Katsumi Iizuka

Background: Accurate estimation of energy requirements is essential for appropriate nutritional therapy. Resting energy expenditure (REE) predictive equations are derived from specific populations and may therefore contain systematic individual-level biases when applied in different clinical settings. In this pilot exploratory study, we compared REE measured by portable indirect calorimetry with estimates obtained using multiple predictive methods in Japanese adults and characterized their association, absolute agreement, and error structure. Methods: Thirty-six university staff members and students were enrolled. The association and absolute agreement between REE measured by portable indirect calorimetry and estimates obtained using four predictive methods (Harris–Benedict, DRIs, Cunningham, and Ganpule) were evaluated using Spearman’s rank correlation coefficients, ICC(2,1), and Bland–Altman analyses. For equations demonstrating significant proportional bias, multivariate linear regression analyses were additionally performed using residual estimation error, calculated as (predicted REE-measured REE)/measured REE × 100, as the dependent variable. Results: Participants included 16 men and 20 women, with a mean age of 28.9 ± 10.3 years and BMI of 22.1 ± 3.1 kg/m2. Spearman’s rho ranged from 0.750 to 0.800, and ICC(2,1) estimates ranged from 0.736 to 0.766. Mean biases (predicted minus measured REE) were 50.7 kcal/day (95% CI, −20.1 to 121.4) for Harris–Benedict, −73.1 kcal/day (95% CI, −148.8 to 2.6) for DRIs, −94.7 kcal/day (95% CI, −161.7 to −27.8) for Cunningham, and −90.6 kcal/day (95% CI, −161.1 to −20.2) for Ganpule. The corresponding proportions of predictions within ±10% of measured REE were 41.7% (95% CI, 27.1–57.8%), 50.0% (95% CI, 34.5–65.5%), 55.6% (95% CI, 39.6–70.5%), and 52.8% (95% CI, 37.0–68.0%), respectively. Multivariate analyses suggested greater underestimation in females and a shift toward overestimation with higher BMI. Conclusions: Despite moderate-to-strong rank associations with measured REE, Bland–Altman analysis revealed proportional bias in three of the four predictive methods that was not apparent from the correlation coefficients alone. Exploratory analyses suggested that sex and BMI should be considered when interpreting the direction of prediction error. Because the precision of the limits of agreement was restricted by the small sample size, larger studies are needed to estimate individual-level agreement more precisely and to examine these error patterns in older adults and individuals with acute or chronic diseases.

AIMS/INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance circulating levels of biologically intact incretins, yet the relative contribution of glucose-dependent insulinotropic polypeptide (GIP) to their metabolic effects remains incompletely understood. While glucagon-like peptide-1 (GLP-1) has long been emphasized in incretin biology, emerging evidence suggests important physiological roles for GIP. This study investigated whether endogenous GIP signaling is indispensable for the glucose-lowering and anti-obesity effects of DPP-4 inhibition. MATERIALS AND METHODS: Male Gipr+/+ and Gipr-/- mice were treated with anagliptin or linagliptin under normal diet or high-fat diet (HFD) conditions. Glucose tolerance, insulin secretion, incretin levels, body weight, and adiposity were assessed. To confirm GLP-1 pathway integrity, dulaglutide was administered to a subset of animals. RESULTS: DPP-4 inhibition significantly improved glucose tolerance and attenuated body-weight gain in HFD-fed Gipr+/+ mice, without affecting food intake. These effects were abolished in Gipr-/- mice, despite similar elevations in circulating biologically intact GIP and GLP-1. Under normal diet, DPP-4 inhibitors enhanced early-phase insulin secretion and lowered glucose levels in Gipr+/+ mice, but not in Gipr-/- mice. Importantly, dulaglutide restored glucose-lowering effects in Gipr-/- mice, confirming preserved GLP-1 receptor function. CONCLUSIONS: Endogenous GIP signaling is essential for both glucose-lowering and anti-obesity actions of DPP-4 inhibitors in mice. GLP-1 elevation alone is insufficient to compensate for GIP receptor deficiency. These findings refined the mechanistic understanding of DPP-4 inhibitors, highlighted the physiological importance of GIP, and suggested context-dependent metabolic actions of incretins.

AIMS/INTRODUCTION: Diabetes is an increasingly prevalent global disease and often accompanied by sarcopenia, particularly in older adults. While insulin resistance is a well-known contributor to muscle loss in diabetes, the role of glucose signaling in diabetic skeletal muscle atrophy, particularly under insulin-deficient conditions, remains poorly understood. This study aimed to elucidate the pathophysiological role of the carbohydrate response element-binding protein (ChREBP), a glucose-sensing transcription factor encoded by the Chrebp gene in mice, in diabetic sarcopenia by generating Chrebp-deficient, insulin-deficient Ins2Akita/+ mice. MATERIALS AND METHODS: We evaluated Chrebp+/+, Chrebp-/-, Ins2Akita/+; Chrebp+/+, and Ins2Akita/+; Chrebp-/- mice for muscle strength, endurance, survival, body composition, and muscle histology. Skeletal muscles were analyzed for gene expressions related to anabolic and catabolic pathways. Results: Ins2Akita/+; Chrebp-/- mice exhibited significant reductions in body weight, grip strength, survival, and skeletal muscle mass-particularly in the tibialis anterior, soleus, gastrocnemius, and quadriceps-compared to Ins2Akita/+ controls, despite similar hyperglycemia. Histological analysis revealed smaller mean muscle fiber size and reduced cross-sectional area of type 2A and 2B fibers, without changes in fiber-type composition. Furthermore, Igf-1 expression were suppressed, while the atrophy marker Fbxo32/Atrogin-1 was upregulated. CONCLUSIONS: These findings demonstrate that Chrebp deletion exacerbates muscle atrophy and frailty in insulin-deficient mice, underscoring a key role for ChREBP-mediated glucose signaling in maintaining muscle mass under diabetic conditions. The Ins2Akita/+; Chrebp-/- model provides a valuable platform for exploring diabetic sarcopenia mechanisms and potential therapeutic targets.

Background and Aim: Underweight young adult women are vulnerable to health risks such as menstrual disorders and vitamin deficiencies. Because few seek medical care for low body weight, the underlying causes remain unclear. This study aimed to examine the associations of body type with dietary patterns and gut microbiota diversity in young women. Methods: We enrolled 40 women aged 20–39 years who visited a nutrition evaluation clinic with a BMI < 17.5 at their first consultation (underweight group) and 40 age-matched women with 18.5 ≤ BMI < 25 (control group). Some women in the underweight group were no longer underweight at the time of analysis but were classified based on their initial BMI. Dietary patterns were assessed based on ten major food categories (meat, fish, eggs, dairy products, soybeans, green and yellow vegetables, seaweed, fruit, tubers, and fats and oil) based on the Food Frequency Questionnaire based on Food Groups. Gut microbiota α-diversity was evaluated using the Shannon, Simpson, and Pielou indices, while β-diversity was analyzed by nonmetric multidimensional scaling (NMDS) and redundancy analysis (RDA). Genera contributing to group differences were identified by RDA and ANOVA-Like Differential Expression tool (ALDEx2). Results: Underweight women had significantly lower gut microbiota α-diversity, while no difference was observed in dietary pattern scores. NMDS revealed significant β-diversity differences in gut microbiota (PERMANOVA: R2 = 0.064, F = 5.31, p = 0.0001) but not in dietary patterns (p = 0.99). RDA showed that body type explained 4.5% of variance (adjusted R2 = 0.032, F = 3.65, p = 0.0005). Bacteroides, Bifidobacterium, Enterocloster, and Erysipelatoclostridium were enriched in underweight women, whereas Fusicatenibacter, Agathobacter, Dorea, and Prevotella were enriched in controls. AldEx2 confirmed increases in Bacteroides, Enterocloster, and Erysipelatoclostridium and a decrease in Dorea. Conclusions: Underweight women demonstrated reduced gut microbiota diversity and enrichment of taxa associated with inflammatory tendencies. Dietary therapies involving not only prebiotics but also probiotics may beneficially modulate gut microbiota and contribute to the management of low body weight.

Background/Objectives: Dietary patterns vary with age and sex. The aim of this study was to clarify the differences in dietary patterns among young and middle-aged Japanese individuals by age group and sex via statistical methods such as alpha diversity and beta diversity analyses. Methods: Using data from a dietary survey of 10 food items during health checkups of 2743 Fujita Health University employees, we examined the effects of age and sex on alpha diversity (Shannon index) and beta diversity (nonmetric multidimensional scaling (NMDS) and RDA). Unlike principal component analysis which assumes linear relationships, redundancy analysis (RDA) incorporates explanatory variables to directly assess how external factors shape multivariate patterns. Results: The Shannon index increased with age and was greater in males across age groups. Type III ANOVA revealed significant main effects of age (p < 0.001) and sex (p < 0.001), and the effect of the interaction between age and sex approached significance (p = 0.08). Visualization of the NMDS data revealed that women aged 20–29 years and women aged 30 years and older and men aged 20–39 years and men aged 50–59 years have different dietary patterns. The RDA model accounted for 2.01% of the variance (adjusted R2 = 1.94%), with age and sex contributing 56.7% and 43.3%, respectively. RDA1 and RDA2 were correlated with age (r = 0.26, −0.14) and sex (r = 0.15, 0.21). The RDA1 values increased with age and were greater in females, whereas the RDA2 values decreased with age and were greater in females. RDA1 (1.41% of the total variance in food group intake, 70.1% of the constrained variance) was positively associated with fruits, milk, and seaweed and negatively associated with meat and eggs. In RDA2 (0.60% of total variance, 29.9% contribution), fruits, potatoes, and vegetables had positive effects, whereas fish had negative effects. Conclusions: Dietary patterns vary by age and sex, with meat, fish, eggs, and fruit as key determinants. Nutritional guidance must account for variations in dietary patterns influenced by age and sex.

Background/Aim: Skeletal muscle mass index (SMI) and body fat percentage (BF%) are components of body mass index (BMI) but are considered to play independent roles. We aimed to clarify whether SMI and BF% are associated with nutritional markers independent of BMI in underweight women. Methods: This retrospective observational study included a total of 102 women aged 20–65 years who were referred to the outpatient nutrition evaluation clinic from 2022 to 2024 with a body mass index (BMI) < 17.5. We performed a multivariate analysis with SMI and BF% as independent variables and BMI, BMI ratio (present-to-age 20 ratio), grip strength, and biochemical nutritional indicators (vitamin B1 level (ng/mL), cholesterol level (mg/dL), lymphocyte count (/μL), and HbA1c (%) level) as dependent variables, adjusting for age. Results: Women aged 30.9 ± 10.2 years (yo) with a BMI of 17.0 ± 0.7 participated in this study. BMI (kg/m2) was positively associated with SMI (kg/m2) (β (95% CI): 1.6 [1.4, 1.9], p < 0.001) and BF% (0.2 [0.1, 0.2], p < 0.001), and the BMI ratio (present-to-age 20 ratio) was positively associated only with BF% (0.5 [0.05, 0.9], p = 0.03). Grip strength was positively associated with SMI (4.0 [1.4, 6.6], p = 0.003), and lymphocyte count was positively associated with BF% (β (36.2 [6.0, 66.5], p = 0.02). BMI was not associated with grip strength or lymphocyte count. Vitamin B1, cholesterol, and HbA1c were not associated with SMI, BF%, or BMI. Conclusions: These results indicate that SMI reflects BMI and grip strength, whereas BF% reflects BMI, the BMI ratio (present to age 20), and lymphocyte count. In addition to BMI and SMI, changes in BF% should also be noted in underweight women.

Background/Aim: Slow eating is recommended for obese individuals. We aimed to determine the associations between meal duration and various factors (sex, numbers of chews and bites, eating tempo (including forced rhythm with a metronome) and BMI). Methods: Using a test meal (a quarter slice of pizza), we tested the sex difference of the meal duration, numbers of chews and bites, and eating tempo for thirty three healthy subjects (M: 15; F: 18) aged 37.2 ± 11.1 years via unpaired t tests. Next, factors influencing meal duration were identified via multivariate analysis (adjusted for sex), with meal duration as the dependent variable. Results: The meal duration and numbers of chews and bites differed significantly between sexes (63.1 ± 20.7 vs. 87.4 ± 22.8, p = 0.003; 80.3 ± 28.7 vs. 107.0 ± 36.1, p = 0.02; 2.1 ± 1.1 vs. 4.5 ± 2.6, p = 0.001, respectively), but the chewing tempo was similar (p = 0.32). Meal duration was associated with the number of chews (β = 0.6 [0.4, 0.7], p < 0.001) and bites (5.8 [2.5, 9.2], p = 0.001) but not with BMI (p = 0.52) or chewing tempo (p = 0.99). Finally, when a metronome was used to force rhythmic stimulation (0/40/80/160 bpm), compared with 0 bpm, slow stimulation (40 bpm) resulted in increased meal duration (mean difference [95% CI] = −47.0 [−66.4, −27.7], p < 0.0001), chews (−28.6 [−44.5, 12.8], p = 0.0003), and bites (−4.9 [−7.9, 1.9] p = 0.001) and delayed tempo (10.4 [4.5, 16.3], p = 0.0004). Conclusions: Meal duration was positively associated with the numbers of chews and bites and negatively associated with chewing tempo. Thus, increasing the numbers of bites and chews and slowing the eating tempo may prolong meal duration.

(1) Background: Proglucagon-derived peptides (PDGPs) including glucagon (Gcg), GLP-1, and GLP-2 regulate lipid metabolism in the liver, adipocytes, and intestine. However, the mechanism by which PGDPs participate in alterations in lipid metabolism induced by high-fat diet (HFD) feeding has not been elucidated. (2) Methods: Mice deficient in PGDP (GCGKO) and control mice were fed HFD for 7 days and analyzed, and differences in lipid metabolism in the liver, adipose tissue, and duodenum were investigated. (3) Results: GCGKO mice under HFD showed lower expression levels of the genes involved in free fatty acid (FFA) oxidation such as Hsl, Atgl, Cpt1a, Acox1 (p < 0.05), and Pparα (p = 0.05) mRNA in the liver than in control mice, and both FFA and triglycerides content in liver and adipose tissue weight were lower in the GCGKO mice. On the other hand, phosphorylation of hormone-sensitive lipase (HSL) in white adipose tissue did not differ between the two groups. GCGKO mice under HFD exhibited lower expression levels of Pparα and Cd36 mRNA in the duodenum as well as increased fecal cholesterol contents compared to HFD-controls. (4) Conclusions: GCGKO mice fed HFD exhibit a lesser increase in hepatic FFA and triglyceride contents and adipose tissue weight, despite reduced β-oxidation in the liver, than in control mice. Thus, the absence of PGDP prevents dietary-induced fatty liver development due to decreased lipid uptake in the intestinal tract.

Diabetes is a disease in which lifestyle-based interventions, including recommendations for a healthy diet, play a critical role, and many countries have established their own nutritional guidelines [...]

AIMS/INTRODUCTION: Glucagon is secreted from pancreatic α-cells and plays an important role in amino acid metabolism in liver. Various animal models deficient in glucagon action show hyper-amino acidemia and α-cell hyperplasia, indicating that glucagon contributes to feedback regulation between the liver and the α-cells. In addition, both insulin and various amino acids, including branched-chain amino acids and alanine, participate in protein synthesis in skeletal muscle. However, the effect of hyperaminoacidemia on skeletal muscle has not been investigated. In the present study, we examined the effect of blockade of glucagon action on skeletal muscle using mice deficient in proglucagon-derived peptides (GCGKO mice). MATERIALS AND METHODS: Muscles isolated from GCGKO and control mice were analyzed for their morphology, gene expression and metabolites. RESULTS: GCGKO mice showed muscle fiber hypertrophy, and a decreased ratio of type IIA and an increased ratio of type IIB fibers in the tibialis anterior. The expression levels of myosin heavy chain (Myh) 7, 2, 1 and myoglobin messenger ribonucleic acid were significantly lower in GCGKO mice than those in control mice in the tibialis anterior. GCGKO mice showed a significantly higher concentration of arginine, asparagine, serine and threonine in the quadriceps femoris muscles, and also alanine, aspartic acid, cysteine, glutamine, glycine and lysine, as well as four amino acids in gastrocnemius muscles. CONCLUSIONS: These results show that hyperaminoacidemia induced by blockade of glucagon action in mice increases skeletal muscle weight and stimulates slow-to-fast transition in type II fibers of skeletal muscle, mimicking the phenotype of a high-protein diet.

Undernutrition among young women at “Cinderella weight” is socially important in Japan. To determine the nutritional status of Cinderella-weight women, we conducted an exploratory cross-sectional study on the health examination results of employees aged 20 to 39 (n = 1457 and 643 for women and men, respectively). The percentage of underweight women was found to be much higher than that of men (16.8% vs. 4.5%, respectively). In underweight women (n = 245), handgrip strength (22.82 ± 5.55 vs. 25.73 ± 5.81 kg, p < 0.001), cholesterol level (177.8 ± 25.2 vs. 194.7 ± 31.2 mg/dL, p < 0.05), and lymphocyte count (1883 ± 503 vs. 2148 ± 765/μL, p < 0.001) were significantly lower than in overweight women (n = 116). Then, the BMI < 17.5 group (n = 44) was referred to the outpatient nutrition evaluation clinic. Lower prealbumin, cholesterol, and lymphocyte levels were also observed in 34%, 59%, and 32% of the patients, respectively. Regarding dietary characteristics, 32% of the underweight women in this study skipped breakfast, and 50% had low dietary diversity scores. Lower total energy intake, carbohydrate and fiber intake, and Ca and Fe intake were also observed in 90% of the patients. Deficiencies in vitamin B1, B12, D, and folate were diagnosed in 4.6%, 25%, 14%, and 98% of the patients, respectively. Thus, young underweight women may be prone to malnutrition.

Excess fructose intake is associated with obesity, fatty liver, tooth decay, cancer, and cardiovascular diseases. Even after the ingestion of fructose, fructose concentration in the portal blood is never high; fructose is further metabolized in the liver, and the blood fructose concentration is 1/100th of the glucose concentration. It was previously thought that fructose was metabolized in the liver and not in the small intestine, but it has been reported that metabolism in the small intestine also plays an important role in fructose metabolism. Glut5 knockout mice exhibit poor fructose absorption. In addition, endogenous fructose production via the polyol pathway has also received attention; gene deletion of aldose reductase (Ar), ketohexokinase (Khk), and triokinase (Tkfc) has been found to prevent the development of fructose-induced liver lipidosis. Carbohydrate response element-binding protein (Chrebp) regulates the expression of Glut5, Khk, aldolase b, and Tkfc. We review fructose metabolism with a focus on the roles of the glucose-activating transcription factor Chrebp, fructolysis, and the polyol pathway.

Mobile food records are currently used to determine the nutrition of healthy subjects. To determine the accuracy of such records, we evaluated the nutritional composition of a test meal (noodles and fruit juice) and a hospital meal (Japanese set meal) using two types of mobile food records. Eighteen healthy subjects (2 males and 16 females) were enrolled. Using these diets and validated nutrient-composition information, we evaluated the accuracy of the dietary assessments made by two dietary-record applications, Asken® and Calomeal®, over 5 days. For the test meal, the values provided by the two applications were close to the actual values. In contrast, for the hospital meal, the values provided by the two applications were approximately 1.5 times higher than the actual values. A linear-mixed-model analysis showed that the total energy, carbohydrate, and salt contents were significantly overestimated in the hospital meal. Protein also tended to be overestimated, while the fat content was not significantly overestimated. Furthermore, the total energy and fat contents increased significantly over time. No association with age was observed. A comparison of the coefficients of variation (CVs) for each nutrient in the hospital meal indicated that the fat levels were significantly higher than those in the test meal. In conclusion, the accuracy of mobile food records depends on the type of meal. Our data will provide lessons for the use of meal-recording applications in special cases, such as hospital food.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant disease, which requires differential diagnosis from relatively common primary hyperparathyroidism (PHPT) in order to avoid unnecessary surgery. CASE PRESENTATION: A 16-year-old female had been followed by the department of psychosomatic medicine at our institution. Throughout the follow-up period, her plasma calcium levels were high, plasma Pi levels were relatively low, and plasma intact PTH was relatively high. She was referred to our department to determine the cause of her hypercalcemia. Her 24 h urinary calcium excretion was as low as 100 mg/day, and calcium creatinine clearance ratio was below 0.01. Moreover, she had a family history of hypercalcemia (proband, her brother, and her father). The genetic testing for her family revealed that she, her brother, and her father were definitively diagnosed with FHH type 1 due to the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu). CONCLUSION: We experienced a 16-year-old female with FHH, in whom genetic testing identified the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu) as pathogenic, permitting a definitive diagnosis of FHH type 1. The genetic testing for calcium sensing receptor is beneficial to distinguish asymptomatic primary hyperparathyroidism from FHH.

We treated a 22-year-old woman suffering from Graves' disease and thymic hyperplasia. She was referred to our institution for a close investigation of thyrotoxicosis and thymic mass. Thyroid tests and magnetic resonance imaging resulted in a diagnosis of Graves' disease and thymic hyperplasia. The thyroid function and thyroid-stimulating hormone receptor antibody (TRAb) were normalized one and five months after thiamazole initiation, respectively. The thymic size began to decrease after 1 month and was further decreased after 5 months; it was normalized after 12 months. The correlation between TRAb titers and the thymic size (R2=0.99) suggested that the patient's autoimmunity might have contributed to the thymic hyperplasia.