DOI: 10.31038/JCRM.2018144

Abstract

The risk of arteriosclerosis may be reduced by increasing the levels of α-linolenic acid (ALA), a omega-3 polyunsaturated fatty acid. Perilla oil contains abundant ALA. This randomized crossover clinical study of perilla oil investigated its safety and effects on the levels of ALA and lipid profile in 10 subjects. Half of the subjects took 1 tablespoon of perilla oil (ALA content = approximately 9.4 g) and the remaining half took 1 tablespoon of olive oil (ALA content = approximately 0.09 g) daily for 1 week. After a 28-day washout period, each group switched and took the other oil for 1 week. Variables were measured before and after each week of oil ingestion. The ratio of low density lipoprotein cholesterol to high density lipoprotein cholesterol significantly decreased after ingestion of perilla oil (2.7 ± 0.6 vs. 2.6 ± 0.6, P = 0.037). The levels of ALA significantly increased after ingestion of perilla oil (31.6 ± 10.32 vs. 67.93 ± 24.35 µg/mL, P = 0.001). There were no adverse effects related to perilla oil. Therefore, as a dietary supplement, perilla oil has beneficial effects on the levels of ALA and lipid profile, suggesting that it contributes to a reduction in the risk of arteriosclerosis.

Keywords

Perilla oil, Olive oil, Arteriosclerosis, Vascular endothelial function, Reactive hyperemia index

Introduction

Arteriosclerosis leads to heart and cerebrovascular diseases and is the leading cause of death worldwide. Risk factors for arteriosclerosis are diabetes (DM), hypertension, dyslipidemia, obesity, and smoking [1]. Omega – 3 polyunsaturated fatty acids have attracted attention for their prophylactic effect against various disorders, including atherosclerosis, coronary artery disease, and inflammatory diseases [2, 3]. There are reports indicating that a high intake of α-linolenic acid (ALA), a plant-derived omega – 3 polyunsaturated fatty acid, is associated with a reduced risk of arteriosclerosis [4, 5]. Perilla oil contains 50%–60% of ALA. This oil can easily be used as a daily dietary supplement. In the human body, ALA synthesizes eicosapentaenoic acid (EPA) [6]. It has been reported that EPA and docosahexaenoic acid (DHA), both omega – 3 polyunsaturated fatty acids contained in fish oil, exhibit antithrombotic and lipid-lowering actions [7, 8]. There have been few studies of perilla oil and its hypothetical effect on reducing arteriosclerosis.

ALA inhibits arteriosclerosis-associated inflammation and reduces oxidative stress, which contributes to improve vascular endothelial function [9, 10]. Reactive hyperemia index (RHI) has been reported to be useful for evaluating vascular endothelial function. Moreover, it is a good predictor of cardiovascular disease [11, 12]. Previous studies have suggested that ALA reduces diastolic blood pressure and increase serum triacylglycerol concentration [13]. Salonen, J.T et al. showed that estimated dietary intake of linolenic acid has an inverse correlation with mean resting blood pressure [14]. However, it must be noted that overdoses of ALA, EPA, and DHA may cause blood coagulation [15].

We conducted a randomized crossover clinical trial of perilla oil to evaluate its safety and effects on the levels of ALA, lipid profile and endothelial function as markers of atherosclerotic risk.

Materials and Methods

Test diets. Perilla oil, extracted from perilla seeds, was used as the study oil. A commercially available olive oil was used as a placebo control. The ALA content of the perilla oil was 62.9 g/100 g, while that of the olive oil was 0.6 g/100 g. The ALA content was measured at the Japan Food Research Laboratories (Tokyo, Japan). Both oils were given in a dose size of 1 tablespoon as a daily supplement at breakfast for 1 week. The estimated content of ALA in each dose was approximately 9.4 g in the perilla oil and 0.09 g in the olive oil.

Subjects. Ten untreated individuals (4 male and 6 female) who had at least two risk factors for arteriosclerosis (aging, first-degree hypertension, dyslipidemia, DM, obesity, and smoking) were enrolled [16]. For the purposes of this study, hypertension was defined as a systolic blood pressure of 140 to 159 mmHg or a diastolic blood pressure of 90 to 99 mmHg. Dyslipidemia was defined as a low-density lipoprotein cholesterol (LDL-C) ≧ 140 mg/dL. Diabetes was defined as a fasting blood glucose concentration ≧ 126 mg/dL, or a hemoglobin A1c (HbA1c) ≧ 6.37%. Obesity was defined as a body mass index (BMI) ≧ 25 kg/m². Smoking was recorded as a risk factor regardless of whether it was past or present. The definition of aging was 45 years or older men and postmenopausal women. Table 1 shows the subjects’ characteristics. The study was approved by the Ethics Committee of Nanpuh Hospital, Kagoshima Kyosaikai, Public Interest Inc. Association, Japan. Clinical examinations were performed according to the principles of the Declaration of Helsinki. Written informed consent was obtained from all individuals.

Table 1. Characteristics of subjects taking perilla oil or olive oil supplements

Study design. This study was designed as a crossover method. The 10 subjects were randomly divided into two groups of 5, the first group took perilla oil daily for 1 week and the second group took olive oil. After a 28-day washout period, the groups were reversed, with the first group took olive oil daily for 1 week and the second group took perilla oil (Table 2).

Table 2. Protocol of clinical study design

¹ Body mass index (kg/m²), ² Reactive hyperemia index (-), ³ Washout

Variables were measured before and after each 1-week period of oil ingestion. All measurements at the beginning of each period were completed on the first day of the period before the supplement was given. The measurements after each period were taken the next day of the last oil supplement.

Physical parameters were measured including blood pressure, BMI, RHI, and blood examinations. RHI, a measure of peripheral endothelial function, was assessed using peripheral arterial tonometry (EndoPAT 2000; Itamar Medical, Caesarea, Israel) according to the manufacturer’s instructions. Serum levels of aspartate and alanine aminotransferase, total protein, γ-glutamyl transferase, and C-reactive protein were determined by latex agglutination using a BM6050 analyzer (Kyowa-Medex Co., Ltd., Tokyo, Japan). Serum levels of uric acid, blood urea nitrogen, glucose, triglycerides, high density lipoprotein cholesterol (HDL-C), LDL-C, and HbA1c were measured using a BioMajesty JCA-BM6050 analyzer (JEOL Ltd., Tokyo, Japan). The white blood cell (WBC), red blood cell (RBC), and platelet counts were measured with an XE-5000 Hematology Analyzer (Sysmex, Co., Hyogo, Japan). Plasma fatty acids (lauric, myristic, myristoleic, myristoleic, palmitic, palmitoleic, stearic, oleic, linoleic, γ-linolenic, α-linolenic, arachidic, eicosenoic, eicosadienoic, 5–8-11 eicosatrienoic, dihomo-γ-linolenic, arachidonic, eicosapentaenoic, behenic, erucic, docosatetraenoic, docosapentaenoic, lignoceric, docosahexaenoic, and nervonic acids) were measured by SRL Inc (Tokyo, Japan).

Subjects were interviewed regarding their intake of the test oils and any symptoms they experienced during the study.

Statistical analysis. Measured values are expressed as means ± standard deviation. The data were assessed using a paired t-test to compare results before and after ingestion of each oil. Data were analyzed using SPSS Version 25 (IBM Co., Armonk, NY, USA). A value of P <0.05 was considered statistically significant.

Results

Physical parameters. There were no significant differences in blood pressure, BMI, or RHI before and after the week-long interventions with perilla oil or olive oil (Table 3).

Table 3. Physical parameters in subjects taking perilla oil or olive oil

Values are presented as mean ± standard deviation; n = 10.

Biochemical markers. After a week of perilla oil, the LDL-C/HDL-C ratio decreased significantly from 2.7 ± 0.6 to 2.6 ± 0.6
(P = 0.037, Fig. 1A). There was no statistically significant difference in the LDL-C / HDL-C ratio after subjects ingested olive oil (2.9 ± 0.8 before vs. 2.8 ± 0.7 after, P = 0.314, Fig. 1B). Perilla oil thus improved the LDL-C / HDL-C ratio.

Figure 1. Ratios of low density lipoprotein cholesterol (LDL-C) to high density lipoprotein cholesterol (HDL-C) before and after 1 week of intake of perilla oil (A) or olive oil (B). Values are presented as mean ± standard deviation; n = 10.

With the exception of significant decrease of the platelet count after a week of olive oil, none of the other biochemical or hematologic markers differed significantly before and after either perilla oil or olive oil (Table 4).

Fatty acids. We compared the levels of ALA before and after test oil intake. Fig. 2 shows the result of the levels of ALA before and after 1 week of intake of perilla oil or olive oil, respectively. The levels of ALA increased significantly after intake of perilla oil (31.60 ± 10.32 vs. 67.93 ± 24.35 μg/mL, P = 0.001, Fig. 2A), while the levels did not change after intake of olive oil (30.52 ± 10.34 vs. 32.74 ± 21.26 μg/mL, P = 0.702, Fig. 2B).

Figure 2. Levels of α-linolenic acid before and after 1 week of intake of perilla oil (A) or olive oil (B). Values are presented as mean ± standard deviation; n = 10.

The levels of EPA also increased significantly after perilla oil but not after olive oil (perilla oil: 46.88 ± 16.40 vs. 64.43 ± 31.32 μg/mL, P = 0.023, Fig. 3A; olive oil: 60.44 ± 44.62 vs. 53.90 ± 28.36 μg/mL, P = 0.598, Fig. 3B).

Figure 3. Levels of Eicosapentaenoic acid before and after 1 week of intake of perilla oil (A) or olive oil (B). Values are presented as mean ± standard deviation; n = 10.

Table 4. Biochemical and hematology markers before and after ingesting perilla oil or olive oil for 1 week

Values are presented as mean ± standard deviation; n = 10.
*Significant difference in values analyzed with a paired t-test.

None of the other fatty acids differed significantly before and after intake of either oil (Table 5).

Table 5. Levels of Fatty acid before and after ingestion of perilla oil or olive oil for 1 week

Values are presented as mean ± standard deviation; n = 10.

Safety. There were no serious adverse events related to the intervention. There were also no significant changes in WBC, RBC, and platelet counts after ingestion of perilla oil.

Discussion

Prevention of arteriosclerosis which leads to cardiovascular disease is very important [17]. Given its apparent preventing effects, we focused our experiments on ALA and confirmed that a week’s daily intake of perilla oil significantly increased the plasma levels of ALA and EPA. It has been reported that 11% to 19% of ALA ingested from a meal is converted to EPA or DHA through an in vivo chain extension process [18]. In this study, ALA and EPA increased significantly after intake of perilla oil.. The levels of LDL-C and HDL-C were not changed after intake of perilla oil, while the LDL-C/HDL-C ratio was significantly improve. Recently, the LDL-C/HDL-C ratio has been regarded as an important index of arteriosclerosis. Even in the presence of normal levels of LDL-C, myocardial infarction may occur with low levels of HDL-C. Prevention of arteriosclerosis thus necessitates balancing the levels of LDL-C and HDL-C, which supports the concept of the LDL-C/HDL-C ratio as an important index [19, 20]. Previous study has been reported that Omega – 3 polyunsaturated fatty acids treatments reduced serum total cholesterol and LDL-C and increased HDL-C [21]. Improving of HDL-C / LDL-C ratio is important for prevention of arteriosclerosis [22]. Improving the ratio would be important to reduce arteriosclerosis risk.

No other significant differences except the changes in the LDL-C/HDL-C ratio and levels of ALA and EPA after ingestion of perilla oils were found in any of the variables we measured. There were no changes in blood pressure or BMI. Overdoses of ALA, EPA, and DHA may affect blood coagulation [15]. However, the platelet counts in our subjects did not change significantly before and after ingestion of perilla oil, and no adverse events related to blood clotting were occurred. No adverse events occurred. Therefore, the daily ingestion of perilla oil for 1 week appears to be safe.

RHI evaluates the vasodilator functions of vascular endothelium-derived vasodilators [23]. In this study, RHI was measured as an indicator of vascular endothelial function. Long-term treatment with EPA has been reported to improve impaired endothelium-dependent relaxations of atherosclerotic blood vessels [24]. In this study, we expected that the RHI might improve by perilla oil-induced increases in ALA, but there was no significant difference in the RHI before and after perilla oil.

Because ours was a short-term study with ingestion of perilla oil occurring for only 1 week and involving a small number of subjects, the study may have been underpowered to detect a significant difference in the RHI. Future studies in large numbers of individuals with long-term intake of perilla oil are needed.

Conclusion

We confirmed significant increases in the plasma levels of ALA and improvement in the LDL-C/HDL-C ratio induced by intake of perilla oil. To the extent that improvement of those markers may have a preventive effect against arteriosclerosis, our study suggests that ingestion of perilla oil may be of value in decreasing or preventing arteriosclerosis. Confirming this hypothesis will require long-term administration of perilla oil supplementation and adequate numbers of subjects so that cardiovascular outcomes can be assessed.

Acknowledgments

We are grateful to J. Saito and M. Kamiaraiso and the staff of the Department of Clinical Laboratory, Nanpuh Hospital for their tireless efforts in the carrying out this study. We also thank the study subjects for their participation.

Conflict of Interest

No potential conflicts of interest were disclosed.

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DOI: 10.31038/JCRM.2018143

Abstract

Objective Preventive screenings and services to assess and monitor health-status in employees give valuable insights for individuals and increase health-consciousness. This may influence health-related behaviour. The BARABAZ-scan is a non-invasive test that is used to screen physiological measures. This study describes the construct validity of the signals from the BARABAZ-scan compared to signals from a golden standard instrument for the variables galvanic skin response, oxygen saturation of the blood and heath rate variability.

Methods: In the spring of 2018 three consecutive measurements per subject were conducted in a private practice. The room where measurements took place was decorated quietly and calming music was played.

Results: Of all 75 participants, 56 were female. The median age of the participants was 50 (21–82) 34 years of age. GSR-scores varied between the BARABAZ-scan and Shimmer and showed a median (range) of respectively µS = 50 (19–60) and µS = 32 (3–80). A strong correlation was found on GSR- scores between both devices ρ = 0.75 (p < 0.001). Oxygen saturation showed a mode of SpO2 = 99 and ranged from SpO2 = 95 to 99 on both instruments. The correlation between the measurements was strong with a ρ = 0.97 (p < 0.001). HRV gave a median (range) score for the RR-intervals from the BARABAZ-scan and Mobi 8 of respectively 0.867 (0>618–1.163) and 0.877 (0.651–1.052) seconds, the RMSSD was calculated at 28 ± 10.8 and 28 ± 9.4. The agreement was found at ICC = 0.98.

Conclusions: Based on this research, strong correlations were found between signals from the BARABAZ-scan and the golden standard references. The measurements from the BARABAZ-scan are useful to gain insight into physiological measures within a working age population.

Keywords

physiology, biometry, employment

Background

Good health of employees is a precondition for sustainable engagement. Preventive screenings and services to assess and monitor health-status in employees give valuable insights for individuals and increase health-consciousness. This may influence health-related behaviour. When risk factors can be identified an early intervention may be prominent to prevent negative health outcomes.

The BARABAZ-scan is a non-invasive test that is used to screen body functions related to personal capacity and stress resilience criteria. Physiological measures like the electrical resistance of the skin also referred to as galvanic skin response (GSR), oxygen saturation of the blood and heart rate variability (HRV). These measures will be explained in the next paragraphs.

The Galvanic Skin Response (GSR) is defined as a change in the electrical properties of the skin as a parameter of the sweat gland function. The signal can be used to describe the function of the autonomous nervous system [1]. The electrical properties of the skin are influenced by emotions and stress. As a result of an emotional stress reaction, there is a small change in the activity of the sweat glands in the skin. As the sweat glands release sweat, small changes of the skin’s moisture change the skin and tissue conductance, which is measured by the GSR-sensor.

Recent studies show that GSR provides diagnostic information of autonomic dysfunction as well as small somatosensory nerves [2,3]. This information is particularly of interest for diabetics, patients with metabolic syndrome, and patients with micro-vascular complications [4–6]. Sudomotor dysfunction is associated with significant peripheral artery disease, vascular inflammation, and impaired glycaemic status [4–6]. Finally, an autonomic dysfunction can be used as an early detection of neuropathy in high- risk populations like diabetics. The clinical importance of GSR measurement now became ever greater, due to the diagnostic value that such a measurement can have.

Oxygen saturation (SpO2) in the blood is monitored by pulse oximetry. A pulse oximeter shines red and infrared light through a part of the body that is relatively translucent and has good arterial pulsed blood flow. The ratio of wavelengths of the red to infrared light that passes through the body part and is received by the oximeter’s detector depends on the percentage of oxygenated versus deoxygenated hemoglobin through which the light passes. The percentage of oxygen saturation thus calculated is normally greater than 95%.

This noninvasive method offers useful insights in a range of patient groups. Pulse oximetry is used for diagnosis in case of acute respiratory failure in patients with chronic obstructive pulmonary disease [7]. Furthermore, low oxygen saturation is associated with a higher risk of cognitive impairment in elderly adults [8]. Finally, pulse oximetry is commonly used in detecting sleep disorders such as apnea and hypopnea [9].

The heart rate variability (HRV) describes the changes in the time intervals between successive heartbeats. Therefore, the accurate detection of heartbeats’ timing is of crucial importance for the HRV analysis. This detection is, generally, accomplished using the ECG signal. An alternative method of measuring HRV is using blood volume pulse (BVP) signals, which seems to be a promising alternative [10]. Detecting beat-to-beat intervals (RR-intervals) using BVP is based on a principle called photopletysmography which consists of measuring the changes in volume using an optical method [11]. Changes in blood volume are caused by the change in blood pressure following every pulse. Compared with an ECG sensor, the BVP sensor can be considered more ‘user-friendly’ and less obtrusive.

The HRV is an indirect measure of the activity of the autonomous nervous system and especially the short-term measurements are suitable for ambulatory care and patient monitoring providing immediate test results [12]. A low HRV is a strong indicator of compromised health in the general population. Reduced regulatory capacity may contribute to functional gastrointestinal disorders, inflammation, and hypertension [13]. Furthermore, low HRV contributes to the prediction of all-cause mortality in prognostic modelling [14,15].

To determine the construct validity, every signal from these physiological measures retrieved from the BARABAZ-scan is compared with a golden standard measurement device. This study aims to under scribe the use of the BARABAZ-scan in daily use answering the following research question: What is the construct validity of the signals from the BARABAZ-scan compared to signals from a golden standard instrument for the variables galvanic skin response, oxygen saturation of the blood and heath rate variability?

Methods

In the spring of 2018 healthy volunteers between 18 and 67 years of age were recruited in a network of joint companies in the south of The Netherlands were invited for the study by email. One week after receiving the invitation people were called to ask for their willingness to participate. Participants were planned on one of five measurement days until a maximum of 75 study subjects was achieved. Exclusion criteria for participation were cardiovascular diseases, a pacemaker, significant skin damage, excessive sweating; metal prostheses in the fingers or limbs; pregnancy; use of medication that can affect the heartbeat. This study was approved by the Ethics Committee in Maasstad Hospital under protocol 2018–20.

Instruments

The bio-impedance sensor of the Barabaz-scan measures electrodermal activity. Besides that, the Barabaz-scan has two sensors placed on the participants’ forehead, which allows the device to measure GSR over different circuits1. A golden standard for this measure was the Shimmer 3 GSR+ which was placed on proximal part of the index- and middle finger. Measurements were taken simultaneously. This instrument was found valid in multiple research situations [16–18].

Signals from the digital pulse oximeter in the Barabaz-scan (Contec CMS 50H) are compared to the measures taken with the Onyx Vantage 9590 oximeter by Nonin. A medical device validated for clinical use and scientific research [19]. Arterial blood gas measurements, obtained by arterial puncture, remain the gold standard for measurement of oxygen saturation [20]. However, this device is able to accurately measure in challenging conditions like when people move, have dark skin pigmentation or poor peripheral blood circulation [21]. The device uses pulse-by-pulse filtering to provide precise oximetry measurements. A good accuracy (difference  < 1.5%) was shown during rest and exercise [21]. Measurements were taken straight after each other on the same index finger.

A 3-lead ECG from a TMSi Mobi 8 was used to collect data on the HRV of the participants and compare these signals with the Barabaz-scan on the RR-intervals and RMSSD. ECG sensors were placed on both clavicula and a ground electrode on the hand. The same oximeter was used on the index finger. To evaluate the correlation between the HRV parameters computed from BVP and ECG signals measures were acquired simultaneously. The ECG directly detects the R-peek, the BVP needs to be converted into a heart signal [13]. For further analysis of the ECG signal the Pan- Tompkins QRS algorithm was applied for QRS detection.

Procedure

Participants were asked not to drink alcohol or train intensively a day before the measurements, not to eat an hour before the measurements but drink sufficiently. All tests were conducted in a controlled environment following a standardized protocol. The protocol was pilot-tested and trained by all testers prior to data collection. Prior to the measurements, the study protocol was explained, and Participants subjects gave their informed consent. Measurements took place in a private practice in a quietly decorated room where calming music was played. Three consecutive measurements were conducted to secure a useful dataset. Measurements lasted two minutes, the participants didn’t speak during the measurements to minimize the chance of artifacts.

Statistical Analysis

The first dataset is being used, unless there is missing data due to possible artifacts, it that case the second or third dataset was used. Descriptive statistics are used to present baseline characteristics and collected measures. The Kolmogorov-Smirnov test showed that data is not normally distributed. Hence, Spearman’s correlation coefficient is used to test the association between instruments for GSR and oxygen saturation. The HRV was compared using intra class correlation (acceptable, 0.75- 0.89, excellent ≥ 0.9) [22]. A sample size calculation according to Bonett and Wright (2000) was performed and showed a minimum required number of 62 subjects [23]. The correlation was classified as poor (0.00 to  ± 0.25), fair ( ± 0.25 to  ± 0.50), moderate ( ± 0.50 to  ± 0.75), or strong ( ± 0.75 to  ± 1.00) [22]. All statistical analyses were performed using SPSS 24 for Windows.

Results

Of all 75 participants, 56 were female. The median age of the participants was 50 (21–82) years of age. GSR-scores varied between the BARABAZ-scan and Shimmer and showed a median (range) of respectively μS = 50 (19–60) and μS = 32 (3–80). A strong correlation was found on GSR-scores between both devices ρ = 0.75 (p < 0.001). Oxygen saturation showed a mode of SpO2 = 99 and ranged from SpO2 = 95 to 99 on both instruments. The correlation between the measurements was strong with a ρ = 0.97 (p < 0.001). HRV gave a median (range) score for the RR-intervals from the BARABAZ-scan and Mobi 8 of respectively 0.867 (0.618–1.163) and 0.877 (0.651–1.052) seconds, the RMSSD was calculated at 28 ± 10.8 and 28 ± 9.4. The agreement was found at ICC = 0.98.

Discussion

Based on this research, strong correlations were found between signals from both the BARABAZ- scan and the golden standard references. The measurements from the BARABAZ-scan are valid and therefore useful to gain insight in physiological measures within a working age population. These measures are relating to personal health status which could be a valuable way to increase sustainable engagement for organizations.

Acknowledgements

The authors of this paper would like to thank C. Posthumus en C. Gunther for their help with data collection and clinical assessment.

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DOI: 10.31038/JCRM.2018142

Commentary

When observing the medical and health situation in the world, diabetes, obesity and metabolic syndrome have been crucial social problems in developed and also developing countries [1]. Especially, the diet therapy would be indispensable which can be continued for long years such as low carbohydrate diet (LCD) and Calorie restriction (CR). LCD was originally begun by Atkins and Bernstein before, and it has been known and popular until now. [2, 3].

After that, there was a meaningful report from Dietary Intervention Randomized Controlled Trial (DIRECT) Group that showed the predominance compared with Mediterranean and Low-Fat Diet for 2 years [4]. Successively, DIRECT group reported the results for 4 years [5]. Thus, several researchers reported the predominance of LCD for weight reduction or HbA1c value [6].

 In contrast, authors and colleagues have introduced and developed LCD in Japan for long years [7]. We have continued practice and research of LCD and activities of Japan LCD promotion association, including educational seminars, medical journals / books and presenting in medical society [8].

There has been lots of discussion about LCD and CR for years. LCD has rather superiority to CR diets and low-fat foods in the light of weight control and blood glucose variety in short period [4]. For more than 1 year or more, continuing discussion has found concerning the comparison of LCD and CR [9]. Some reports showed beneficial effect of LCD and others revealed unremarkable difference between them [6, 10, 11].

There is a prospective randomized controlled trial (RCT) that LCD of 130g /day for 6 months reduced HbA1c and BMI more than CR [12]. However, the benefit for LCD after intensive intervention has not always maintained in the light of HbA1c and BMI between LCD and CR. This study was continued and summarized one year after regarding the comparison between LCD and CR. The result showed the beneficial efficacy for the LCD on reduction of HbA1c and BMI, but improved levels did not persist compared with that of CR. However, when combined the data of both groups, HbA1c and BMI values were significantly decreased from the baseline. The superiority of LCD seemed to disappear 1 year after, but those results would suggest the comparative efficacy to improve HbA1c value at least 1 year [12].

As described above, the discussion of the clinical effect for LCD and CR has been continued for long years. However, we cannot induce the final conclusion which is superior. They are various factors involved in the evaluation and measurement of the both methods. The research has been not in vitro research or in vivo study of the same feeds to rat every day, but clinical meal study for human in their ordinary daily life.

In the primary care setting, general efficacy of LCD has been understood rather widely. On the other hand, a problem has been known about whether the LCD continuation is possible, or whether the effect of weight reduction is possible during rather long period. After a while, some patients return to their previous meal style [13]. There are some reports that the effect of LCD can be sustained rather long term [14]. Since there are various influential factors, it will be necessary to investigate related influence into detail analysis [15].

 A recent report was found that revealed several results against the previous clinical effect for LCD. There has been the Atherosclerosis Risk in Communities (ARIC) Study which has continued its research development for some decades [16]. The ARIC study has many subjects more than 430 thousand for 25 years [17]. According to the results of ARIC cohort study, they have reported a U-shaped association between the percentage of energy of carbohydrate (mean 48·9%, SD 9·4) and mortality, after calculating for multivariable adjustment. Furthermore, they calculated and compared the total carbohydrate ratio of the diet. As a result, daily meal including high (>70%) percentage or low (<40%) percentage of energy from carbohydrates were observed, in association with elevated mortality rate, and with minimal risk found between carbohydrate content ratio in 50–55% [17].

In order to evaluate the optimal intake amount of carbohydrate for the guidance recommendations associated with certain medical evidence, the protocol included the population-based study of overall carbohydrate consumption [17]. Especially, it investigated the association of carbohydrate intake amount in accordance with mortality and residual lifespan levels. As a daily meal method, LCD was applied for reducing body weight and decreasing the cardiovascular and metabolic risk. At the same time, they recommended to replace of carbohydrate food with other proteins and plant-based fats. This procedure can give the subjects practical approach for daily healthy life in the light of anti-aging medicine [17].

In the practice and research on diabetes, how should we think about the relationship between clinical matters and the Evidence-Based Medicine (EBM)? [18] EBM has not only critically examined evidence, but also considered practicality, reality and individual tastes and situations. Short-term LCD has been effective by conventional reports and may increase the motivation feeling for progressive cure and care for the patients [19]. However, on the other hand, for long-term LCD, we have to consider the required daily calorie and also carbohydrate intake amount. Based on this situation, we would like to aim for Taylor-made diet therapy according to each patient, taking account of feasibility, continuity and safety [20, 21].

 In summary, the discussion on the comparison of LCD and CR has been continued for years. The main point would be the clinical efficacy for rather long term. Each report includes each definition of LCD such as the different amount or ratio of carbohydrate in the food. Consequently, further accumulation of the data would be expected for future practice and research development.

Key words: low carbohydrate diet (LCD), Calorie restriction (CR), Dietary Intervention Randomized Controlled Trial (DIRECT), Atherosclerosis Risk in Communities (ARIC), Japanese LCD Promotion Association (JLCDPA)

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