this study, is capable of consenting, who voluntarily participate after understanding well, and who can participate with a written consent; A person who can visit and take the examinations on the designated day.
Survey items and examination contents
As a background survey, the subjects filled out a questionnaire on their age, medical history and food allergy, and underwent a blood examination (Table 2). The test used FreeStyle Libre Pro (Abbott Laboratories, Chicago, USA) and the glucose concentration in the tissue interstitial fluid measured during the test period was used as the BG level 12).
Testing protocol
In this study, as in the previous report 4-11), the test was conducted according to a uniform protocol by the Japanese Association for the Study of Glycemic Index (GI) 13).
Subjects were instructed to observe the following items during the test period: Avoid irregular life such as lack of sleep or overeating, and live a normal life; Diet, exercise, and sleep should be maintained in the same quantity and quality as before participation in this study; It is prohibited to start taking health foods and supplements; Other than that, it is prohibited to affect the test results.
Instructions were given on the day before and on the day of the test so that the following items were observed:
Excessive exercise is prohibited the day before the pre- examination and test; Sleep 6 hours or more the day before
A B C
200 215 230
Table 3. Nutrition facts of test foods.
Serving unit (g)
294 299 304 Energy
(kcal)
4.2 4.2 4.2 Protein
(g)
0 0 0 Fat(g)
67.8 69.2 70.6 Carbohydrate
(g)
0.6 0.6 0.6 Fiber
(g)
0.0 0.95
1.9 Citric acid Test foods (g)
Test foods A, cooked rice; B, lemon juice (15 g) before cooked rice; C, lemon juice (30 g) before cooked rice.
the test; Intake of alcoholic beverages is prohibited from the day before the test until the end of the test; For dinner on the day before the pretest and the test, avoid high fat foods and do not ingest anything other than water after 22:00;
On the day of the test, physical activity that may result in exercise and sweating is prohibited until the end of the test;
For women, the test is not conducted during the menstrual period.
During the test, participants were kept in a sitting and rest position; Prohibited phone calls, sleep, excessive brain activity (i.e. e-mail, computer) and physical activity; Fasted after eating the test food until the end of the test.
Subjects self-attached the Libre Pro sensor to the outside of the upper arm two days or more before the test.
During the wearing period of the sensor, no restrictions were placed on bathing, swimming, or exercise. In the test, the test food was ingested for 10 min at 10:00. Subjects then watched the DVD in a sitting position, allowing them to remain relaxed until 12:00, when the test ended.
The test food was swallowed 30 times or more after chewing. The BG level was expressed as the measurement value collected 15 min after starting the test food (first time), 15 min after starting the intake (second time), 30 min (third time), 45 min (forth time), 60 min (fifth time), 90 min (sixth time), and 120 min (seventh time).
Test foods
In this study, the nutritional components of the test foods used were calculated using the values displayed on each food (Table 3). Commercial packed rice and lemon juice products were used as test foods. The test foods used were as follows: a packaged cooked rice, "Sato no Gohan, 200 g of Koshihikari from Niigata" (Sato Foods Co., Ltd., Niigata, Japan), and a lemon juice product, "Pokka Lemon 100"
(Pokka Sapporo Food & Beverage Co., Ltd., Nagoya, Aichi, Japan). The test foods were classified from A to C, and each intake were as follows:
Test food A : Cooked rice 200 g
(total carbohydrate: 67.8 g)
Test food B : Lemon juice 15 g + Cooked rice 200 g (total carbohydrate: 69.2 g)
Test food C : Lemon juice 30 g + Cooked rice 200 g (total carbohydrate: 70.6 g)
As for the intake method of the test food, both A to C were ingested within 10 min after the start of the test. In particular, when the test foods B and C were ingested, lemon
juice was ingested for the first 5 min, followed by the ingestion of 200 g of rice. Lemon juice was ingested after diluting it with 150 mL of water.
Selection of safety analysis objects
The objects for safety analysis selected the subjects who took the test food only once.
Selection of efficacy analysis objects
The objects for efficacy analysis selected the subjects who completed all the prescribed test schedules and test contents, however, those who met the following exclusion criteria were excluded: A person who was found to be prominent in acts that impair the reliability of test results; A person who was found to have met the exclusion criteria or was unable to comply with the restrictions after the start of ingestion.
Statistical analysis
Evaluation and analysis of the study were conducted by the safety analysis objects. The adverse events and side effects were evaluated by tabulating the symptoms, degree, frequency, and relevance to the test food.
The efficacy analysis was conducted by the efficacy analysis objects. The change in BG level (ΔBG) was obtained by subtracting the value before ingesting the test food (first time; 0 min value) from the BG level after the test food was ingested. The maximum change in BG level up to 120 min after the start of the test was defined as the maximum BG change value (ΔCmax; maximum BG concentration).
Incremental area under curve (iAUC) was calculated according to the uniform protocol of the Japan GI Study Group 13). IMB SPSS Statics 26 (IMB Japan, Tokyo, Japan) was used for the statistical analysis. The BG level was expressed as the average value ± standard error (SE). For comparison of test results between groups, Bonferroni multiple test was performed, and it was judged as a significant difference when the risk rate was less than 5% (p < 0.05) in a two-sided test.
Ethical standards
This study was conducted in compliance with the Declaration of Helsinki (revised at the 2013 WMA Fortaleza General Assembly) and the ethical guidelines for human-based medical research (notification by Ministry of Education, Culture, Sports, Science and Technology [MEXT]
0 min 15 min 30 min 45 min 60 min 90 min 120 min
Table 4. Blood glucose level transition after a test food intake.
Time
Results are expressed as mean ± standard error and parentheses show 95% confidence interval, n = 12. Test foods A, cooked rice; B, lemon juice (15 g) before cooked rice; C, lemon juice (30 g) before cooked rice.
73.8 95.8 129.8 143.5 133.4 110.3 99.5
4.0 5.2 5.7 6.3 8.2 7.4 3.8
(8.8) (11.4) (12.5) (13.8) (18.0) (16.2) (8.4)
±
±
±
±
±
±
± A (mg/dL)
77.3 101.5 133.0 141.3 127.8 106.0 91.8
3.0 7.4 6.2 5.9 7.4 5.2 3.9
(6.5) (16.4) (13.7) (12.9) (16.4) (11.3) (8.6)
±
±
±
±
±
±
± B (mg/dL)
73.7 89.8 115.3 126.8 118.3 101.2 93.3
4.7 5.1 4.9 5.3 6.2 5.1 4.2
(10.2) (11.3) (10.8) (11.7) (13.6) (11.3) (9.2)
±
±
±
±
±
±
± C (mg/dL)
A B C
† †
＊
0 15 30 45 60 75 90 105 120 135
80 70 60 50 40 30 20 10 0
Blood glucose (mg/dL)
Time (min)
Fig. 1. Fluctuation of the blood glucose level at the time of intaking lemon juice ahead of rice.
Results are expressed as mean ± standard error, n = 12, * p < 0.05, † p < 0.1 by Bonferroni test. Test foods A, cooked rice;
B, lemon juice (15 g) before cooked rice; C, lemon juice (30 g) before cooked rice.
and Ministry of Health, Labour and Welfare [MHLW]). The test content was fully explained to the subjects in advance.
The test was implemented after the applicant requested participation in the test and received a voluntary consent form. This study was conducted under the deliberation and approval of the Ethics Review Committee of Doshisha University (application No. 18039) and Sapporo Holdings Group Research Ethics Committee (reception No. 19-005).
Concurrently, this test was registered in the public database established by the National University Hospital Meeting (UMIN Test ID: 000034009).
Results
Safety evaluation
There were no reports of adverse events in this study (data not shown).
Efficacy evaluation
In this study, none of the subjects met the exclusion criteria. Therefore, all 12 participants were included for the efficacy analysis.
Effect of ingestion of lemon juice and cooked rice on postprandial BG level
Table 4 shows the changes in BG levels after the start of the test. There was no significant difference in fasting BG levels (0 min) before ingesting the test foods A to C.
The BG level of the subjects increased after ingestion of each test food, reached the maximum value after 45 min, and then reduced until after 120 min. The BG level at each measurement time was slightly different between the test foods, but it was not significant.
The transition of ΔBG is shown in Fig. 1. ΔBG increased in all test foods A to C until 45 min after the start of the test.
＊
A B C
100 80 60 40 20 0
Cmax (mg/dL)
Test foods
†
A B C
Test foods 6,000
4,000 5,000
3,000 2,000 1,000 0
iAUC (mg/dL・min)iAUC (mg/dL・min)iAUC (mg/dL・min)
Fig. 2. The amount of maximum blood glucose level change (ΔCmax) after intaking test food.
Results are expressed as mean ± standard error, n = 12, * p < 0.05 by Bonferroni test. Test foods A, cooked rice; B, lemon juice (15 g) before cooked rice; C, lemon juice (30 g) before cooked rice.
Fig. 3. The area under curve blood glucose level change (iAUC) after intaking test food.
Results are expressed as mean ± standard error, n = 12, † p < 0.1 by Bonferroni test. Test foods A, cooked rice; B, lemon juice (15 g) before cooked rice; C, lemon juice (30 g) before cooked rice.
After 30 minutes, ΔBG of test food C tended to be lower than that of test foods A and B (p < 0.1). ΔBG showed the highest value 45 min after ingesting the test foods A to C, and ΔBG of C was lower than that of A (p < 0.05). ΔBG of A to C decreased from 45 min to 120 min. The average value of ΔBG at each time was lower in B and C than in A, however, the difference was not significant.
ΔCmax was A: 71.3 ± 4.2 mg/dL, B: 67.4 ± 4.2 mg/dL, C: 56.8 ± 3.6 mg/dL (Fig. 2). ΔCmax of C was 20.3 % (–14.5 mg/dL) lower than in A (p < 0.05).
The iAUC was A: 5,032 ± 433 mg/dL
.
min, B: 4,368 ± 354 mg/dL.
min, C: 3,784 ± 323 mg/dL.
min (Fig. 3). The iAUC of C tended to be 24.8% (–1,248 mg/dL.
min) lower than that of A (p < 0.1).Discussion
Postprandial hyperglycemia suppression effect of lemon juice
For the purpose to examine the effect of lemon juice on postprandial BG levels when ingesting cooked rice, the effects on postprandial BG changes were compared and verified under the following three test foods: A single ingestion of cooked rice (A) as a standard, and 15 g (B) or 30 g (C) of lemon juice before ingested rice.
The intake of test food C was lower than that of A in ΔBG (p < 0.1) after 30 min and in ΔBG (p < 0.05), ΔCmax (p < 0.05), and iAUC (p < 0.1) after 45 min. The test food B was lower than that of A in ΔBG (15.4 %), ΔCmax (5.5 %) and iAUC (13.2%) after 60 min, but that was not significant.
When the effects of test foods B and C were compared with those of A, reduction in ΔBG, ΔCmax and iAUC was observed depending on the intake of lemon juice. Therefore, the inhibitory effect on postprandial hyperglycemia was
considered to be the effect of the components contained in lemon juice.
The lemon juice used in the test contained 6.3% citric acid. The amount of citric acid in the test food calculated from the intake was B: 0.95 g and C: 1.9 g (Table 3). Thus, it was estimated that the effective amount of citric acid for suppressing postprandial hyperglycemia when ingesting 200 g of cooked rice was 1.9 g.
It has been already reported that the intake of one grapefruit prior to bread can suppress postprandial hyperglycemia 8). The amount of citric acid contained in one grapefruit (about 200 g) is estimated to be about 2 g 14), that was comparable to 30 g of lemon juice (test food C) in this study. As well as citric acid, lemon contains various organic acids such as ascorbic acid, malic acid, oxalic acid, and acetic acid 15). Vinegar 6) and plain yogurt 9) have been reported to suppress postprandial hyperglycemia when food containing acid is ingested before carbohydrate intake. It has been reported that the postprandial hyperglycemia suppressing action of acetic acid contained in vinegar involves delayed gastric emptying 16), α-glucosidase inhibition 17), and improvement of glucose metabolism 18). The inhibitory effect of plain yogurt on postprandial hyperglycemia has been reported to relate to the gelation of digests by lactate contained in whey 19), the energy production by mitochondria in muscle tissue via monocarboxylate transporter 21), the elongated gastric emptying by suppressing the gastrin secretion due to stimulated cholecystokinin (CCK) and secretin release 20), the elevated incretin secretion by whey peptide 22). The organic acids other than citric acid may be involved in the suppressing action of lemon juice on postprandial hyperglycemia. Concurrently, it has been reported that polyphenols contained in fruits have an α-glucosidase inhibitory effect 23), that has shown also in lemon peel extract 24). Taken together, these findings suggest that the postprandial hyperglycemia-suppressing action of lemon juice may have been due to the organic acids, mainly citric acid, and polyphenols contained in lemon.
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Reduction of glycative stress by suppressing postprandial hyperglycemia
Measures for reducing glycative stress include suppressing postprandial hyperglycemia, inhibition of the production and accumulation of AGEs, and reducing the intake of dietary
AGEs2, 3). Since postprandial hyperglycemia leads to excessive
secretion of insulin, repeated extreme hyperglycemia is involved in the induction of insulin resistance 25). It has also been reported that blood levels of glycation intermediates, i.e.
3-deoxyglucosone, glyoxal, and methylglyoxal, increase in response to an elevation in postprandial BG 26). Methylglyoxal in blood damages vascular endothelial cells 27). Therefore, suppression of postprandial hyperglycemia may prevent tissue or organ damage secondary to microangiopathy. On the other hand, the dietary guidance to eat vegetables first prior to staple food may continue to suppress postprandial hyperglycemia, thus is linked to HbA1c reduction and prevention of complications in diabetic patients 28). There is also a meta-analysis that the habit of eating fruits reduces the risk of type 2 diabetes 29). Taken together with these findings, the dietary habit of ingesting a beverage or food containing lemon juice before meal may reduce glycative stress by suppressing postprandial hyperglycemia, thus contributing to the prevention of aging and age-related diseases.
Conclusion
This study showed that a diet that ingest lemon juice prior to rice suppressed postprandial hyperglycemia that was observed when 30 g of lemon juice was taken. A dietary habit of ingesting a beverage containing lemon juice before meals may reduce glycative stress by suppressing postprandial hyperglycemia, and may contribute to the prevention of aging and disease progression.
Conflict of Interest Statement
This research received support from Pokka Sapporo Food & Beverage Ltd.
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