Risa Araki a , Keiko Fujie a , Nanako Yuine a, b , Yuta Watabe a, b , Yoshio Nakataa , Hiroaki Suzuki c , Hiroko Isodad , Koichi Hashimoto a, ⁎
a Department of Clinical and Translational Research Methodology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan b Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan c Department of Internal Medicine, Metabolism and Endocrinology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan d Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan
Received 28 December 2018, Revised 26 April 2019, Accepted 6 May 2019, Available online 11 May 2019, Version of Record 31 May 2019.
Keywords: Olive leaf tea, Oleuropein, Triglyceride, LDL cholesterol, Human health, Prediabetes
Abstract
Olive leaves are rich in oleuropein, which has been shown to have beneficial effects on dyslipidemia, type 2 diabetes, and obesity. However, we previously found no significant health benefits of olive leaf tea (OLT) on nonobese and nondiabetic individuals. Thus, we performed this study to further explore the health benefits of OLT in individuals with prediabetes and compare the health benefits between low-concentration OLT (LOLT) and OLT. We hypothesized that OLT will have a more pronounced effect on abdominal obesity as well as glucose and lipid metabolism in prediabetic individuals. Individuals between 40 and 70 years of age with a body mass index of 23.0-29.9 kg/m2 and prediabetes status were recruited and randomly assigned to the OLT or the LOLT group. The intervention, which was the consumption of 330 mL of the test beverage 3 times daily during mealtime, lasted for 12 weeks. After the intervention, serum levels of log-transformed triglycerides (P < .05) and low-density lipoprotein cholesterol (P < .01) decreased significantly in the OLT group (n = 28), with the reductions higher in the OLT group than those in the LOLT group (n = 29, log-transformed triglycerides: P = .079, low-density lipoprotein cholesterol: P < .05). Whereas body weight, waist circumference, and insulin levels were not significantly changed in both groups, fasting plasma glucose levels in the OLT group were significantly decreased compared to those in the LOLT group (P < .05). In conclusion, although the effect of OLT on abdominal obesity and glucose metabolism remains unclear, OLT has been found to have lipid-lowering effects.
1. Introduction
Oleuropein is the most abundant phenolic compound of the olive [1], and studies have shown its beneficial effect against dyslipidemia [2], [3], [4], type 2 diabetes [5], and obesity [6], [7]. Olive leaves are richer in oleuropein and other polyphenols than olive oil [2], as olive leaves contain 1%-14% oleuropein, whereas olive oil contains only 0.005%-0.12% [8]. Olive leaf tea (OLT) is also rich in oleuropein and is thus hypothesized to have health benefits. Among olive products, OLT is considered the most convenient for daily consumption because it is consumable at room temperature and does not require cooking. Additionally, OLT does not contain energy or salt unlike olive oil and pickled olive, and thus, OLT could be useful for preventing metabolic syndrome (MetS) and lifestyle-related diseases.
Olive leaves are accumulated in great volumes as waste from the olive oil industry [9]. If the health benefit of OLT can be established, olive leaves could be effectively used for high–value added products.
We previously conducted an exploratory study to examine the effects of OLT for nonobese and nondiabetic adults and observed that OLT may have antiobesity effects [10]. However, there was no significant difference in the body weight (BW) and waist circumference (WC) between the OLT group and the control group who received green tea. The beneficial effects of OLT on glucose and lipid metabolism were only noticed among participants with high baseline levels of fasting plasma glucose (FPG). We considered that green tea may not have been suitable as a control beverage because catechins, the main polyphenols of green tea, have been reported to improve serum lipid levels [11], glucose intolerance [12], and abdominal adiposity [13]. Thus, we performed the present study with the aim of investigating the health effects of OLT in Japanese prediabetics adults who are mildly obese or have normal-high body mass index (BMI). Low-concentration OLT (LOLT) was used as the control beverage, and we hypothesized that the beneficial effect of daily OLT intake on abdominal obesity, glucose, and lipid metabolism will be more pronounced in prediabetic adults than in nonobese, nondiabetic adults.
2. Methods and materials
2.1. Study population
Participants were recruited via posters in the university and the hospital or via advertisements in local newspapers. The inclusion criteria were as follows: age between 40 and 70 years, BMI of 23.0-29.9 kg/m2, and prediabetic status (ie, FPG level of 100-125 mg/dL and/or hemoglobin a1c [HbA1c] level of 5.7%-6.4%). Participants were excluded if they (1) received pharmacotherapy for diabetes, dyslipidemia, and/or alimentary disease; (2) regularly took supplements (including “food for specified health use” and “foods with function claims” approved by the Japan Consumer Affairs Agency) that affect weight and glucose metabolism; and/or (3) participated in other interventional studies. Written informed consent was obtained from all participants prior to study enrollment. If a participant decided to withdraw consent, the intervention was terminated. The participants were recruited by research staff between 1 February 2017 and 23 June 2017. The intervention period lasted for 12 weeks, and the study was conducted between 15 April 2017 and 28 October 2017. The study was performed at the University of Tsukuba, according to the guidelines laid down in the Declaration of Helsinki, with approval by the Ethics Committee of University of Tsukuba Hospital (approval number: H28-249). Moreover, the study was registered on 20 January 2017 at University Hospital Medical Information Network–Clinical Trials Registry (http://www.umin.ac.jp/ctr) as UMIN000025741.
2.2. Study design
The present study was a parallel-group randomized control trial with the goal of comparing the health effects of OLT and LOLT for mildly obese or normal-high BMI adults with prediabetes. Of the 110 participants assessed for eligibility, 57 were included and randomly assigned to either the OLT (n = 28) or the LOLT (n = 29) group for intention-to-treat (ITT) analysis (Fig. 1).
Fig. 1
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Fig. 1. Flowchart of participant selection.
Of the 110 participants identified, 57 were eligible and were randomly assigned to either the LOLT group or the OLT group. They were then included in the ITT analysis after the intervention. Participants who had high WC (male: ≥ 85 cm, female: ≥ 90 cm) were included in the subgroup analysis for physique and glucose metabolism.
Olive leaves from Kagawa Prefecture were used as the raw tea leaves for both test beverages. The primary processing of the tea leaves was performed at Yamahisa Co, Ltd (Kagawa, Japan). The secondary processing of both test beverages was performed at the factory of Morita Co, Ltd (Fukui, Japan), which is an ISO 9001–certified company. In total, 5 g and 0.5 g of tea leaves were steeped in 1 L boiled water for OLT and LOLT, respectively. The extracts were then diluted 3 times with water. After adding ascorbic acid to prevent oxidation, it was heat sterilized under conditions based on the food hygiene laws, poured in a 330-mL plastic bottle, and sealed. The component composition of the test beverage is shown in Table 1.
Table 1. Composition of the test beverages
LOLT OLT
Energy (kJ/100 g) 0 0
Total ascorbic acid (mg/100 g) 10 10
Oleuropein (mg/100 g) 2.4 32.4
Hydroxytyrosol (mg/100 g) 0.3 1.2
Each participant was instructed to drink 330 mL of the test beverage 3 times daily at mealtimes and to maintain their normal lifestyle as before the examination. Individuals were requested to record the following daily information in a study diary: consumption of test beverages, stool frequency, any signs or symptoms of illnesses, use of medication, and any other complaints.
2.3. Clinical measurements
BW and height were measured with the participants wearing light indoor clothing without shoes. BMI was calculated as BW in kilograms divided by height in meters squared (kg/m2). WC was obtained at the midpoint between the lowest rib and the iliac crest [14]. These data were collected at baseline and at 12 weeks.
2.4. Blood sampling and analyses
Blood samples were taken at baseline and at 12 weeks after an overnight fast. FPG levels were measured using the glucose dehydrogenase method. HbA1c was determined using the latex coagulation method and was expressed using the National Glycohemoglobin Standardization Program scale. FPG and HbA1c were analyzed using the JCA-BM9130 analyzer (Japan Electron Optics Laboratory, Tokyo, Japan). Insulin levels were measured via chemiluminescence immunoassays using Roche Modular Analytics E170 (Roche Diagnostics GmbH, Mannheim, Germany). The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated according to the following formula: fasting insulin (μU/mL) × FPG (mg/dL)/405 [15]. Serum levels of triglycerides (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C) were measured via the enzymatic method using the JCA-BM8060 analyzer (Japan Electron Optics Laboratory, Tokyo, Japan). Serum LDL-C levels were calculated using Friedewald formula, as follows: TC − HDL-C − 1/5 × TG [16]. All laboratory examinations were performed at Kotobiken Medical Laboratories Inc (Ibaraki, Japan).
2.5. Dietary habits and physical activity
Participants completed a brief self-administered diet history questionnaire [17] to estimate food intake for the last full month at baseline for the 12-week study. Each brief self-administered diet history questionnaire was immediately checked by a skilled dietician in the presence of the participants.
Physical activity (PA) at each point was assessed via the global physical activity questionnaire [18]. The duration and frequency of physical activity (min/d) in 3 domains (activity at work, travel to and from locations, and recreational activities) over a typical week were recorded. Activities were classified into 3 intensity levels: vigorous (8 metabolic equivalents of task [METs]), moderate (4 METs), and inactivity (1 MET). A summary estimate of moderate-to-vigorous physical activity (MVPA) per week was calculated by combining the activity score of both moderate and vigorous PAs for each PA domain.
2.6. Statistical analyses
Participants who consumed the test beverages were included in the ITT analysis. Subgroup analysis, based on the Japanese WC criteria for abdominal obesity (male: ≥ 85 cm, female: ≥ 90 cm) that are equivalent to visceral fat area ≥ 100 cm2 [19], was performed to further clarify the effect of OLT on physique and glucose metabolism.
Results are presented as means ± SD, unless otherwise indicated. Distributions of dependent variables were checked for normality, and log-transformations were applied for serum TG levels. Non-normally distributed MVPA data were presented as median (interquartile range), and the nonparametric test was used for the analysis.
Baseline characteristics and changes from baseline to 12 weeks of the 2 groups were compared using unpaired t tests. Between-group differences at 12 weeks were analyzed using analysis of covariance, with each baseline value as covariates to minimize the potential influence of differences in baseline values. Within-group differences for normally distributed data were compared using the paired t test. The χ2 test or Fisher exact test was used to analyze categorical data.
Statistical significance was defined as P < .05. All statistical analyses were performed using SPSS 22.0 for Windows (IBM Corp, Armonk, NY).
3. Results
3.1. Baseline characteristics
The baseline characteristics of the study participants are shown in Table 2. In total, 66.7% of the overall population were women. The mean age and BMI were 53.5 ± 7.1 (mean ± SD) years and 26.0 ± 1.6 kg/m2, respectively. There were no significant differences in demographic characteristics between the 2 groups.
Table 2. Baseline characteristics of participants
LOLT group OLT group Pb
(n = 29) (n = 28)
Age (y) 51.8 ± 6.3a 53.6 ± 7.5 .363c
BMI (kg/m2) 26.0 ± 1.6 26.0 ± 1.7 .911c
Female, n (%) 20 (69.0) 18 (64.3) .708
Smokers, n (%) 6 (20.7) 12 (42.9) .698
Drinkers, n (%) 13 (44.8) 12 (42.9) .881
Have a family history of diabetes, n (%) 12 (41.4) 13 (46.4) .701
a
Values are means±SD.
b
Significant differences between the LOLT group and the OLT group were assessed via χ2 test.
c
Significant differences between the LOLT group and the OLT group were assessed via unpaired t test.
3.2. Test beverage and dietary intake
The rate of complete consumption of the test beverages during the study period was not significantly different (P = .599) between the LOLT and OLT groups at 94.9% ± 14.9% and 96.5% ± 6.1%, respectively. Only 1 participant dropped out (in the LOLT group). No test-related adverse events occurred.
The mean amounts of energy and nutrients are shown in Table 3. During the intervention, the total energy intake decreased in both groups (LOLT group: P < .05; OLT group: P < .01), whereas protein and carbohydrate intake decreased only in the OLT group (protein: P < .05; carbohydrate: P < .01). However, there were no significant differences in the intake amount of these nutrients at each point and in the changes in the levels during the intervention between the 2 groups.
Table 3. Energy and nutrient intake during the intervention
LOLT group OLT group Pb
(n = 29) (n = 28)
Total energy (kJ/kg/d) Baseline 130.5 ± 37.7a 142.7 ± 40.6 .256
12 wk 116.3 ± 34.3⁎ 127.2 ± 41.4⁎⁎ .751c
Δ12 wk −14.2 ± 33.5 −15.1 ± 25.9 .917
Protein (g/kg/d) Baseline 1.2 ± 0.4 1.3 ± 0.4 .168
12 wk 1.1 ± 0.4 1.2 ± 0.5⁎ .795c
Δ12 wk −0.1 ± 0.2 −0.1 ± 0.3 .545
Fat (g/kg/d) Baseline 0.8 ± 0.3 0.9 ± 0.3 .263
12 wk 0.9 ± 0.3 1.0 ± 0.4 .664c
Δ12 wk 0.1 ± 0.3 0.1 ± 0.3 .915
Cholesterol (mg/kg/d) Baseline 6.7 ± 3.0 7.9 ± 3.6 .191
12 wk 6.2 ± 2.7 7.2 ± 3.3 .741c
Δ12 wk −0.5 ± 1.5 −0.7 ± 2.3 .778
Carbohydrate (g/kg/d) Baseline 4.1 ± 1.6 4.4 ± 1.4 .507
12 wk 3.6 ± 1.3 3.8 ± 1.4⁎⁎ .722c
Δ12 wk −0.5 ± 1.6 −0.5 ± 1.0 .938
Within-group differences from baseline were analyzed via paired t test. *P < .05, **P < .01.
a
Values are means ± SD.
b
Significant differences were computed via unpaired t test.
c
Significant differences were computed via analysis of covariance with each baseline value as covariate.
3.3. Physical activity
During the intervention, there was no change in MVPA in both the LOLT group (from 120 [40-250] [median {interquartile range}] min/wk to 120 [25-315] min/wk; P = .435) and the OLT group (from 130 [0-563) min/wk to 180 [0-353] min/wk; P = .211).
3.4. Anthropometric profiles and glucose and lipid metabolism in the ITT population
As shown in Table 4, WC tended to decrease in both the LOLT group (from 93.4 ± 4.8 cm to 92.9 ± 5.2 cm; P = .079) and the OLT group (from 90.4 ± 7.3 cm to 89.8 ± 7.2 cm; P = .093) during the intervention. FPG and immunoreactive insulin (IRI) levels tended to increase only in the LOLT group (FPG: P = .063; IRI: P = .069). The FPG levels in the OLT group were significantly decreased compared with those in the LOLT group (−1.4 ± 6.9 mg/dL vs 2.3 ± 6.4 mg/dL, P < .05). The log-TG and LDL-C levels were significantly decreased only in the OLT group (log-TG: from 2.02 ± 0.20 to 1.95 ± 0.17 mg/dL, P < .05; LDL-C: from 150.6 ± 37.6 to 140.0 ± 28.3 mg/dL, P < .01). LDL-C levels in the OLT group were significantly decreased compared with those in the LOLT group (−10.4 ± 15.4 mg/dL vs 1.5 ± 24.9 mg/dL; P < .05). The log-TG levels in the OLT group tended to be more decreased than those in the LOLT group (−0.07 ± 0.17 mg/dL vs 0.02 ± 0.18 mg/dL; P = .079).
Table 4. Anthropometoric profiles and glucose and lipid metabolism in the ITT populationa, b, c
LOLT group OLT group Pb
(n = 29) (n = 28)
BW (kg) Baseline 69.0 ± 9.2a 69.7 ± 9.3 .767
12 wk 68.7 ± 9.7 69.3 ± 9.7 .751c
Δ12 wk −0.3 ± 1.4 −0.4 ± 1.5 .809
WC (cm) Baseline 93.4 ± 4.8 90.4 ± 7.3 .075
12 wk 92.9 ± 5.2 89.8 ± 7.2 .673c
Δ12 wk −0.5 ± 1.5 −0.6 ± 1.9 .791
FPG (mg/dL) Baseline 100.7 ± 9.0 98.4 ± 7.8 .301
12 wk 103.0 ± 10.6 97.0 ± 6.7 .016c
Δ12 wk 2.3 ± 6.4 −1.4 ± 6.9 .042
IRI (μU/mL) Baseline 8.2 ± 4.1 8.0 ± 3.5 .826
12 wk 9.1 ± 5.0 8.0 ± 3.7 .234c
Δ12 wk 1.0 ± 2.6 −0.1 ± 3.8 .236
HOMA-IR Baseline 2.07 ± 1.08 1.97 ± 0.97 .730
12 wk 2.38 ± 1.48* 1.92 ± 0.96 .123c
Δ12 wk 0.32 ± 0.79 −0.05 ± 1.08 .144
HbA1c (%) Baseline 5.95 ± 0.23 5.91 ± 0.19 .436
12 wk 5.97 ± 0.20 6.01 ± 0.30⁎⁎ .108c
Δ12 wk 0.01 ± 0.19 0.10 ± 0.19 .080
log-TG (mg/dL) Baseline 1.99 ± 0.21 2.02 ± 0.20 .695
12 wk 2.01 ± 0.17 1.95 ± 0.17⁎ .059c
Δ12 wk 0.02 ± 0.18 −0.07 ± 0.17 .079
LDL-C (mg/dL) Baseline 151.6 ± 28.5 150.6 ± 37.6 .909
12 wk 153.2 ± 32.7 140.0 ± 28.3⁎⁎ .015c
Δ12 wk 1.5 ± 24.9 −10.4 ± 15.4 .036
HDL-C (mg/dL) Baseline 63.5 ± 13.8 59.3 ± 13.9 .260
12 wk 60.3 ± 14.3⁎ 56.6 ± 13.1⁎⁎ .998c
Δ12 wk −3.2 ± 7.8 −2.7 ± 5.0 .777
Within-group differences from baseline were analyzed via paired t test. *P < .05, **P < .01.
a
Values are means ± SD.
b
Significant differences were computed via unpaired t test.
c
Significant differences were computed via analysis of covariance with each baseline value as covariate.
HbA1c levels increased only in the OLT group (P < .01), whereas HDL-C levels decreased in both groups (LOLT group: P < .05; OLT group: P < .01). However, all change levels remained within the reference range.
3.5. Anthropometric profiles and glucose metabolism in participants with high WC at baseline
During the intervention, WC decreased significantly from 95.0 ± 4.9 to 94.0 ± 5.5 cm (P < .05), and FPG levels decreased from 97.8 ± 8.2 to 94.8 ± 6.6 mg/dL (P = .060) only among participants with high WC in the OLT group (Table 5). Additionally, the decrease in FPG levels was more pronounced in the OLT group than that in the LOLT group (−3.1 ± 6.2 mg/dL vs 2.5 ± 7.1 mg/dL; P < .05).
Table 5. Anthropometric profiles and glucose metabolism in participants with high WC at baselinea, b, c
LOLT group OLT group Pb
(n = 22) (n = 17)
BW (kg) Baseline 71.8 ± 8.6a 73.7 ± 8.2 .486
12 wk 71.5 ± 9.2 73.2 ± 8.8 .491c
Δ12 wk −0.3 ± 1.6 −0.5 ± 1.5 .643
WC (cm) Baseline 95.2 ± 3.8 95.0 ± 4.9 .896
12 wk 94.7 ± 4.6 94.0 ± 5.5⁎ .358c
Δ12 wk −0.5 ± 1.6 −1.0 ± 1.7 .364
FPG (mg/dL) Baseline 102.4 ± 8.2 97.8 ± 8.2 .092
12 wk 105.0 ± 10.5 94.8 ± 6.6 .005c
Δ12 wk 2.5 ± 7.1 −3.1 ± 6.2 .014
IRI (μU/mL) Baseline 9.1 ± 4.3 8.7 ± 3.9 .797
12 wk 10.2 ± 5.3 8.5 ± 3.9 .231c
Δ12 wk 1.2 ± 2.8 −0.2 ± 4.6 .262
HOMA-IR Baseline 2.30 ± 1.12 2.15 ± 1.08 .665
12 wk 2.70 ± 1.57⁎ 2.02 ± 1.02 .114c
Δ12 wk 0.39 ± 0.87 −0.13 ± 1.27 .138
HbA1c (%) Baseline 5.95 ± 0.25 5.87 ± 0.21 .293
12 wk 5.95 ± 0.20 5.95 ± 0.31 .391c
Δ12 wk 0.00 ± 0.21 0.08 ± 0.22 .240
Within-group differences from baseline were analyzed via paired t test. *P < .05, **P < .01.
a
Values are means ± SD.
b
Significant differences were computed via unpaired t test.
c
Significant differences were computed via analysis of covariance with each baseline value as covariate.
4. Discussion
The present study evaluated the effects of OLT for Japanese prediabetic adults who are mildly obese or have high-normal BMI. BW, WC, and parameters of glucose metabolism in the OLT group of the ITT population were not significantly reduced during the intervention.
Olive leaves are rich in polyphenols, of which the most abundant phenolic compound is oleuropein [20]. Previous studies that reported remarkable effects of olive polyphenols or oleuropein for antiobesity [21] and glucose metabolism improvement [22], [23] in enrolled participants who had MetS, obesity, or type 2 diabetes, with the intervention period lasting 3 years, 30 weeks, and 14 weeks. Meanwhile, our participants had lower BMI and FPG levels, and the duration of intervention was shorter. These differences in the intervention methods might have affected the results of our study. In addition, human studies on the antiobesity and anti-hyperglycemia effect of olive leaf extract or oleuropein have reported contrasting results. For example, one study observed reductions in blood lipid levels from olive leaf extract supplementation for 6 weeks (136 mg of oleuropein daily) in prehypertensive male volunteers, but the BMI, percentage of body fat, FPG, IRI, and HOMA-IR of these participants did not change [24]. Wainstein et al reported improvements in HbA1c and fasting IRI levels in type 2 diabetes via a 500-mg daily treatment of olive leaf extract for 14 weeks, but the participants’ postprandial IRI levels did not change [23].
However, in this study, the reduction in WC of the OLT group became significant when the analysis was limited to participants with abdominal obesity. FPG levels in the OLT group decreased more significantly than that in the LOLT group in both the overall population and those with abdominal obesity only. These findings indicate that the continuous intake of OLT may only weakly affect the decline of WC and FPG levels, but such an effect is more pronounced in participants with abdominal obesity.
Meanwhile, significant reductions in LDL-C and TG levels were only observed during the intervention in the OLT group, as expected. Changes in LDL-C levels in the OLT group were significantly lower compared with those in the LOLT group, and changes in TG levels in the OLT group tended to be lower than those in the LOLT group. Subgroup analysis with abdominal obesity showed a marked decrease in LDL-C levels in the OLT group at 12 weeks. These results indicate that OLT suppresses blood lipid elevation.
Lockyer et al demonstrated a significant reduction in TC, LDL-C, and TG levels in prehypertensive male volunteers who consumed a phenolic-rich olive leaf extract (136 mg of oleuropein daily) for 6 weeks [24], whereas a reduction in TC and LDL-C levels from oleuropein supplementation (100 mg of oleuropein daily) for 12 months among postmenopausal women had been also reported [25]. However, these studies were limited to a specific sex, whereas our study enrolled both men and women. Nonetheless, the results of the present study, which provided 321 mg of oleuropein daily, were similar to these findings.
Malliou et al reported that oleuropein is a PPARα ligand, and they also observed that oleuropein lowered serum TG and cholesterol in mice supplemented with 100 mg/kg of oleuropein daily for 6 weeks [3]. Priore et al observed a reduced activity of hydroxymethylglutaryl-CoA reductase, the rate-limiting enzyme of cholesterol synthesis, from oleuropein treatment in rat hepatocytes [4]. In the present study, the log-TG and LDL-C levels might have been reduced in the OLT group due to similar mechanisms.
This study has some limitations. First, the target population was only the general population in a specific area, thus limiting the generalizability of the results. Second, the effect of OLT on body weight and HbA1c has not been elucidated. However, the present study is the first to report the serum lipid-lowering effect of OLT in both men and women. Although such an effect may be limited to certain participants, our previous study has already shown that regular OLT intake leads to a significant decrease in WC and FPG [10]. Further investigation is needed to confirm the effect of OLT for human health.
Acknowledgment
This work was supported by a fund for joint research with Yamahisa Co, Ltd (Kagawa, Japan). The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results. Katsutaro Uematsu, chairman of Yamahisa Co, Ltd, and Koichi Matsui, an employee of Yamahisa Co, Ltd, helped in the preparation of the test beverage. We would also like to thank Hiroyuki Shibasaki, an employee of Kagawa Prefectural Industrial Technology Center, for his help and advice on the analysis of components in the test beverage. We also thank Editage (www.editage.jp) for English-language editing. The authors declare no conflicts of interest associated with this manuscript.
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