33

REVIEWParadigm Shifts in Nutrition Therapy for Type 2 Diabetes

– Nutrition Therapy for Diabetes –Satoru Yamada

Kitasato Institute Hospital Diabetes Center, Tokyo, Japan

(Received for publication on November 4, 2016)(Revised for publication on March 15, 2017)(Accepted for publication on April 13, 2017)

(Published online in advance on April 25, 2017)

Currently, the low-energy diet is the only recognized nutrition therapy for type 2 diabetes in Japan. However, in recent decades, many foreign scientific organizations have accepted various nutritional approaches to manage diabetes, such as the low-carbohydrate diet, the Mediterranean diet, diet ap-proaches to stop hypertension (DASH), and the vegetarian diet. Moreover, growing evidence has called into question classical nutritional approaches such as the low-fat diet for the prevention of cardiovascu-lar disease and the low-protein diet for the prevention of diabetic kidney disease. Similarly, the recom-mended nutrition therapy for diabetes may change in near future. Such changes in nutrition therapy must be dynamic and based on not only scientific evidence but also each patient’s narrative. (DOI: 10.2302/kjm.2016-0016-IR) ; Keio J Med 66 (3) : 33–43, September 2017)

Keywords: low-carbohydrate diet, low-fat diet, patient-centered communication

Introduction

Nutrition therapy is the initial treatment for diabetes. However, recommended nutrition therapies tend to be largely based on consensus among experts rather than on scientific evidence. The principles of nutrition therapy in Japan have been inherited from the pioneers of diabetes research, but they lack current updates reflecting advanc-es in nutrition science. Nutrition science is a constantly advancing field, just like other fields of science, and the accepted knowledge base changes over time. This article reviews nutrition therapy for diabetes. First, the history of nutrition therapy for diabetes will be described and then the future directions will be discussed.

History of Nutrition Therapy for Diabetes

Nutrition therapy in the early years of diabetology (starvation diet or low-carbohydrate diet)

Before the discovery of insulin in 1921, there was no pharmacotherapy for type 1 diabetes mellitus. The treat-ment options consisted of the starvation diet (proposed by Dr. Frederic Allen) or the extremely low-carbohydrate diet (proposed by Dr. Elliot Joslin). In 1922, insulin be-came available, and type 1 diabetes mellitus became treatable. Thereafter, with the advent of insulin, the starvation diet fell out of use and the low-carbohydrate diet was recommended less frequently. Liberalization of carbohydrate intake was recommended by some experts. In 1971, the first American Diabetes Association (ADA) Dietary Guidelines emphasized the liberalization of car-bohydrate intake.1 The guidelines implied that carbohy-drate restriction had been recommended at least until the 1960s. In Japan, The Food Exchange Table for Diabetes

Reprint requests to: Satoru Yamada, MD, PhD, Kitasato Institute Hospital Diabetes Center, 5-9-1 Shironake, Minato-ku, Tokyo 108-8642, Japan E-mail: yamada-s@insti.kitasato-u.ac.jpCopyright © 2017 by The Keio Journal of Medicine

Yamada S: Nutrition Therapy for Diabetes34

(first edition), published in 1965, emphasized the impor-tance of energy restriction and carbohydrate restriction in parallel, reflecting the prevailing thought in nutrition science at the time.

Nutrition therapy for diabetes in the late 20th century (the golden age of the low-fat diet)

In the 1970s, nutrition therapy for diabetes entered a new phase. The worldwide increase of type 2 diabetes mellitus and its complications became a major health con-cern. The prevention of cardiovascular disease in patients with type 2 diabetes received more attention than the glycemic control of patients with type 1 diabetes, lead-ing to a greater interest in nutrition therapy. The Seven Countries Study was designed to investigate the relation-ship between diet and cardiovascular disease. The results, reported in 1953, showed that cardiovascular deaths were more frequent in countries with higher fat consumption than in countries with lower fat consumption, and this finding led to a general belief that a low-fat diet was use-ful for the prevention of cardiovascular deaths.2 However, some ethnic groups with higher fat consumption, such as those living in the Mediterranean region, had fewer car-diovascular deaths.3 In addition, a randomized controlled trial conducted in the 1970s did not find an association between the low-fat diet and reduced total mortality or cardiovascular mortality.4 Despite these negative find-ings, the McGovern Report was published in 1977, and the importance of the low-fat diet was increasingly em-phasize in the United States. In response, the ADA re-vised their recommendations in 1979, emphasizing the importance of the low-fat diet.5 The ADA recommended that carbohydrate intake should make up 50–60% of the total energy intake, whereas, in 1971, it recommended that carbohydrate intake should not exceed 45% of the total energy intake. This change occurred when the lib-eralization of carbohydrate intake was being more widely suggested.5 A similar change took place in Japan. The importance of carbohydrate restriction had been empha-sized until the Food Exchange Table 4th edition (1980) and its supplement (1983); however, carbohydrate re-striction was excluded from the Food Exchange Table 5th edition (1993). In 2002, the Evidence-based Practice Guidelines for the Treatment of Diabetes in Japan recom-mended that carbohydrate intake should be 50–60% of the total energy intake.

Current nutrition therapy for diabetes (re-evaluation of carbohydrate restriction, decline of fat restriction, and the emergence of a variety of diet therapies)

As mentioned above, the benefits of carbohydrate re-striction were de-emphasized in the 1979 ADA guide-lines; however, the clinical significance of the low-carbo-

hydrate diet continued to be recognized as the Atkins diet for obesity and the Bernstein diet for diabetes became prevalent in the field of popular medicine. The A TO Z Weight Loss Study was scientifically designed to test the effectiveness of popular diets; it demonstrated that the Atkins diet was the most effective for treating obesity.6 In response to this, the ADA guidelines in 2008 recom-mended a low-carbohydrate diet as the first choice for the treatment of obesity.7 In 2008, the Dietary Intervention Randomized Controlled Trial (DIRECT) reported that the low-carbohydrate diet was the most effective for im-proving hemoglobin A1c (HbA1c) levels in patients with diabetes.8 In DIRECT, 322 Israelis with body mass in-dexes (BMIs) of 27 or higher and who were at risk for car-diovascular disease were randomly allocated to three diet groups: the low-carbohydrate diet group (carbohydrates were initially restricted to 20 g/day and then increased to 120 g/day), the low-fat and low-energy diet group, and the Mediterranean low-energy diet group. All groups showed weight reduction at 2 years after the start of the diet. Among the three groups, the low-carbohydrate diet group showed the best results in energy intake and weight reduction, despite having no energy restriction (Fig. 1). This group also had the best improvements in lipid pro-files and in levels of high-sensitivity C-reactive protein and adiponectin.8 Interestingly, the mean HbA1c level in this group decreased by 0.9%; however, there was almost no change in fasting blood glucose levels. These results suggest that the low-carbohydrate diet can stabilize blood glucose fluctuations. Furthermore, subsequent subanaly-ses showed that the improvement in body weight and lipid profiles induced by the low-carbohydrate diet was main-tained for up to 6 years.9 The low-carbohydrate diet also reportedly improves the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease stage 310 and contributes to regression of atherosclerosis.11

As part of the re-evaluation of the low-carbohydrate diet, in 2012, Santos et al. conducted a meta-analysis of randomized controlled trials of this diet. A total of 23 articles (17 studies) were selected from published clini-cal trials involving at least 100 subjects with an interven-tion period of at least 3 months. The results showed that the low-carbohydrate diet had positive effects not only on blood glucose, lipid profiles (in particular, high-den-sity lipoprotein cholesterol and triglycerides), and body weight but also on blood pressure; moreover, the effects were not influenced by the duration of the clinical study.12

Thus, the benefits of the low-carbohydrate diet for im-proving blood glucose levels, body weight, lipid profiles, and blood pressure have been demonstrated in random-ized controlled trials (evidence level 1). In response to these findings, the ADA 2013 guidelines recommended the low-carbohydrate diet as a first-choice treatment for diabetes.13

In contrast, the low-fat diet was found to be ineffec-tive in a randomized controlled trial conducted in the

35Keio J Med 2017; 66 (3): 33–43

21st century, although, based on the results of the Seven Countries Study and other observational studies, it was expected to have a preventive effect on cardiovascular events.2,3,14 For example, the Women’s Health Initiative study reported that the low-fat diet failed to prevent car-diovascular events and cancer and also impaired glyce-mic control in patients with diabetes.15–17 Moreover, in 2013, the PREDIMED (Prevención con Dieta Mediter-ránea) study reported that higher fat intakes were useful for the prevention of cardiovascular disease.18 The PRE-DIMED study was conducted in Spain to examine the preventive effects of the Mediterranean diet on cardio-vascular disease. A total of 7477 subjects with no history of cardiovascular disease and with a risk of type 2 diabe-tes mellitus or cardiovascular disease were allocated to three groups (the low-fat diet group, the Mediterranean diet + nuts [30 g/day] group, and the Mediterranean diet + olive oil [1 L/week] group) and were followed for ap-proximately 6 years. The results showed that the two Mediterranean diet groups had fewer cardiovascular events, despite higher intakes of fat and energy than the

low-fat diet group. Moreover, subanalyses showed that the Mediterranean diets delayed the onset of diabetes.19 In addition, diets other than the low-carbohydrate and the Mediterranean diets were reported to be effective for the management of diabetes in a meta-analysis of random-ized controlled trials.20 Currently, the diets listed in Ta-ble 1 are considered useful for the treatment of diabetes worldwide.13,21 However, the Dietary Guideline Advisory Committee in the United States revised their recommen-dations in 2015: they noted that “reducing total fat does not lower cardiovascular disease risk.” Limiting total fat was also not recommended for obesity prevention, and the recommendation on fat restriction was withdrawn.22 The era of the low-fat diet was over.

Decline in Support for the Nutrition Therapies of the 20th Century

Currently, there are many dietary approaches for man-aging diabetes. However, the scientific evidence for some diets is insufficient. In particular, support for the low-fat

Fig. 1 Body weight changes in DIRECT.DIRECT revealed that the low-carbohydrate diet without energy restriction was most effective against all traits of metabolic syn-drome. Reprinted from Shai I, Schwarzfuchs D, Henkin Y, et al., Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med 359, 2008, 229-241, with permission of Massachusetts Medical Society.

Yamada S: Nutrition Therapy for Diabetes36

diet, low-protein diet, and low-energy diet is declining. In the previous section, the low-fat diet was reviewed. Therefore, this section covers the current status of the low-protein diet and the low-energy diet that were rec-ommended in the 20th century.

Low-protein diet

Some clinicians might think that the effectiveness of protein restriction in the treatment of nephropathy is clearly established. However, it should be borne in mind that the hypothesis that high protein intake accelerates renal dysfunction was proposed according to findings from animal experiments with rats and mice; the hypoth-esis has not been fully tested in humans.23 Later, in the United States, an observational study of women with an eGFR of 80 mL/min or below found that the high-pro-tein-diet group had a greater decline in eGFR than the other groups, indicating the effectiveness of protein re-striction in patients with renal dysfunction.24 However, it should also be noted that the second worst eGFR group in this study was the group with the second smallest pro-tein intake and that there was no dose-dependent relation-ship between protein intake and changes in eGFR.24 In addition, an observational study of the general Japanese population showed that the higher-protein diet group had a lower odds ratio of chronic kidney disease,25 and an intervention study did not prove the effectiveness of the low-protein diet.26 Furthermore, the Modification of Diet in Renal Disease study, a famous randomized controlled trial in the United States, compared the low-protein diet and extremely low-protein diet in subjects with renal dysfunction and found that there was no significant dif-ference in the time to end-stage renal failure (requiring hemodialysis or kidney transplantation) between the two diet groups, and that the extremely low-protein diet group had a higher mortality rate.27 After the results were re-ported in 2009, Ikizler summarized the advantages and disadvantages of the low-protein diet; the details are shown in Table 2.28 Overall, the low-protein diet poses a greater risk to patients’ health, although it may prolong

the time to the initiation of dialysis. This is a controver-sial issue. Some researchers argue that the low-protein diet is effective in protecting renal function and improv-ing the prognosis.29 Until 2008, the ADA guidelines had recommended protein restriction (0.8–1.0 g/kg for early nephropathy; 0.8 g/kg for late nephropathy).7 However, in 2013, the ADA stated that protein restriction was not recommended for nephropathy.13

Here, I would like to mention the recommended dietary allowance (RDA) of protein intake in the United States, which is 0.8 g/kg. Some clinicians may consider the RDA as “the ideal dose,” which would be incorrect. The RDA is the minimum dose necessary to achieve the desired outcome (i.e., 97.5% of the population can satisfy their requirement). This means that patients must be advised to take in at least the RDA amount of protein. In Japan, the RDA was set at 0.9 g/kg for adults and 1.06 g/kg for the elderly.30 However, the guidelines in Japan recommend 0.8–1.0 g/kg of protein intake for stage 3 nephropathy and 0.6–0.8 g/kg for stage 4 nephropathy.31 Therefore, patients, in particular the elderly, are instructed to con-sume protein at levels below the RDA. The Evidence-based Practice Guidelines for the Treatment of Diabetes in Japan state that there is no clear scientific evidence concerning the effectiveness of the low-protein diet.32 There is also no clear evidence about its safety. Therefore, clinicians should be aware of the risk of the low-protein diet. It should also be recalled that the subjects of the ran-domized controlled trial investigating the effectiveness of the extremely low protein diet were also taking supple-mentations of nitrogen, essential amino acids, folic acids, or multivitamins.29 These facts are important for under-standing the risks associated with the low-protein diet.

Low-energy diet

Initially, in 1971, control of the total energy intake was the single most important objective in ADA recom-mendations for nutrition therapy for managing diabetes.1 However, in 1994, the ADA changed their recommenda-tion of the low-energy diet, calling into question its long-

Table 1. Diets currently considered useful for managing diabetes worldwide

Dietary pattern ElementsMediterranean diet Includes abundant plant-based food, olive oil as the principal source of dietary lipids, dairy products

consumed in low to moderate amounts, low red meat consumption, and low to moderate wine consumption.DASH Emphasizes fruits, vegetables, and low-fat dairy products and includes whole grains, poultry, fish, and nuts.

Reduced consumption of saturated fat, red meat, sweets, and sodium.Vegetarian diet Avoids all animal flesh-based foods and animal-derived products. Some modified versions allow eggs (ovo)

and/or dairy products (lacto).Low-carbohydrate diet Carbohydrate intake reduced to 20 –40 g/meal with sweets containing 10 g of carbohydrate per day (our

definition). There are several other definitions: lower than 130 g/day (Accurso et al.) and lower than 150 g/day (Westman et al.)

37Keio J Med 2017; 66 (3): 33–43

term effectiveness.33 It should be noted that the ADA had been recommending the low-energy diet for achieving the ideal body weight1; in other words, the ADA had not been recommending energy restriction for non-obese people. In 2004, the European Association for the Study of Dia-betes also stated that energy restriction is not necessary for non-obese patients with type 2 diabetes.34 In Japan, energy restriction to 25–30 kcal/kg of ideal body weight is recommended for patients with stage 1–3 nephropathy, irrespective of their body size.31 Some clinicians may con-sider that such energy restriction is beneficial or healthy. However, according to the Japanese Dietary Reference Intake, the energy requirement for persons aged 20–70 years is 30–40 kcal/kg.35 Therefore, energy restriction to 25–30 kcal/kg of ideal body weight will likely be rather difficult to achieve and may be unsafe to maintain. Given that the mean BMI of Japanese patients with type 2 dia-betes is 24.4 at the time of onset and <25 even before the onset of the disease,36 the benefits of energy restriction for many Japanese patients with type 2 diabetes should be carefully considered.

In addition, the Look AHEAD (Action for Health in Diabetes) study found that aggressive energy restriction for 10 years was not effective in preventing cardiovascu-lar events and led to a reduction in bone mineral density of the male femur.37,38 Thus, the efficacy and safety of the low-energy diet, as well as those of the low-fat and low-protein diets, are still controversial.

Acceptable Diets for Asian People

Currently, the low-carbohydrate diet and the “carbo-last” diet (eating carbohydrates last) seem to be accept-able diets for Asian populations because their effective-ness was demonstrated in a randomized controlled trial for Japanese patients with type 2 diabetes. It is expected that these two dietary patterns will form the mainstay of diet therapy for diabetes in Japan. In addition, the Medi-terranean diet, the dietary approaches to stop hyperten-sion (DASH) diet, and the vegetarian diet are reported to be effective worldwide,13,21 and they may be useful

for the Japanese population also. Clinical studies in the Asian population examining the efficacy and safety of these diets are awaited.

Low-carbohydrate diet

There is no clear definition for the low-carbohydrate diet. The positive effects of a variety of low-carbohydrate diets on body weight, blood glucose levels, and lipid profiles have been demonstrated worldwide.12 The low-carbohydrate approach is an acceptable eating pattern based on scientific evidence given in the guidelines in the United States.13 Our research group has been recom-mending the low-carbohydrate diet (70–130 g/day made up of 20–40 g/meal and 10 g sweets/day) and has dem-onstrated its effectiveness in glycemic control and im-proving triglyceride levels (Fig. 2A, B).39 In our clinical experience, the body weight of lean patients with diabetes did not decrease, but rather increased, after following the low-carbohydrate diet. Therefore, the low-carbohydrate diet is much safer than the low-energy diet for Japanese people (Fig. 3).40 Figure 4 shows a low-carbohydrate lunch that is served in Kitasato Institute Hospital. These results indicate that the low-carbohydrate diet is effective and safe for the Japanese population. Recently, a study group at Juntendo University conducted research based on our regimen and reported similar results.41 Further-more, NIPPON DATA 80 showed that lower carbohydrate intake is associated with lower mortality in a Japanese population.42 These findings support the opinion that the low-carbohydrate diet is safe and effective for long-term use in the Japanese population.

However, an extremely low carbohydrate diet (less than 50 g/day of carbohydrate intake), which is called a ketogenic diet and is used therapeutically to treat epilep-sy, may be associated with lipid profile deterioration.43 Therefore, clinicians should pay attention to cardiovas-cular risk as well as to the intake of certain vitamins and micronutrients44 when their patients are considering a ketogenic diet.

Table 2. The advantages and disadvantages of dietary protein restriction

Advantages DisadvantagesProven Decreased toxin load

Slower progression Better BP control Better phosphorus control Better H+ control Improved insulin sensitivity Improved proteinuria in nephritic syndrome

Predisposition to PEM Complex diet Need for close supervision Decreased muscle mass

Controversial Extended time to ESRD Possible weight gain Increased mortality in very low protein diet

BP, blood pressure; ESRD, end-stage renal disease; PEM, protein energy malnutrition. Reprinted from Ikizler TA, Dietary pro-tein restriction in CKD: the debate continues. Am J Kidney Dis 53, 2009, 189-191, with permission of Elsevier.

Yamada S: Nutrition Therapy for Diabetes38

Fig. 2 HbA1c and TG levels in our study.Our study showed that a low-carbohydrate diet without energy restriction was effective for glycemic control and lipid profile improve-ment. *p<0.05. Reprinted from Yamada Y, Uchida J, Izumi H, et al. A non-calorie-restricted low-carbohydrate diet is effective as an alternative therapy for patients with type 2 diabetes. Intern Med 53, 2014, 13-19, with permission of The Japanese Society of Internal Medicine.

Fig. 3 Body weight change after low-carbohydrate diet instruction to 200 patients with diabetes.In our experience, a low-carbohydrate diet without energy restriction can improve glycemic control and body composition.

39Keio J Med 2017; 66 (3): 33–43

“Carbo-last” diet (i.e., eating carbohydrates last)

Eating vegetables first, followed by fish or meat, and then the staple food reportedly leads to improved glyce-mic control.45,46 This effect is considered to result from the suppression of gluconeogenesis47 and prolonged gas-tric emptying due to the incretin effect.46 Whatever the mechanisms are, the “carbo-last” diet (i.e., eating carbo-hydrates last) appears to be useful.

Mediterranean diet and DASH diet

The typical ingredients of the Mediterranean diet in-clude olive oil, fish (rather than meat), vegetables, nuts, and fruits. Table 3 shows the major ingredients (14 items) of the Mediterranean diet used in the PREDIMED study.18,48 Each ingredient is important for the Mediter-ranean diet. The PREDIMED study reported that the Mediterranean diet was effective in preventing diabetes19 but was not significantly effective in improving glycemic control in patients with diabetes.49 This may be related to the recommended fruit intake in the Mediterranean diet. However, some of the ingredients are unfamiliar to the Japanese population; therefore, there is a need for an eclectic mix of the Japanese and Mediterranean diets (Mediterranean–Japanese diet, or Mediterr-Asian diet50). The DASH diet can be considered as the Mediterranean diet aimed at salt reduction.

Vegetarian diet

The vegetarian diet is a diet based on plants. There are different types of vegetarians. Vegans do not consume any animal products. Ovo-vegetarians eat eggs. Lacto-ovo vegetarians eat eggs and dairy products. Ajala et al. conducted a systematic review and reported that only three studies have suggested the effectiveness of the veg-etarian diet on HbA1c; thus, there is a need for further investigations.20 Recently, Yokoyama at al. conducted a meta-analysis and reported that six studies had demon-strated the effectiveness of the vegetarian diet on reduc-ing HbA1c levels.51 Clinicians should be aware that the vegetarian diet can exacerbate blood glucose levels, as suggested by Mozaffarian.52 In my clinical experience, I encountered a vegetarian patient who ate a lot of fruit, potatoes, and root crops, which led to impairment of gly-cemic control.

Future Perspectives in Dietary Therapy in Japan

It is expected that more dietary options will become available in the future. However, it should be noted that nutrition therapy is based on a trusted relationship be-tween healthcare professionals and patients. The pater-nalistic attitudes of some healthcare professionals toward patients can be a barrier to communication and may lead to the discontinuation of nutrition therapy. Healthcare professionals are expected to have good communication skills and good supporting skills. It is important to offer

Fig. 4 Typical example of low-carbohydrate lunch.

Yamada S: Nutrition Therapy for Diabetes40

productive suggestions rather than merely to complain about noncompliance and expect a change to result. I be-lieve that patient-centered communication is essential to achieve a successful diet therapy.

One of my patients, who worked in a nuclear power plant, once told me that all beverages supplied by his em-ployer were sugar sweetened. Consequently, this patient was not able to take sugar-free beverages during work hours and eventually failed to control blood glucose. This is a case of poor glycemic control resulting from a social factor. I believe that improving public awareness of dia-betes is important to ensure that all patients with diabetes can have access to low-carbohydrate foods and drinks. To promote this, our research group founded the Eat & Fun Health Association. We have collaborated with some food companies that produce low-carbohydrate products (see the website https://locabo.net/partners/). We have created a trademark named “locabomark” for the purpose of improving the awareness of low-carbohydrate products (Fig. 5).53

Conclusion

Nutrition therapies for diabetes have been described and reviewed. Evidence-based clinical practice is a dy-namic process. Clinicians create an individualized treat-ment plan based not only on accumulated evidence but also on patient preference and original lifestyle. In this

process, patient-centered communication skills are es-sential. I believe that such shared decision making is es-sential for successful clinical practice54,55 and supports patient longevity and quality of life.

Table 3. Validated 14-item questionnaire of Mediterranean diet adherence

Questions Criteria for 1 point1. Do you use olive oil as the main culinary fat? Yes2. How much olive oil do you consume in a given day (including oil used for frying, salads, eating out, etc)?

4 tbsp or more

3. How many vegetable servings do you consume per day? (1 serving; 200g (consider side dishes as half a serving))

2 or more (at least 1 portion raw or as a salad)

4. How many fruit units (including natural fruit juices) do you consume per day? 3 or more5. How many servings of red meat, hamburger, or meat products (ham, sausage, etc) do you consume per day? (1 serving; 100–150g)

Less than 1

6. How many servings of butter, margarine, or cream do you consume per day? (1 serving; 12g) Less than 17. How many sweet or carbonated beverages do you drink per day? Less than 18. How much wine do you drink per week? 7 glasses or more9. How many servings of legumes do you consume per week? (1 serving; 150g) 3 or more10. How many servings of fish or shellfish do you consume per week? (1 serving; 100–150g of fish or 4–5 units or 200g of shellfish)

3 or more

11. How many times per week do you consume commercial sweets or pastries (not homemade), such as cakes, cookies, biscuits, or custard?

Less than 3

12. How many servings of nuts (including peanuts) do you consume per week? (1 serving; 30g) 3 or more13. Do you preferentially consume chicken, turkey, or rabbit meat instead of veal, pork, hamburger, or sausage?

Yes

14. How many times per week do you consume vegetables, pasta, rice, or other dishes seasoned with sofrito (sauce made with tomato and onion, leek, or garlic and simmered with olive oil)?

2 or more

Tbsp, table spoon. Reprinted from Martinez-Gonzalez MA, Garcia-Arellano A, Toledo E, et al. A 14-item Mediterranean diet assessment tool and obesity indexes among high-risk subjects: The PREDIMED trial. PLoS ONE 7, 2012, e43134 with permission of The Public Library of Science (PLOS).

Fig. 5 Trademark of LOCABO.The Japanese characters in this mark say that a low carbohydrate diet will realize delicious, joyful, and healthy eating.

41Keio J Med 2017; 66 (3): 33–43

Conflicts of Interest

The authors declare no conflicts of interest.

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