Medical nutrition therapy and dietary counseling for patients with diabetes-energy, carbohydrates, protein intake and dietary counseling

Preface

The “Japanese Clinical Practice Guideline for Diabetes” are revised and published every 3 years, with the aim of promoting evidence-based diabetes care and equal accessibility to diabetes care. The formulation of the “Japanese Clinical Practice Guideline for Diabetes” needs to be based on a specific process, making it difficult to publish updated items, necessary for diabetes care as guidelines, every year. Therefore, the Japan Diabetes Society has decided to publish updated items as appropriate consensus statements. For this purpose, “The Consensus Statements Committee of the Japan Diabetes Society” was set up under the Board of Directors of the Japan Diabetes Society, consisting of the Secretary-General, acting Secretary-General, and Secretary. The committee took the lead in selecting themes requiring an update and their authors, including writing articles upon receiving the Board's approval. All directors were reviewers of this consensus statement. Furthermore, from the viewpoint of consistency with the guidelines of other academic societies, we also asked related societies to conduct external evaluations. This consensus statement should be interpreted as a compilation of views on consensus among Japanese experts, including the newest evidence possible for each theme, concerning the concept of diabetes care in Japan, so we would like you to utilize this in providing the best diabetes medical care. Diabetes is growing faster in Asia than anywhere else in the world, with one-third of the world's diabetic population concentrated in this region; therefore, the timely presentation of a consensus statement from Japan is considered to be of crucial importance.

This time, a consensus statement was created on the theme of “Medical Nutrition Therapy and Dietary Counseling for Patients with Diabetes,” as the first report. It consists of four focus areas that need to be updated, on the concept of dietary guidances for patients with diabetes in Japan and their guidance (setting target body weights and total energy intake, carbohydrate intake, protein intake, and dietary counseling by a registered dietitian). Although it is mainly aimed at diabetes management, it also refers to diabetic nephropathy, sarcopenia, and the elderly, with respect to protein intake.

The consensus statement will continue to select themes that need to be updated as appropriate for diabetes care and published regularly with as much evidence as possible. We look forward to the consensus statement contributing to the improvement of diabetes care in Japan and hope that it will continue to evolve to better versions while adding new evidence.

Setting of target weight and total energy intake

Consensus recommendation

The purpose of nutrition therapy for type 2 diabetes mellitus is to prevent complications and suppress the progress thereof by maintaining a good metabolic state throughout the body. To this end, the total energy intake is set in accordance with body weight. Energy intake should be personalized taking into consideration the fact that the target weight will differ depending on the age, physical activity, metabolic state etc. of patients. We first set a total energy intake target at the beginning of treatment, then make changes thereto as appropriate based on changes in the body composition, adherence, and metabolic parameters of patients.

Setting the target weight and total energy intake

As described above, the target weight and energy intake should be personalized and will differ depending on age, current weight, amount of physical activity, etc. The tentative initial target can be set as provided below. The actual counseling given is modified according to various parameters such as the weight and blood glucose control of patients. We also need to accumulate further evidence.

Target body weight (kg)

The target is calculated using the following formulas, taking into consideration the fact that the BMI with the lowest all-cause mortality differs by age and is within a certain range.

• Under 65: [Body height (m)]² × 22.

• 65 to 74: [Body height (m)]² × 22 to 25.

• 75 or older: [Body height (m)]² × 22 to 25*

  *For advanced elderly individuals age 75 or older, the target weight is determined based on their current weight along with an evaluation of frailty, weakening of (basic) ADL, complications, body composition, shortening of stature, food intake, and metabolic state.

Energy factor (kcal/kg) based on the level of physical activity and condition

1. Light activity (mostly static activities in sitting position): 25–30

2. Moderate activity (mostly in sitting position but include commuting, housework, and light exercise): 30–35

3. Heavy activity (physical labor and active exercise habits): 35 or more

For the prevention of frailty, the energy factor can be set larger than the real level of physical activity. If planning to lose weight due to obesity, the energy factor can be set smaller than the real level of physical activity. In all cases, if there is a large discrepancy between the target weight and the current weight, the energy factor can be flexibly set based on the abovementioned (1)–(3).

Standard of total energy intake

Total energy intake (kcal/day) = Target weight** × Energy factor (kcal/kg).

**In principle, use the target weight taking age into account.

Approach to target weight

Because type 2 diabetes associated with obesity is caused by insulin resistance due to visceral fat accumulation, improvement of overweight is significant in the prevention and management thereof, with a lifestyle intervention, mainly the optimization of total energy intake, being effective in terms of this improvement. Total energy intake is calculated based on the target weight. Based on a report indicating that the total number of abnormal findings was fewest at BMI = 22 upon an occupational health examination in 1980s [1], we have deemed this as the standard weight. The formula (BMI = 22 multiplied by the level of physical activity) has been widely accepted and used,because the average BMI of Japanese people at that time was close to this value. However, recent studies on the relation between BMI and mortality revealed that the BMI with the lowest mortality is 20 to 25 for Asians [2] and the Dietary Reference Intakes for Japanese (2020) suggests a target BMI of 20–24.9 [3] as well. For type 2 diabetes, the BMI showing the lowest all-cause mortality of Chinese subjects [4] and Japanese subjects [5, 6] was reportedly 20–25, with no increase in mortality among the elderly aged 75 or older with a BMI of 25 or more [5, 7]. As indicated above, the target BMI in connection with all-cause mortality ranges between 20 and 25; in particular, the correlation is different among the elderly, a fact which has also been reported in overseas studies [8]. We should also consider the shortening of height in the elderly, in that the BMI may not accurately reflect the body mass. On the other hand, the body composition is significantly related to the correlation of body mass and all-cause mortality. According to a Canadian study on the correlation of all-cause mortality with BMI and body fat percentage, respectively, both BMI and body fat percentage independently indicated a U-shaped relationship with mortality; however, a re-examination after adjusting the two factors revealed that it was only the body fat percentage, not the BMI, that indicated a U-shaped relationship, suggesting the significance of conducting a body composition assessment [9]. It has also been reported that health condition cannot be understood based on BMI alone [10, 11]. Even if the BMI does not indicate obesity, those with metabolic syndrome symptoms such as dyslipidemia and hypertension have significantly higher mortality than healthy non-obese people, while overweight subjects without metabolic syndrome have no increased mortality. In other words, while BMI = 22 can be a certain standard for setting the total energy intake, if the rationale therefore is a healthy body mass with low mortality, the desirable BMI is 20–25 and BMI = 22 is not the standard that should be uniformly used. In Japan, where the number of the elderly with diabetes is increasing and those that are obese with a BMI of 30 or more are no longer rare, it is necessary to set a different target weight for individuals, taking into consideration the fact that the desirable weight differs depending on the age, metabolic state, etc. of patients. Therefore, it is reasonable to set the target weight based on the current weight by evaluating patient characteristics such as age, organ disorders, etc. and the metabolic state, then change the target weight on a stage-by-stage basis, rather than setting a uniform target. For the advanced elderly aged 75 or older, in particular, the target weight should be determined as appropriate taking into consideration frailty, complications, body composition, shortening of stature, food intake, and nutrition state.

Approach to target total energy intake

According to the Dietary Reference Intakes for Japanese (2020), the energy requirement is set based on the estimated energy requirement calculated using the basal metabolic rate and level of physical activity [3]. However, the energy requirement changes with age and physical exertion is variable. The energy requirement significantly varies from individual to individual and is difficult to accurately determine in daily clinical practice. If the level of physical exertion is invariable, the management of total energy intake can be considered equivalent to the management of body weight. Therefore, for determination of the target energy intake, as described above, it is realistic to first calculate it from the target weight and energy factors based on the level of physical activity then modify the energy intake as appropriate based on the observation of physical exertion, metabolic parameters, change in weight, and adherence of patients. We believe it also continues with the personalization of total energy intake.

A Diabetes Prevention Study (DPS) investigated the influence of lifestyle intervention, mainly the reduction of total energy and increased level of physical activity, on the incidence of diabetes among those with impaired glucose tolerance (IGT) for 4 years, revealing that the group who underwent an intervention and reduced their weight by 5% over the course of 1 year significantly reduced their incidence of diabetes [12]. The Diabetes Prevention Program (DPP) showed that this 5% weight loss in subjects with a higher risk of diabetes onset over the course of 3 years reduced the incidence of diabetes by 55% [13]. On the other hand, in Look AHEAD (Action for Health in Diabetes), while the rate of weight loss was 0.7% in the control group in the first year of the study, it was 8.6% in the intervention group, indicating a decline in HbA1c by approximately 0.6% [14]. A recent meta-analysis revealed that 5% weight loss in overweight type 2 diabetes patients significantly improved the clinical parameters associated with diabetes [15]. According to another study on the relation between the rate of weight loss with insulin resistance in the liver and adipose tissue among obese subjects in metabolic chambers, weight loss of 5% or more improved the insulin sensitivity of the organs [16]. Based on the above, a recent consensus report on nutrition therapy from the American Diabetes Association (ADA) states that the most important factor in the prevention and management of diabetes is to improve obesity by optimizing gross energy, with an immediate target weight loss of 5%, followed by maintaining this weight after a weight loss of 7–10% [17]. According to the Guidelines on the management of obesity disease 2016 by the Japan Society for the Study of Obesity, the target weight loss of obese subjects to improve HbA1c is 3–5%, based on the survey results of Specific Health Guidance [18]. However, it is difficult to find an evidence to determine how much the energy should be reduced for 5% weight loss.

The double labeling water method using a stable isotope is believed to be the most reliable method to calculate the energy expenditure while free living. Recently, Yoshimura et al. used this method to calculate the energy expenditure of Japanese males with an average age of 55. The result was approximately 35 kcal/day/kg (actual weight) and there was no difference between those with diabetes and those without diabetes [19]. Morino et al. conducted the same study among Japanese subjects aged 67–70. The result was approximately 35–40 kcal/day/kg (actual weight) and there was no difference between those with diabetes and those without diabetes in this case as well [20]. These values are significantly higher than the standards for energy setting used before. They are important studies providing evidence for energy setting to achieve the target weight, although, going forward, we still have to learn regarding the changes associated with age, level of physical exertion, and weight.

Carbohydrate intake

Consensus recommendation

There is no clear evidence for setting the desirable proportion of energy-yielding nutrient intake for the prevention and control of diabetes. Therefore, the proportion should be flexibly determined for individuals based on their level of physical exertion, condition of complications, age, preferences, etc.

Although many studies have attempted to identify the appropriate proportion of energy-yielding nutrient intake for control among the patients with diabetes, none of them have yielded clinical data suggesting any particular proportion of energy-yielding nutrient intake that can be recommended to all patients. Therefore, in the practice of providing dietary counseling, the proportion should be flexibly determined based on the level of physical exertion, condition of complications, age, preferences, etc. As a reference, according to the Dietary Reference Intakes for Japanese (2020), the reference intake proportion for adults should be carbohydrates: 50–65% energy, proteins: 13–20% energy, and lipids: 20–30% energy (saturated fatty acid 7% or less). However, these are values for healthy individuals. According to the “Proposals by the Japan Diabetes Society on medical nutrition therapy for Japanese patients with diabetes” [21] published in 2013, from a medical point of view, the standard proportion of energy-yielding nutrient intake should be carbohydrates 50–60% energy (≥ 150 g/day) and proteins 20% energy or less, with the remainder being lipids; wherein, if the lipids make up more than 25% energy, polyunsaturated fatty acids should be increased to take care of the fatty acid composition. In reference to these values, the proportion of energy-yielding nutrient intake should be set on an individual basis mainly based on the metabolic state (high blood glucose, dyslipidemia), amount of activities, and preferences. However, because there is no clear evidence, the allowable range of the proportion should be flexibly set to be wide.

The patients sometimes receive the guidance of “low-carbohydrate diet”. Carbohydrates consist of glucides and dietary fiber. The term “low-carbohydrate diet” is used in the US, where these “carbohydrates” refer to digestible carbohydrates. According to Dietary Reference Intakes (2002) published by the US Institute of Medicine on the glucides requirements per day among healthy individuals, the “minimum allowable amount of digestible carbohydrates is 130 g/day” [22]. However, this is estimated from the amount of glucides consumed by the brain per day. In actuality, glucides are produced by gluconeogenesis and glycogen decomposition, while ketone bodies are used when the brain lacks energy, so the minimum allowable amount is unclear.

One study investigated the efficacy of a mild low-carbohydrate diet (carbohydrate 130 g/day) for half a year among Japanese patients with type 2 diabetes [23]. 66 subjects were randomly placed into a low-calorie diet group and a mild low-carbohydrate diet group, then provided systematic dietary counseling in the 0, 1st, 2nd, 4th, and 6th months. The background of the low-calorie diet group was age 58.4 ± 10.0, BMI 26.5 kg/m² (24.6–30.1 kg/m²), HbA1c 8.3% (8.0–9.3%), and disease duration 13.0 years (9.0–20.0 years); while that of the mild low-carbohydrate diet group was age 60.5 ± 10.5, BMI 26.7 kg/m² (25.0–30.0 kg/m²), HbA1c 8.0% (7.6–8.9%), and disease duration 14.0 years (7.8–18.5 years). There was no significant difference between the two groups. The mild low-carbohydrate diet group maintained a glucides intake level of 130 g/day. Although there were no restrictions on other foods, they were advised to consume more unsaturated fatty acids than saturated fatty acids. In 6 months, the mild low-carbohydrate diet group had significantly lower glucides and energy intake, along with significantly lower HbA1c [mild low-carbohydrate diet group: ΔHbA1c − 0.65% (− 1.53 to − 0.10%), low-calorie diet group: ΔHbA1c 0.00% (− 0.68 to 0.40%) (p < 0.01)] and BMI [mild low-carbohydrate diet group ΔBMI − 0.58 kg/m² (− 1.51 to − 0.16 kg/m²), low-calorie diet group ΔBMI − 0.22 kg/m² (− 0.58 to 0.24 kg/m²) (p = 0.03)] than the low-calorie diet group. There was no deterioration of renal function during the study. For obese, non-elderly diabetic patients, as in this study, a mild low-carbohydrate diet for half a year (130–150 g/day) can be said to be effective for improving HbA1c and obesity. However, taking into consideration the influence of a low-carbohydrate diet on metabolism, it is not recommended for pregnant or nursing women, patients having problems with feeding behaviors, and patients with renal impairment. Furthermore, patients using an SGLT2 inhibitor require extra care due to a higher risk of ketoacidosis [24–26]. Although a systematic review on Japanese subjects including this study also indicated that a mild low-carbohydrate diet for a short duration is effective for improving HbA1c [27], the number of subjects in the randomized trials conducted in Japan was very small (the 66 subjects as mentioned above [23] and a study including 24 subjects [28], thus definitive conclusion cannot be drawn. Indeed, the follow-up study of the abovementioned study indicated no difference in HbA1c and BMI, in one and a half year, between the two groups [29]. The long-term efficacy of a low-carbohydrate diet remains unclear.

Though the efficacy of a low-carbohydrate diet on vascular complications and the long-term prognosis are both unclear, a study on the amount of glucides and mortality published in the West in 2018 [30], including a cohort of 15,428 subjects in the United States, indicated there is a U curve correlation between energy intake proportion from glucides and all-cause mortality, with an intake proportion of 50–55% resulting in the lowest all-cause mortality. In a meta-analysis among 432,179 subjects, with a focus on the relation between the intake proportion of glucides and mortality, a low-carbohydrate diet with intake proportion less than 40% and high-carbohydrate diet with an intake proportion of 70% or more resulted in increased mortality. Regarding a low-carbohydrate diet, the replacement of glucides with plant-based foods such as vegetables and nuts reduced the risk of death [0.82 (0.78–0.87)], while replacement thereof with meats such as beef, pork, and chicken [1.18(1.08–1.29)] increased the risk. Therefore, not only the amount of glucides but also what replaces the glucides significantly affect the prognosis.

Taken together, although the mild low-carbohydrate diet (130–150 g/day) is effective for short-term blood glucose improvement and weight loss among some patients, the long-term efficacy and safety thereof remains unclear. Therefore, it is necessary to select appropriate patients and initiate treatment upon obtaining their informed consent.

It is known that unlike glucides, the dietary fiber in carbohydrates is effective for controlling blood glucose elevation by delaying absorption in the small intestine [31]. In point of fact, it has been demonstrated that adequate and regular dietary fiber intake inhibits the onset of type 2 diabetes, improves blood glucose control, and reduces all-cause mortality [32–37]. Specifically, the desirable level of intake is 20 g/day or more [34, 37]. It is important to intentionally consume food rich in dietary fiber (vegetables, fruits, whole grains, beans, etc.). However, in the field of dietary counseling, attention should be paid to some ingredients in which a clear distinction between glucides and carbohydrates is not mentioned. In addition, among the foods containing high dietary fiber, the excessive consumption of fruits is not recommended, because fruits contain a high amount of glucides.

The concept of “carb counting” is important considering the relation between glucide intake and the postprandial blood glucose level. “Carb counting” means counting the amount of carbohydrates (strictly glucides) included in the diet and using this information for good blood glucose control. Carb counting is effective for improving blood glucose control to advise especially patients during insulin therapy [38, 39]. However, it is not recommended to excessively reduce glucides to improve the blood glucose. The aim of conducting carb counting is not for achieving a low-carbohydrate diet [40]. The use of glinides and sulfonylurea, instead of insulin, may result in hypoglycemia, unless matching the amount of glucides and drug efficacy in reference to the concept of this carb counting. The concept of “carb counting” was widely spread from early on in the US. In 2004, the American Diabetes Association proposed “The influence of the amount and type of carbohydrates (strictly glucides) on the prevention and management of diabetes [41].” In 2017, the Japan Diabetes Society also published “Guidelines for carb counting” and a “Textbook for carb counting counseling [for medical staff]”, incorporating the concept of carb counting in the field of dietary counseling.

Overconsumption of sweets and juices with saccharose [sugar (sucrose) = glucose + fructose] should be restricted, because they may significantly increase the risk of deterioration of glucose control, promotion of metabolic syndrome, weight gain, heart disease, kidney disease, non-alcoholic steatohepatitis (NASH), dental caries, etc. [42–47]. There is no unified view on the onset risk of diabetes and metabolic syndrome caused by and long-term usefulness of low-calorie, non-nutritive artificial sweeteners such as saccharin, neotame, acesulfame potassium, aspartame, sucralose, advantame and stevia. Excessive intake thereof should be avoided. These artificial sweeteners do not include sugar alcohol such as xylitol [48–53].

GI (glycemic index) indicates how much the carbohydrate (strictly glucides) in the diet raises blood glucose after eating, indicating the quality of carbohydrates. GL (glycemic load) indicates both the quality and quantity of carbohydrates (strictly glucides). While a meta-analysis on the relation of GI and GL with the onset risk of type 2 diabetes reported that the intake of ingredients with low GI and GL reduces the onset risk of type 2 diabetes [54, 55], another study reported negative results for blood glucose control and onset risk of type 2 diabetes [56, 57]. There is no sufficient evidence to determine whether or not they should be actively introduced to medical nutrition therapy for patients with diabetes.

Protein intake

1. Protein intake and diabetes: usefulness and safety.

Consensus recommendations

Increasing animal protein intake may increase the risk of developing type 2 diabetes. Furthermore, long-term safety related to the excessive consumption of protein has not been confirmed.

There is currently no evidence clearly laying out protein intake and the usefulness or safety thereof in diabetes. Although a number of reports exist regarding the relationship between protein intake and the risk of developing type 2 diabetes, demonstrating that the risk of developing type 2 diabetes increases with increased protein intake [58–65], conflicting data has also been reported recently [66]. According to a 12-year prospective cohort study implemented in Sweden, a group with protein intake ratio of 20% had an increased risk of developing type 2 diabetes compared to a group with a 12% intake ratio [62].

In terms of protein types, a relationship between animal protein, particularly red meat, and the risk of type 2 diabetes has been strongly indicated [58, 61–63, 65], mainly in Europe and the United States. Among red meat, processed meat intake has been reported to increase the risk of type 2 diabetes [58, 62]. However, Kurotani et al. showed the intake of red meat increased the risk of developing type 2 diabetes in men, but processed meat did not [59]. In addition to red meat, higher protein intake from fish has also been reported to increase the risk of developing type 2 diabetes [65]. It has been suggested that insulin resistance is involved in the increased risk of developing type 2 diabetes due to animal protein intake [67]. In recent years, there have been numerous reports indicating that the intake of plant protein is not a risk of developing type 2 diabetes [61–66]. Furthermore, it has been indicated that the intake of plant protein leads to reduced risk [63, 64, 66] and has been clarified to be particularly true in women [63, 68].

With respect to the safety associated with diabetic complications, the excessive consumption of protein has been reported to increase the incidence of cardiovascular diseases (CVD), all-cause mortality [69–71] and cancer deaths [71], in addition to the abovementioned increased risk of developing type 2 diabetes. Levine et al. reported the results of an 18-year follow-up study with 6381 people, which indicated greater overall mortality, cancer deaths, and diabetes-related mortality due to high protein intake in those aged 50–65. They concluded that animal protein was related to overall and cancer mortality, while no increase was observed in individuals whose protein intake mainly consisted of plant protein [71]. Furthermore, in a study of middle-aged residents in Europe and the United States who do not suffer from any existing CVD or cancer, red meat consumption [72, 73], particularly processed meat consumption [72], or an increase in the animal/plant protein ratio [73] has been reported to increase overall mortality. On the other hand, in Japan, it has been reported that moderate red or processed meat intake of up to 100 g/day does not increase CVD, including ischemic heart disease and stroke [74]. In a recent prospective study of approximately 70,000 Japanese individuals with no cancer, cerebrovascular diseases, or CVD, it was reported that plant protein intake was associated with a decrease in overall and cardiovascular disease-related mortality and that isocaloric substitution of 3% energy from plant protein for red meat protein correlated with reduced overall, cancer-related, and cardiovascular disease-related mortality [75].

Although most of the reported studies did not target patients with diabetes alone, it is assumed that this information is important and enough to consider the safety of protein intake in patients with diabetes. Although there is currently no clear answer to specific amount and ratios of protein intake, a systematic review published in 2013 calls for attention to be paid to the fact that the safety of protein intake ratios exceeding 20–23% cannot be confirmed [76].

It is anticipated that protein intake is strongly related to type 2 diabetes and its complications through incretin and glucagon secretion. Eating the main protein meal before the staple food (carbohydrate) suppress postprandial hyperglycemia in patients with type 2 diabetes, which would be mediated through incretin secretion [77, 78]. Eating appropriate protein in proper sequence would play an important role in the management of blood glucose control in patients with type 2 diabetes.

While research on protein intake is limited, it is expected that differences in gender, in addition to the issue of racial differences between Westerners, Asians, and Japanese, will be further clarified going forward. Although the evidence for patients with diabetes is not sufficient as of yet, taking the above into consideration, protein intake of 20% or less of the total energy is considered appropriate, as indicated in Japanese Clinical Practice Guideline for Diabetes 2019 [79]. Furthermore, it is necessary to consider protein intake, not only in terms of “quantity” but also “quality” including the source (animal or plant-derived) of protein, lipids and carbohydrates contained within protein meal, and the processing methods of protein including the cooking methods thereof, then finally it is recommended that protein intake should be proposed with consideration of the condition and dietary habit of each “individual” patients with diabetes.

• 2.Protein intake and diabetic nephropathy (diabetic kidney disease).

Consensus recommendations

A low-protein diet should be considered for patients at a high risk of progression to end-stage renal disease when the benefits outweigh the risks in individual cases.

(*Weight kg refers to the target weight. However, the actual weight or standard weight is used in the evidence and guidelines.)

Low-protein diet and diabetic nephropathy (diabetic kidney disease)

Glomerular hyperfiltration/hypertension is closely involved in the progression of renal function decline in chronic kidney disease (CKD), including diabetic nephropathy [80]. Because a high-protein diet induces and promotes glomerular hyperfiltration, a low-protein diet is considered to reduce it. In the Modification of Diet in Renal Disease study, conducted to verify the renal protective effect of a low-protein diet against CKD (Baseline GFR: 25–55 ml/min/1.73 m²), the glomerular filtration rate (GFR) temporarily decreased after the initiation of a low-protein diet (0.58 g/weight kg/day); however, the decline in the subsequent GFR became gradual, suggesting that GFR is maintained in the long term with a low-protein diet compared with a standard protein diet (1.3 g/weight kg/day) [81]. Furthermore, results of a meta-analysis/systematic review of 19 randomized controlled trials (RCT) (n = 2492) targeting CKD including diabetic nephropathy indicated that a low-protein diet decreased the risk of renal failure (defined as a > 25% decrease in eGFR, doubling of serum creatinine, or end-stage renal disease (ESRD); odds ratio 0.59, 95% CI 0.41–0.85) and ESRD (odds ratio 0.64, 95% CI 0.43–0.96). A low-protein diet also had beneficial effects on the decline of eGFR and proteinuria [82]. However, in numerous intervention studies, including RCT, there is insufficient clinical evidence that a low-protein diet has beneficial effects on diabetic nephropathy [83–100]. Conversely, the results from another meta-analysis showed that compared with a standard diet (1.0–1.6 g/weight kg/day), eGFR improves with a low-protein diet (0.6–0.8 g/weight kg/day) in patients with diabetic nephropathy over the course of an average observation period of 18 months [96]. This report is cited in the Japanese Clinical Practice Guideline for Diabetes 2019 as evidence that a low-protein diet may suppress the progression of nephropathy [100]. In a retrospective cohort study performed in a single medical center, the relationship between estimated protein intake and initiation of renal replacement therapy (RTT) in Japanese patients with type 2 diabetes mellitus having urinary albumin excretion of ≥ 300 mg/gCr or eGFR of < 30 ml/min/1.73 m² (n = 449, average protein intake 0.8 ± 0.13 g/weight kg/day) was evaluated. Each decrease of 0.1 g/weight kg/day in dietary protein intake was associated with a lower incidence of RTT initiation with an adjusted hazard ratio of 0.81 (95% CI 0.72–0.92, p < 0.001), and a decrease in dietary protein intake of approximately < 0.7 g/weight kg/day was significantly associated with a reduced risk of RTT initiation [101]. However, lower dietary protein intake may lead to increased mortality in malnourished patients; thus, although the clinical evidence is limited, a low-protein diet may be effective in suppressing the progression of diabetic nephropathy.

As a part of comprehensive treatment for diabetic nephropathy, a low-protein diet should be considered for patients who are at a high risk of progression to ESRD [102, 103]. In patients with overt albuminuria (GFR: < 45 ml/min/1.73 m²) or microalbuminuria (GFR: < 45 ml/min/1.73 m²) and progressive renal function decline (from >  − 3 to − 5 ml/min/1.73 m²/year), the protein intake should be 0.6–0.8 g/weight kg/day (Fig. 1). In patients with a GFR of < 30 ml/min/1.73 m², protein intake of 0.6–0.8 g/weight kg/day should be considered to suppress the accumulation of phosphorus, uremic toxin, and acid load, in addition to the slowing renal function decline (Fig. 1). Although a standard weight or ideal weight was used as the “weight” in each clinical study, target weight was used in this report based on the Japanese Clinical Practice Guideline for Diabetes 2019 [100].

Fig. 1.

Low-protein diet recommendation

Low-protein diet for patients at a risk of malnutrition/sarcopenia and frailty

Medical nutrition therapy by a low-protein diet should be performed under the instruction of a specialist and dietitian with careful observation when the benefits outweigh the risks based on the total assessment for age, malnutrition, sarcopenia/frailty, and the rate of renal function decline and adherence. A protein intake of 0.66 g/weight kg/day obtained by the nitrogen balance method [104] was adopted as the protein maintenance requirement for all age categories, including adults and the elderly, in the Dietary Reference Intakes for Japanese (Version 2020). However, a low-protein diet of 0.6 g/weight kg/day is below that standard. Moreover, because the protein maintenance requirement in adults, as estimated by the indicator amino acid oxidation method, has been reported to be 0.85–0.96 g/weight kg/day [105–111], protein intake of 0.6 g/weight kg/day may be significantly below the protein maintenance requirement. Therefore, it is necessary to ensure sufficient energy intake (30–35 kcal/weight kg/day) when a low-protein diet is consumed [112, 113]. Medical nutrition therapy by a low-protein diet that prioritizes the renal protective effect should not be performed when the nutritional status is poor or when it is difficult to ensure energy intake.

Protein intake is not the only factor involved in the onset and progression of sarcopenia and frailty. Therefore, it is possible to administer a low-protein diet that prioritizes renal protection even in patients who are at risk of malnutrition or sarcopenia and frailty (the elderly in particular). However, a low-protein diet, particularly for those with sarcopenia and frailty (or risk of) or for patients aged > 75 years, may increase the risk of malnutrition, sarcopenia, frailty, and cognitive impairment. Therefore, in principle, protein intake should be set for individual cases (Fig. 1). Additionally, one report indicated that the protein maintenance amount in the elderly (measured by the nitrogen balance method) is 0.83 g/weight kg/day or 0.91 g/weight kg/day [114, 115] (Fig. 1). Therefore, when a low-protein diet is newly initiated for patients with sarcopenia and frailty or risk thereof, it is appropriate to set the lower limit of protein intake to 0.8 g/weight kg/day. In Dietary recommendations for moderate CKD in the case of complications of sarcopenia and frailty 2019 [116], which identified patients that prioritized or mitigated a low-protein diet, an indication of the amount of protein intake was shown when sarcopenia occurred during standard medical nutrition therapy for patients with CKD. Therefore, for patients to whom a low-protein diet has already been administered, protein intake is considered by referring to these recommendations.

Excessive protein intake and diabetic nephropathy (diabetic kidney disease)

There is no clear clinical evidence that excessive intake of protein contributes to renal function decline. However, a previous report demonstrated that a high protein intake of 2.0 g/weight kg/day increases the risk of kidney damage in the healthy elderly population [117]. Additionally, in women with an eGFR of 55–80 ml/min/1.73 m², protein intake of 1.3 g/weight kg/day indicated a higher risk of progression of renal function by > 15% in 11 years than that with protein intake of 0.9 g/weight kg/day (eGFR decreased by 7.72 ml/min/1.73 m² with an increase in protein intake of 10 g/day) [118]. Additionally, high protein intake correlated with a linear increase in the risk of end-stage renal failure; however, there was no threshold for the protein intake against the increased risk of end-stage renal failure [119]. Conversely, in an average of 6.4 years of follow-up from the Cardiovascular Health Study in patients aged > 65 years, no association between protein intake and renal impairment was found [120]. Thus, it is unclear whether excessive protein intake contributes to renal function decline. It should be noted that these reports do not target CKD, including diabetic nephropathy, and are based on results from observational or cohort studies. Glomerular hyperfiltration, which is closely involved in the pathogenesis of diabetic nephropathy, may be promoted by excessive protein intake.

Excessive protein intake and the risk of cardiovascular disease

Several reports state that high protein intake is associated with the onset of CVD events and an increased risk of cardiovascular-related mortality and overall mortality [121]. In an observational study on elderly patients at a high risk of CVD (median 4.8 years), it was reported that high protein intake of > 1.5 g/weight kg/day was associated with CVD-related mortality risk and overall mortality risk compared with protein intake of 1.0–1.5 g/weight kg/day [122]. A protein intake exceeding 20% of the energy ratio may be related to pathological conditions, including diabetes mellitus and cancer, in addition to CVD (see other section). As described above, in patients with diabetic nephropathy who are at a high risk of developing CVD, excessive intake of protein should be avoided from the viewpoint of suppressing CVD.

The upper limit of protein intake

Because individuals with excessive protein intake may include those with an excessive overall energy and nutrient intake or with a low-carbohydrate diet, it is necessary to understand individual dietary intake patterns. Although the underlying clinical data are insufficient, the indication for the upper limit of protein intake should be set at 1.3 g/weight kg/day (Fig. 1), and a protein intake of > 1.3 g/weight kg/day or 20% of the energy ratio should be avoided even if a low-protein diet is not administered. In patients at a risk of malnutrition, sarcopenia, and frailty, protein intake of up to 1.5 g/weight kg/day may be allowed if their GFR is > 60 ml/min/1.73 m² (Fig. 1).

Source of protein and healthy diet patterns

Intake of animal protein, especially red meat, is more related to a decline in renal function than the amount of protein itself. The Singapore Chinese Health Study reported that in an average 15.5-year observation period of 63,257 people aged 45–74 years, 951 people developed ESRD [123], and individuals with the highest red meat intake were at an approximately 1.4-fold higher risk for end-stage renal failure than those with the lowest red meat intake. Conversely, this relationship was not observed with chicken, fish, egg, and soybean. Additionally, the possibility of decreasing the risk of end-stage renal failure by approximately 45–60% was indicated when the intake protein source was changed from red meat to chicken, fish, egg, and soybean [123]. In a meta-analysis of 18 prospective cohort studies involving 630,108 individuals (mean observation period: 10.4 years), healthy diet patterns (higher intake of vegetables, fruits, beans, nuts, whole grains, fish, and low-fat dairy products versus lower intake of red meat, processed meat, salt, and soft drinks) were related to a lower incidence of CKD [odds ratio 0.70 (95% CI 0.60–0.82); I² = 51%; 8 studies] and a lower incidence of albuminuria (odds ratio 0.77, 95% CI 0.59–0.99; I² = 37%; 4 studies) [124]. In a meta-analysis of seven longitudinal cohort studies involving 15,285 people, healthy diet patterns were associated with lower mortality (relative risk 0.73, 95% CI 0.63–0.83, I² = 0%; 6 studies) but were not related to the risk of end-stage renal failure (relative risk 1.04, 95% CI 0.68–1.40, I² = 0%; 3 studies) [125].

Several other reports have suggested a relationship between animal protein, particularly red meat intake, and diabetes and other diseases (see other section). However, currently, clinical evidence as to whether red meat intake is related to the onset and progression of diabetic nephropathy or whether healthy diet patterns suppress the onset and progression of diabetic nephropathy is unclear.

• 3.Protein intake in elderly diabetic patients.

Consensus recommendation

To prevent frailty and sarcopenia in the elderly, it is necessary to consume sufficient protein, in addition to a relatively large amount of energy, taking nutritional balance consideration. In elderly patients with renal dysfunction, the amount of protein intake should be set individually.

(*Weight kg refers to the target weight. However, actual weight or standard weight is used in the evidence and guidelines.)

Generally speaking, even with medical nutrition therapy for elderly patients with diabetes, it is a fundamental rule that 50–60% of the indicated energy be consumed from carbohydrates, with protein limited to about 15–20% and the remaining 20–30% consumed from lipids. The J-EDIT study reported that the nutritional balance of carbohydrates, proteins, and lipids in elderly Japanese patients with diabetes was 59.5%, 15.2%, and 25.4% for men, versus 58.6%, 15.7%, and 25.8% for women, respectively [126], exhibiting the same trend as the results among the elderly in the 2017 National Health and Nutrition Survey, the results of which indicated a low percentage of protein and a high percentage of carbohydrates [127]. According to a report from South Korea, patients with insufficient blood glucose control have a low protein and lipid ratio, with high carbohydrates as well [128]. With respect to energy intake in the elderly, it is recommended that they consume sufficient energy, from the viewpoint of sarcopenia and frailty prevention, with the BMI value used in the formula for calculating their target weight revised from 22 to 22–25 for patients over 65 years of age, in the formula for calculating the total energy intake presented by the Japan Diabetes Society [79].

While attention should be paid to the onset of sarcopenia and frailty, due to insufficient protein intake, in elderly patients with diabetes, there is little evidence regarding the protein intake required to maintain muscle mass and strength in elderly patients with diabetes. While the required protein in the elderly is reportedly 0.83 g/weight kg/day and 0.91 g/weight kg/day [114, 115], the ESPEN expert group recommends a healthy elderly population with protein intake of at least 1.0 g to 1.2 g/weight kg/day, and 1.2 g to 1.5 g/kg weight kg/day in case of undernutrition or risk of undernutrition [129]. Some cohort studies indicated that protein intake should be at least 1.2 g to 1.5 g/weight kg/day (equivalent to 15–20% of energy intake ratio), when taking the muscle mass, strength, bone mass, morbidity and mortality. of the elderly into consideration [130]. It has been reported that men and women over 60 years of age in Japan have a higher skeletal muscle index when their protein intake is high [127]. It has also been indicated that the rate of decrease in lean body mass is low when the elderly have a high protein intake (average protein intake: 1.2 g/ weight kg/day) [131], and, furthermore, the occurrence of frailty is low when protein intake is high [132]. In a cross-sectional study in Japan, although it was reported that there is a significant positive correlation between the plant protein intake rate and muscle mass [133], Kobayashi et al. reported that frailty was less frequent with high protein intakes of 70 g or more a day, regardless of whether it was animal protein or plant protein [134]. However, at present, there are no reports on the prevention or improvement of sarcopenia and frailty by increasing protein intake. On the other hand, with regard to the prognosis thereof, according to a previous report by Levine et al., 50–65 years old had greater overall mortality, cancer deaths, and diabetes-related deaths in the high protein intake group than in the low protein intake group, however, for those older than 66 years of age, overall mortality and cancer deaths were reduced in the high protein group [71].

Needless to say, there are many cases of renal dysfunction in elderly patients with diabetes. Cases with renal dysfunction require protein restrictions to some extent, even if sarcopenia and frailty coexist (See Chapter on protein intake and diabetic nephropathy (diabetic kidney disease)). The “Dietary recommendation for moderate CKD in the case of complications of sarcopenia and frailty” by Japanese Society of Nephrology [116] proposes guidelines, dividing cases into mitigation and priority, on protein intake in cases involving the complications of sarcopenia and frailty, during the implementation of standard CKD diet therapies. However, at the moment, there is not enough evidence which dietary therapy should be selected, a low-protein diet to protect renal function or increasing protein intake to prevent sarcopenia and frailty in elderly patients, especially aged ≥ 75 years old. Taking the above into account, it is recommended that elderly people consume sufficient protein, taking renal function into consideration. Especially, in elderly people with sarcopenia and frailty, or the risk thereof and aged ≥ 75 years old, the amount of protein intake should be set individually.

Regarding total protein intake, it has been reported that the protein intake of each meal is associated with muscle protein synthesis [135]. Because it has been pointed out that protein intake is insufficient for breakfast and lunch among the Japanese elderly [136], it is desirable for them to consume protein in three meals. Paying attention to a balanced diet that includes not only these three macronutrients but also vegetables, vitamins, minerals, etc., and combining exercise therapy (especially resistance exercise) after meals, make it possible to maintain muscle mass and strength, which is consequently expected to lead to sarcopenia and frailty prevention.

Dietary counseling by a registered dietitian

Consensus recommendation

Medical nutrition therapy for diabetes requires flexible, personalized counseling, taking into account diversity of age, condition, and the eating habits of patients.

The increasing number of people with type 2 diabetes in Japan is partly due to the westernization of the diet. The westernization of dietary habits of Japanese people, who have a lower body mass index (BMI) than Westerners, promotes obesity and insulin resistance and increases the incidence of diabetes [137]. Focusing on the optimization of total energy intake and guiding patients to consume various necessary nutrients are essential in diet therapies for diabetes. On the other hand, Medical nutrition therapies for patients with diabetes are expected to be continued over the course of remaining lifetime. To this end, a flexible treatment based on age, condition, life habits, and eating preferences of individual patients is required. In medical nutrition therapy for elderly patients with diabetes, their cognitive function and a burden of preparing meal on caring persons should be considered. It has been demonstrated that conducting dietary counseling from the early stage of the onset of diabetes and increasing the number of sessions thereafter effectively improves hyperglycemia [138]. Furthermore, comprehensive dietary counseling by registered dietitians has been shown to be effective for blood glucose control [139]. According to the results of meta-analysis, dietary counseling by registered dietitians significantly reduced body weight, HbA1c, and LDL-C compared to that by doctors and other medical staff [140]. Especially, diet counseling provided by registered dietitians can be expected to optimize total energy intake and correct nutrient balance [141]. Therefore, it is recommended that registered dietitians with ample counseling skills are involved in medical nutrition therapy for patients with diabetes from an early stage.

In Japan, registered dietitians have mainly conducted individual counseling for medical nutrition therapy for diabetes using the Food Exchange Lists for many years. The Food Exchange Lists categorize food into four groups and six tables in accord with the main nutrients contained in the food. Food containing the same nutrients can be "exchanged" within the same group, enhancing the flexibility of daily diet. The first edition of the Food Exchange Lists was published in 1965 to ensure the minimum protein and total energy intake, after which repeated revisions have been made in response to the westernization of diet and change in total energy intake of Japanese people [142]. The Lists have played a significant role in promoting appropriate energy intake and correcting the nutrient balance for Japanese patients with diabetes. However, with the ongoing diversification of eating habits and the aging of patients with diabetes in Japan, it is difficult to put a uniform dietary counseling regimen into practice. Sticking to counseling can lead to inappropriate medical nutrition therapy and, finally, to self-discontinuation of medical nutrition therapy. To achieve the better practice of medical nutrition therapy by patients, it is necessary to evaluate the comprehension of medical nutrition therapy and behavior changes of patients in the process of medical nutrition therapy. Contriving methods of therapy by registered dietitians, to improve the understanding of patients, and counseling flexibly depending on behavior changes in patients lead to less self-discontinuation by patients [143]. In summary, desirable dietary counseling should be effective and continuous, evaluating the understanding of patients and their behavioral changes while accepting their opinions.

Consensus recommendation

Counseling on regular eating habits and manner of eating meals should be included in medical nutrition therapy for patients with diabetes.

In Japan, the percentage of people who skip breakfast is high, mainly among youngsters, with a later dinner time [127, 144]. Irregular eating habits disturb the circadian rhythm, reduce energy expenditure and promote steatogenesis [145–147]. Furthermore, eating only once or twice a day, compared to three times per day, is more likely to lead to hyperglycemia after meals [148]. Meta-analysis reveals that the habit of skipping breakfast can lead to the risk of onset of type 2 diabetes [149]. Moreover, a late-night dinner just before sleep may contribute to the promotion of obesity, deterioration in blood glucose control, and increased risk of diabetic complications [150]. Indeed, shift workers who have irregular eating habits have increased risk of body weight gain [151] and onset of type 2 diabetes [152]. Thus, poor eating habits such as skipping breakfast and eating a late dinner promote obesity and contribute to onset of diabetes and deterioration of blood glucose control. Furthermore, irregular eating habits are associated with snacking, which leads to increased intake of energy, especially carbohydrates, thereby causing obesity and deterioration of blood glucose control [153]. Continuous dietary counseling by registered dietitians can reduce the intake frequency and amount of snack intake and correct the total energy intake and energy composition ratio between breakfast and dinner [154].

Recently, it has been noticed that the manner of consuming meals may affect blood glucose levels after meals. Eating vegetables rich in dietary fiber first reportedly inhibits increase in postprandial blood glucose, decreases HbA1c, and reduces body weight [155]. Not only eating vegetables first but also eating the main protein dish before the staple food (carbohydrates) suppress postprandial hyperglycemia [77, 78]. Moreover, eating quickly is less likely to produce a feeling of fullness than eating slowly [156], and the habit of eating fast is associated with less intake of dietary fiber and increased risk of obesity [157, 158]. Therefore, counseling regarding the manner of consuming meals is also required.

In summary, dietary counseling by registered dietitians for patients with diabetes should consider both content and the manner of eating meals.

Funding

The society received no specific funding for this work.

Compliance with ethical standards

Conflict of interest

Toshimasa Yamauchi received honoraria from Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Sanofi K. K., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Novo Nordisk Pharma Ltd., and Novartis Pharma K. K. Author TY received research funding from AstraZeneca K.K., Kowa Company, Ltd., Merck, Daiichi Sankyo Co., Ltd., Sanofi K. K., Boehringer Ingelheim GmbH Japan, and Aero Switch. Author TY received subsidies/donations from Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Sanofi K.K., Taisho Pharma Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., and Daiichi Sankyo Co., Ltd. Author TY belongs to endowed departments by Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd., Mitsubishi Tanabe Pharma Corporation, Merck, Boehringer Ingelheim GmbH Japan, Kowa Company, Ltd., and Asahi Mutual Life Insurance Company. Hideki Kamiya received honoraria from Sanofi K. K., Novartis Pharma K. K., Ono Pharmaceutical Co., Ltd., MSD K.K., Eli Lilly Japan K.K., Novo Nordisk Pharma Ltd., Astellas Pharma Inc., Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd. Hirotaka Watada received honoraria from Astellas Pharma Inc., AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly Japan K.K., MSD K.K., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho Co., Ltd., Kyowa Kirin Co., Ltd., Terumo Corporation, FUJIFILM Pharma, and Takeda Pharmaceutical Co., Ltd. Author HW received research funding from Nippon Boehringer Ingelheim Co., Ltd., Kowa Company, Ltd., Sanofi K.K., Yakult Honsha Co., Ltd., Eli Lilly Japan K.K., Novartis Pharma K. K., and Sanwa Kagaku Kenkyusho Co., Ltd. Author HW received subsidies/donations from Abbott JAPAN Co., Ltd., Astellas Pharma Inc., Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Pfizer Japan Inc., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novo Nordisk Pharma Ltd., Novartis Pharma K. K., Ono Pharmaceutical Co., Ltd., Sanofi K.K., TEIJIN Ltd., and Taisho Pharma Co., Ltd. Author HW belongs to endowed departments by Nippon Boehringer Ingelheim Co., Ltd., Kowa Company, Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Soiken, and Takeda Pharmaceutical Co., Ltd. Daiji Kawanami received honoraria from Takeda Pharmaceutical Co., Ltd., Sanofi K.K., and Novo Nordisk Pharma K.K. Junko Sato received research funding from Sanofi K.K. Daisuke Koya received honoraria from MSD K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Taisho Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., Novo Nordisk Pharma Ltd., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Sumitomo Dainippon Pharma Co., Ltd. Author DK received research funding from Mitsubishi Tanabe Pharma Corporation, AstraZeneca K.K., and A2 Healthcare Corporation. Author DK received subsidies/donations from Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Kowa Company, Ltd., Sanofi K.K., Johnson & Johnson K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Japan Tobacco Inc. Novo Nordisk Pharma Ltd., Bayer Yakuhin, and Pfizer Japan Inc. Author DK belongs to endowed departments by Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Taisho Pharma Co., Ltd., and Kyowa Kirin Co., Ltd. Norio Harada received research funding from Japan Diabetes Foundation. Author NH received subsidies/donations from Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanofi K.K., and MSD K.K. Erina Joo received research funding from Japan Diabetes Foundation. Ryo Suzuki received honoraria from MSD K.K., Novartis Pharma K. K., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., Sanofi K.K., Novo Nordisk Pharma K.K., and Astellas Pharma Inc. Kazunori Utsunomiya, Munehiro Kitada, Kenichiro Shide, Ryotaro Bouchi, Yasuharu Ohta and Tatsuya Kondo declare that they have no conflict of interest. Organizational Conflict of Interest: Co-sponsored seminar: Abbott Diagnostics Medical, Abbott Japan, Abbott Vascular Japan, Aegerion Pharmaceuticals, Ajinomoto, AR Brown, Arkray, Arkray Global Business, Asahi Kasei Pharma, ASKA Pharmaceutical, Astellas Pharma, AstraZeneca, Bayer Yakuhin, Cosmic Corporation, Covidien Japan, Daiichi Sankyo, Eiken Chemical, Eizai, Eli Lilly Japan, Fujifilm Pharma, Fujifilm Toyama Chemical, Fukuda Colin, Fukuda Denshi, Gilead Sciences, Hakubaku, Healthy Network, Hitachi Chemical Diagnostics Systems, Horiba, InBody Japan, Johnson & Johnson, Kaken Pharmaceutical, Kissei Pharmaceutical, Kotobuki Pharmaceutical, Kowa, Kracie Pharmaceutical, Kyowa Kirin, LifeScan Japan, LSI Medience, Medtronic Japan, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Mylan EPD, Nikkiso, Nippon Becton Dickinson, Nippon Boehringer Ingelheim, Nipro, Novartis Pharma, Novo Nordisk Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Rizap Group, Roche DC Japan, Sanofi, Santen Pharmaceutical, Sanwa Kagaku Kenkyusho, SRL, Sumitomo Dainippon Pharma, Taisho Pharma, Taisho Pharmaceutical, Takeda Pharmaceutical, Terumo, Unex, Welby. Supporting member: Abbott Japan, Arkray Global Business, Astellas Pharma, AstraZeneca, Bunkodo, Chugai Pharmaceutical, Daiichi Sankyo, EA Pharma, Eizai, Eli Lilly Japan, H+B Life Science, Horiba, Japan Tobacco, Johnson & Johnson, Kaken Pharmaceutical, Kissei Pharmaceutical, Kowa, Kyowa Kirin, LifeScan Japan, Medtronic Japan, Mitsubishi Tanabe Pharma, MSD, Nippon Boehringer Ingelheim, Nipro, Novo Nordisk Pharma, Ono Pharmaceutical, PHC, Roche DC Japan, Sanofi, Sanwa Kagaku Kenkyusho, Sekisui Medical, Shionogi, SRL, Sumitomo Dainippon Pharma, Sysmex, Taisho Pharma, Taisho Pharmaceutical, Takeda Pharmaceutical, Terumo, Tosoh. Research grant: Abbott Japan, Eli Lilly Japan, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Pharma, Sanofi, Takeda Pharmaceutical. Award system: Eli Lilly Japan, Novo Nordisk Pharma, Sanofi.

Ethical approval

The article does not contain any studies with human or animal subjects performed by any of the authors.