Associations of adipose insulin resistance index with pancreatic ß cell function (inverse) and glucose excursion (positive) in young Japanese women.

The relationship of adipose tissue insulin resistance (AT-IR, a product of fasting insulin and free fatty acids) and homeostasis-model assessment-insulin resistance (HOMA-IR) to ß-cell function was studied cross-sectionally in the setting of subtle glucose dysregulation. Associations of AT-IR and HOMA-IR with fasting and post-glucose glycemia and ß-cell function inferred from serum insulin kinetics during a 75 g oral glucose tolerance test were studied in 168 young female Japanese students. ß-cell function was evaluated by disposition index calculated as a product of the insulinogenic index (IGI) and Matsuda index. AT-IR, not HOMA-IR, showed positive associations with post-glucose glycemia and area under the glucose response curve although both indices were associated with fasting glycemia. HOMA-IR, not AT-IR, was associated positively with log IGI whereas both indices were inversely associated with Matsuda index. AT-IR, not HOMA-IR, showed inverse associations with log disposition index. Associations of adipose tissue insulin resistance with ß-cell function (inverse) and glucose excursion in young Japanese women may suggest that lipotoxicity to pancreatic ß-cells for decades may be associated with ß cell dysfunction found in Japanese patients with type 2 diabetes. Positive association of HOMA-IR with insulinogenic index may be associated with compensatory increased insulin secretion.

The different associations of serum gamma-glutamyl transferase and alanine aminotransferase with insulin secretion, ß-cell function, and insulin resistance in non-obese Japanese.

The present study investigated the associations of serum gamma-glutamyl transferase (GGT), a marker of fatty liver and oxidative stress, and ALT/AST, a marker of fatty liver, with percentage trunk fat and postload glucose, insulin resistance, and ß-cell function in middle-aged Japanese individuals, whose BMI averaged < 23.0 kg/m2. Pancreatic ß-cell function was assessed using the disposition index calculated by a product of the insulinogenic index (IGI) and Matsuda insulin sensitivity index, a biomarker of early-phase glucose-stimulated insulin secretion and whole-body insulin sensitivity, respectively. Multivariate linear regression analyses revealed that the disposition index was associated inversely with GGT independently of percentage trunk fat, homeostasis model assessment insulin resistance (HOMA-IR), a marker of insulin resistance, and Matsuda index. When IGI was included instead of the disposition index, IGI (inversely) and HOMA-IR were associated with GGT independently of percentage trunk fat and Matsuda index. When the area under the glucose concentration curve (AUCg) during an oral glucose tolerance test was included instead of the disposition index, AUCg and HOMA-IR emerged as independent determinants of GGT. ALT/AST was associated with HOMA-IR alone. Results suggest a different pathophysiologic basis between GGT and ALT/AST in predicting diabetic risk in non-obese Japanese.

Low muscle mass is associated with low insulin sensitivity, impaired pancreatic ß cell function, and high glucose excursion in nondiabetic nonobese Japanese women.

Aim: We tested whether skeletal muscle mass is associated with insulin sensitivity, pancreatic ß-cell function, and postglucose glycemia. Methods: Appendicular skeletal muscle mass (ASM) (relative to body size, %ASM) by DXA, surrogate measures of insulin sensitivity, insulin secretion and the disposition index (insulin sensitivity adjusted insulin secretion: a product of the insulinogenic index and Matsuda insulin sensitivity index) inferred from serum insulin kinetics during a 75 g oral glucose tolerance test (OGTT) were evaluated in 168 young and 65 middle-aged women, whose BMI averaged <23.0 kg/m2 and HbA1c â‰¦ 5.5 %. Results: In two groups of women, %ASM was associated negatively with homeostasis model assessment insulin resistance (HOMA-IR) and 2-h insulin (both p < 0.01 or less). In middle-aged women not in young women, %ASM was associated inversely with the Matsuda index (p < 0.001). In middle-aged women only, it also showed a positive association with the disposition index (p = 0.02) and inverse associations with 1-h and 2-h glucose (both p < 0.01) and area under the glucose concentration curve during OGTT (p = 0.006). On multivariate linear regression analyses, 2-h insulin emerged as a determinant of %ASM independently of HOMA-IR in young women (standardized ß: 0.287, p < 0.001, R2 = 0.077). In middle-aged women, the Matsuda index emerged as a determinant of %ASM (standardized ß: 0.476, p < 0.001) independently of HOMA-IR, log ODI and AUCg and explained 21.3 % of %ASM variability. Post-glucose glycemia and AUCg were higher and log ODI was lower in middle-aged women with low compared with high %ASM. Conclusion: Low skeletal muscle mass (relative to body size) was associated with low insulin sensitivity in young and middle-aged Japanese women who were neither obese nor diabetic. Middle-aged women with low muscle mass had low disposition index, an early marker of inadequate pancreatic ß-cell compensation, and hence high glucose excursion. Low skeletal muscle mass may be associated with the development of type 2 diabetes at a much lower BMI in Japanese people.

Adipose tissue insulin resistance index was inversely associated with gluteofemoral fat and skeletal muscle mass in Japanese women.

Associations of adipose tissue insulin resistance index (AT-IR, a product of fasting insulin and free fatty acids) with body fat mass and distribution and appendicular skeletal muscle mass (ASM) were compared with results of homeostasis-model assessment-insulin resistance (HOMA-IR) in 284 Japanese female university students and 148 their biological mothers whose BMI averaged < 23 kg/m2. Although mothers compared with daughters had higher BMI, body fat percentage, trunk fat to body fat (TF/BF) ratio and lower leg fat to body fat (LF/BF), AT-IR and HOMA-IR did not differ. We had multivariable linear regression analyses which included TF/BF ratio, LF/BF ratio, weight-adjusted ASM (%ASM), height-adjusted ASM index (ASMI), fat mass index (FMI), and body fat percentage. In young women, AT-IR was independently associated with LF/BF ratio (Standardized ß [Sß]: - 0.139, p = 0.019) and ASMI (Sß: - 0.167, p = 0.005). In middle-aged women, LF/BF ratio (Sß: - 0.177, p = 0.049) and %ASM (Sß: - 0.205, p = 0.02) emerged as independent determinants of AT-IR. HOMA-IR was associated with TF/BF ratio and FMI, a proxy of abdominal and general adiposity, respectively, in both young and middle-aged women. The inverse association of AT-IR with leg fat may support the notion that limited peripheral adipose storage capacity and small skeletal muscle size are important etiological components in insulin-resistant cardiometabolic disease in Japanese women.

Associations of adipose insulin resistance index with leg (gluteofemoral) fat (inverse) and serum alanine aminotransferase (positive) in young Japanese women.

Aim: Associations of the adipose tissue insulin resistance index (AT-IR, a product of fasting insulin and free fatty acid) with body fat distribution and the ratio of alanine to aspartate aminotransferase (ALT/AST), a marker of hepatosteatosis, were examined in the context of the metabolic syndrome. Methods: Legs, the trunk and body fat by DXA, blood pressure (BP) and blood chemistry were measured in 284 young Japanese female university students and 148 middle-aged biological mothers whose BMI averaged <23 kg/m2. Results: Young women had higher leg fat/body fat and lower trunk fat/body fat ratio (both p < 0.001) compared with middle-aged women but AT-IR did not differ between the two groups. We had multivariable linear regression analysis for AT-IR as a dependent variable including leg fat/body fat ratio, trunk fat/body fat ratio, fasting glucose, triglyceride, HDL cholesterol and systolic BP as independent variables. Leg fat/body fat ratio, fasting glucose and triglyceride (p = 0.013, 0.009 and 0.016, respectively) emerged as determinants of AT-IR in young women. Trunk fat/body fat ratio and fasting glucose (p = 0.003 and 0.019, respectively) emerged in middle-aged women. In a model which included ALT/AST as an additional independent variable, ALT/AST (p = 0.016) was the fourth independent determinant in young women and the single determinant of AT-IR in middle-aged women (p < 0.001). Conclusion: In young Japanese women, adipose tissue insulin resistance was associated with reduced leg fat, a subtle partial lipodystrophy-like phenotype associated with reduced adipose tissue expandability. It was associated with elevated trunk (abdominal) fat in middle-aged women and with ALT/AST, a marker of hepatosteatosis, in two groups of Japanese women, suggesting ectopic fat deposition associated with reduced adipose tissue expandability.

Associations of ALT/AST, a marker of hepatosteatosis, with pulse rate in young women and with blood pressure in middle-aged women independently of abdominal fat accumulation and insulin resistance.

We examined whether alanine aminotransferase/aspartate aminotransferase (ALT/AST), a marker of hepatosteatosis, may be associated with a wider constellation of variables related to metabolic syndrome in Japanese women. Body fat and distribution, and metabolic syndrome-related variables were measured in 311 young and 148 middle-aged women. We had Pearson's correlation analysis and then stepwise multivariate linear regression analyses. In both middle-aged and young women, ALT/AST was associated with homeostasis model assessment insulin resistance (HOMA-IR), trunk/leg fat ratio and pulse rate. In middle-aged women but not in young women, ALT/AST was associated with waist circumference, fasting glucose, triglyceride, HDL cholesterol (inversely), systolic, diastolic and mean blood pressure (BP). Further, in middle-aged women only, the ratio was associated with BMI, percentage body fat, apolipoprotein B and plasminogen activator inhibitor-1. Among these variables, pulse rate in young women and systolic BP in middle-aged women were associated with ALT/AST independently of trunk/leg fat ratio, a sophisticated measures of abdominal fat accumulation,　HOMA-IR, fasting glucose, triglyceride and HDL cholesterol. In conclusion, ALT/AST was associated with pulse rate in young women and with systolic BP in middle-aged women independently of abdominal fat accumulation and insulin resistance. It is noted that their waist circumference averaged < 80 cm and ALT < 30 U/L, suggesting minimum accumulation of abdominal and hepatic fat, respectively, key drivers of insulin resistance and metabolic syndrome. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00689-z.

Higher childhood weight gain, lower skeletal muscle mass, and higher cereal consumption in normal-weight Japanese women with high-percentage trunk fat: a subanalysis study.

Normal-weight but high-percentage trunk fat phenotype was characterized in a setting where adiposity is not associated with educational and socioeconomic status. Body size trajectory since birth, current body composition measured using whole-body dual-energy X-ray absorptiometry, cardiometabolic traits, serum adipokines, and dietary intake were measured cross-sectionally in 251 normal weight Japanese female university students whose fasting triglyceride and homeostasis model assessment-insulin resistance (HOMA-IR) averaged 56 mg/dL and 1.2, respectively. They were grouped according to tertile of percentage trunk fat. Although HOMA-IR did not differ among three groups, high-percentage trunk fat was associated with higher triglyceride and apolipoprotein B, and lower HDL cholesterol and apolipoprotein A1. In multivariate logistic regression analyses, weight-adjusted skeletal muscle mass (OR: 0.13, 95% CI: 0.04-0.38, p < 0.001), weight gain from birth to age 12 years (OR: 1.214、95% CI: 1.008-1.463、p = 0.04), and cereal consumption (OR:1.008, 95% CI: 1.000-1.016, p = 0.04) were associated with high-percentage trunk fat independent of birthweight, HOMA-IR, adipose tissue-insulin resistance index (the product of fasting insulin and free fatty acid), triglyceride, HDL cholesterol, apolipoprotein A1 and B, leptin, adiponectin, blood pressure, and high-sensitivity C-reactive protein. Early childhood growth, lower skeletal muscle mass, and higher cereal consumption may be associated with normal-weight but high-percentage trunk fat phenotype in Japanese female university students in this subanalysis study. Atherogenic profile of lipids and apolipoproteins may be directly related to abdominal fat accumulation.

An effective visible-light driven fumarate production from gaseous CO2 and pyruvate by the cationic zinc porphyrin-based photocatalytic system with dual biocatalysts.

Fumaric acid is a useful unsaturated dicarboxylic acid that serves as a precursor for the biodegradable plastics poly(butylene succinate) and poly(propylene fumarate). Currently, fumaric acid is mainly synthesised from petroleum resources such as benzene. It is therefore desirable to develop methods to produce fumaric acid from renewable resources such as those derived from biomass. In this work, an effective visible-light driven fumarate production from gaseous CO2 and pyruvate with the system consisting of triethanolamine, cationic water-soluble zinc porphyrin, zinc tetrakis(4-N,N,N-trimethylaminophenyl)porphyrin, pentamethylcyclopentadienyl coordinated rhodium(III) 2,2'-bipyridyl complex, NAD+, malate dehydrogenase (NAD+-dependent oxaloacetate-decarboxylating) and fumarase was developed.

Associations of Alanine Aminotransferase/Aspartate Aminotransferase, a Marker of Hepatosteatosis, with Adipose Tissue Insulin Resistance Index and Leptin/Adiponectin Ratio in Japanese Women.

Objective: We assessed whether alanine aminotransferase/aspartate aminotransferase (ALT/AST), a marker of hepatic steatosis, may be associated with adipose tissue dysfunction more closely than hepatic and muscle insulin resistance (IR). Methods: Associations with adipose tissue IR index (AT-IR) calculated as a product of fasting insulin and free fatty acids, leptin/adiponectin ratio, a proxy of adipocyte dysfunction, homeostasis model assessment IR (HOMA-IR), hepatic and muscle IR inferred from plasma insulin kinetics during a 75 grams oral glucose tolerance test (OGTT) were studied in nondiabetic 307 young and 148 middle-aged Japanese women, whose body mass index averaged 20 and 22 kilograms/m2, respectively. Results: On multivariate linear regression analysis in young women, ALT/AST was associated with trunk/leg fat ratio (standardized ß = 0.202, P = 0.007), a marker of abdominal fat accumulation, and AT-IR (standardized ß = 0.185, P = 0.003) independently of HOMA-IR and Matsuda index (R2 = 0.07). In middle-aged women, leptin/adiponectin ratio (standardized ß = 0.446, P < 0.001) and AT-IR (standardized ß = 0.292, P = 0.009) emerged as determinants of ALT/AST independently of trunk/leg fat ratio, OGTT-derived hepatic IR, leptin, and adiponectin (R2 = 0.34). Conclusions: ALT/AST was associated with AT-IR and adipocyte dysfunction more closely than hepatic and muscle IR even in nondiabetic lean Japanese women.

Associations of alanine aminotransferase/aspartate aminotransferase with insulin resistance and ß-cell function in women.

We tested whether alanine aminotransferase/aspartate aminotransferase (ALT/AST), a marker of hepatosteatosis, associates with insulin resistance, ß-cell function and postglucose glycemia. We studied 311 young and 148 middle-aged Japanese women, whose BMI averaged < 23.0 kg/m2. Insulinogenic index and Matsuda index were evaluated in 110 young and 65 middle-aged women. In two groups of women, ALT/AST was associated positively with homeostasis model assessment insulin resistance (HOMA-IR) and inversely with Matsuda index. In middle-aged women only, the ratio was also associated positively with fasting and postload glycemia and HbA1c. The ratio showed negative association with disposition index (a product of insulinogenic index and Matsuda index). On multivariate linear regression analysis, HOMA-IR emerged as a single determinant of ALT/AST in young and middle-aged women (standardized ß: 0.209, p = 0.003 and 0.372, p = 0.002, respectively). ALT/AST was associated with insulin resistance and ß-cell function even in non-obese Japanese women, suggesting a pathophysiologic basis in its prediction of diabetic risk.

Association between serum leptin concentrations and homeostasis model assessment-insulin resistance of 2.5 and higher in normal weight Japanese women.

Normal weight insulin resistant phenotype was characterized in 251 Japanese female university students using homeostasis model assessment-insulin resistance. Birth weight, body composition at age 20, cardiometabolic traits and dietary intake were compared cross-sectionally between insulin sensitive (< 1.6, n = 194) and insulin resistant (2.5 and higher, n = 16) women. BMI averaged < 21 kg/m2 and waist < 72 cm and did not differ between two groups. The percentage of macrosomia and serum absolute and fat-mass corrected leptin concentrations were higher in insulin resistant women although there was no difference in birth weight, fat mass index, trunk/leg fat ratio and serum adiponectin. In addition, resting pulse rate, serum concentrations of free fatty acids, triglycerides and remnant-like particle cholesterol were higher in insulin resistant women although HDL cholesterol and blood pressure did not differ. In multivariate logistic regression analyses, serum leptin (odds ratio:1.68, 95% confidential interval:1.08-2.63, p = 0.02) was associated with normal weight insulin resistance independently of macrosomia, free fatty acids, triglycerides, remnant-like particle cholesterol and resting pulse rate. In conclusion, normal weight IR phenotype may be associated with increased plasma leptin concentrations and leptin to fat mass ratio in young Japanese women, suggesting higher leptin production by body fat unit.

Clinical phenotypic diversity of NOTCH2NLC-related disease in the largest case series of inherited peripheral neuropathy in Japan.

BACKGROUND: NOTCH2NLC GGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a few NOTCH2NLC-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations of NOTCH2NLC-related IPNs. METHOD: Among 2692 Japanese patients clinically diagnosed with IPN/Charcot-Marie-Tooth disease (CMT), we analysed NOTCH2NLC repeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination of NOTCH2NLC repeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR. RESULTS: NOTCH2NLC repeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8-59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7-61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear. CONCLUSIONS: These findings of this study help us understand the clinical heterogeneity of NOTCH2NLC-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.

Weight trajectories since birth, current body composition and metabolic traits in young, normal-weight Japanese women with high percentage body fat.

INTRODUCTION: We tested whether normal-weight obesity might be associated with weight trajectories, body composition and metabolic traits. RESEARCH DESIGN AND METHODS: Body size trajectory since birth, body composition at age 20 years and metabolic traits were compared cross-sectionally among normal-weight Japanese women with low (<25.0%, n=67), normal (25.0-34.9%, n=160) and high (≥35.0 %, n=24) percentage body fat. Multivariate logistic regression analyses were used to identify most important determinants of normal-weight obesity (high percentage body fat). RESULTS: Fasting glucose averaged <84 mg/dL, homeostasis model assessment-insulin resistance <1.4 and triglyceride <70 mg/dL and did not differ among three groups. However, waist and trunk/leg fat ratio were higher, and weight-adjusted skeletal muscle mass was lower in normal-weight obesity. Serum and LDL cholesterol, apolipoprotein B (ApoB) and high-sensitivity C reactive protein were higher, and apolipoprotein A1 was lower in normal-weight obesity compared with the other two groups, whereas HDL cholesterol did not differ. Weight gain from birth to age 12 years was higher in normal-weight obesity. In multivariate logistic regression analyses, weight gain until 12 years (OR: 1.17,95% CI 1.02 to 1.34, p=0.02), ApoB (OR: 1.15, 95% CI 1.06 to 1.24, p<0.001) and weight-adjusted skeletal muscle mass (OR: 0.22, 95% CI 0.10 to 0.49, p<0.001) were associated with normal-weight obesity independently of trunk/leg fat ratio, high-sensitivity C reactive protein and apolipoprotein A1. CONCLUSIONS: Normal-weight obesity may be associated with early childhood growth, lower skeletal muscle mass and higher serum ApoB in young Japanese women through mechanisms unrelated to abdominal adiposity, inflammation and insulin resistance.

Influence of the nutritional status on facial morphology in young Japanese women.

Evidence regarding the possible influence of nutritional status on the facial morphology has thus far been insufficient. We examined whether or not the physical body compositions and dietary behaviors were correlated with any morphological characteristics of the face. One hundred and fifteen young Japanese women participated. Variables representing the dietary behaviors were extracted from self-reported survey data, and corresponding three-dimensional (3D) facial images and body compositions were examined. Multivariate analyses identified significant relationships between the nutritional status and facial topography (p < 0.05). The clustering method revealed the existence of three dietary condition patterns ("balanced diet", "high-calorie-diet" with obesity tendency, and "imbalanced low-calorie-diet" with sarcopenic obesity tendency). Among these three patterns, a round face (increased facial width; analysis of variance [ANOVA], p < 0.05) was observed in the high-calorie-diet pattern, while the imbalanced low-calorie-diet pattern showed a more masculine face (increased face height, decreased eye height, increased non-allometric sexual shape differences; ANOVA, p < 0.05), thus suggesting the possibility of sex-hormonal influences. In summary, the body composition and dietary behaviors were found to influence the facial morphology, and potential biological influences were discussed.

Genetic and clinical features of cerebellar ataxia with RFC1 biallelic repeat expansions in Japan.

The recessive intronic pentanucleotide repeat AAGGG expansion of replication factor complex subunit 1 (RFC1) is associated with cerebellar ataxia, sensory neuropathy, and vestibular areflexia syndrome. And the clinical spectrum has been continuously expanding. We conducted this study to demonstrate the clinical and genetic features of a large-scale case series of Japanese patients with cerebellar ataxia with RFC1 repeat expansions. We examined 1,289 Japanese patients with cerebellar ataxia and analyzed RFC1 repeat expansions in 840 patients, excluding those with genetic diagnoses or an autosomal dominant inheritance pattern. For individuals where no product was obtained by flanking polymerase chain reaction (PCR), repeat-primed PCR was performed using primers specific for the following four repeat motifs: AAAAG, AAAGG, AAGGG, and ACAGG. RFC1 analysis revealed multitype biallelic pathogenic repeat expansions in 15 patients, including (AAGGG)exp/(AAGGG)exp in seven patients, (ACAGG)exp/(ACAGG)exp in three patients, (AAGGG)exp/(ACAGG)exp in four patients, and (AAGGG)exp/(AAAGG)15(AAGGG)exp in one patient. Clinical analysis showed various combinations of cerebellar ataxia, vestibular dysfunction, neuropathy, cognitive decline, autonomic dysfunction, chronic cough, pyramidal tract disorder, parkinsonism, involuntary movement, and muscle fasciculation. Pathological RFC1 repeat expansions account for 1.8% (15/840) of undiagnosed patients with cerebellar ataxia and sporadic/recessive/unclassified inheritance. Screening of RFC1 repeat expansions should be considered in patients with cerebellar ataxia, irrespective of their subtype and onset age.

Comprehensive Genetic Analyses of Inherited Peripheral Neuropathies in Japan: Making Early Diagnosis Possible.

Various genomic variants were linked to inherited peripheral neuropathies (IPNs), including large duplication/deletion and repeat expansion, making genetic diagnosis challenging. This large case series aimed to identify the genetic characteristics of Japanese patients with IPNs. We collected data on 2695 IPN cases throughout Japan, in which PMP22 copy number variation (CNV) was pre-excluded. Genetic analyses were performed using DNA microarrays, next-generation sequencing-based gene panel sequencing, whole-exome sequencing, CNV analysis, and RFC1 repeat expansion analysis. The overall diagnostic rate and the genetic spectrum of patients were summarized. We identified 909 cases with suspected IPNs, pathogenic or likely pathogenic variants. The most common causative genes were MFN2, GJB1, MPZ, and MME. MFN2 was the most common cause for early-onset patients, whereas GJB1 and MPZ were the leading causes of middle-onset and late-onset patients, respectively. Meanwhile, GJB1 and MFN2 were leading causes for demyelinating and axonal subtypes, respectively. Additionally, we identified CNVs in MPZ and GJB1 genes and RFC1 repeat expansions. Comprehensive genetic analyses explicitly demonstrated the genetic basis of our IPN case series. A further understanding of the clinical characteristics of IPN and genetic spectrum would assist in developing efficient genetic testing strategies and facilitate early diagnosis.

Reduced gluteofemoral (subcutaneous) fat mass in young Japanese women with family history of type 2 diabetes: an exploratory analysis.

Limited expandability of subcutaneous adipose tissue may be characteristics of first-degree relatives of type 2 diabetes. We tested the hypothesis that family history of type 2 diabetes (FHD) may be associated with reduced peripheral fat mass. Body composition and metabolic variables were compared between 18 and 111 Japanese female collegiate athletes, and between 55 and 148 nonathletes with positive (FHD +) and negative FHD (FHD-), respectively. We had multivariate logistic regression analyses for FHD + as dependent variable in a total population.BMI averaged < 21 kg/m2 and did not differ between FHD + and FHD- nonathletes. Despite comparable BMI, body fat percentage and serum leptin were lower in FHD + nonathletes. This was due to lower arm and gluteofemoral fat percentage (both p = 0.02) whereas the difference in trunk fat percentage was not significant (p = 0.08). These differences were not found between two groups of athletes. FHD + women had lower HDL cholesterol despite lower BMI in a total population. Fasting insulin, serum adiponectin and high-sensitivity C-reactive protein did not differ between FHD + and FHD- athletes or nonathletes. Multivariate logistic regression analyses revealed independent associations of FHD + with BMI (odds ratio, 0.869; 95% confidential interval, 0.768-0.984; p = 0.02) and HDL cholesterol (odds ratio, 0.977; 95% confidential interval, 0.957-0.997, p = 0.02). In conclusion, FHD may be associated with reduced subcutaneous fat mass in young Japanese women, suggesting impaired adipose tissue expandability.

Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease.

BACKGROUND: Recessive mutations in SLC12A6 have been linked to hereditary motor sensory neuropathy with agenesis of the corpus callosum. Patients with early-onset peripheral neuropathy associated with SLC12A6 heterozygous variants were reported in 2016. Only five families and three variants have been reported to date, and the spectrum is unclear. Here, we aim to describe the clinical and mutation spectra of SLC12A6-related Charcot-Marie-Tooth (CMT) disease in Japanese patients. METHODS: We extracted SLC12A6 variants from our DNA microarray and targeted resequencing data obtained from 2598 patients with clinically suspected CMT who were referred to our genetic laboratory by neurological or neuropediatric departments across Japan. And we summarized the clinical and genetic features of these patients. RESULTS: In seven unrelated families, we identified one previously reported and three novel likely pathogenic SLC12A6 heterozygous variants, as well as two variants of uncertain significance. The mean age of onset for these patients was 17.5 ± 16.1 years. Regarding electrophysiology, the median motor nerve conduction velocity was 39.6 ± 9.5 m/sec. For the first time, we observed intellectual disability in three patients. One patient developed epilepsy, and her brain MRI revealed frontal and temporal lobe atrophy without changes in white matter and corpus callosum. CONCLUSIONS: Screening for the SLC12A6 gene should be considered in patients with CMT, particularly those with central nervous system lesions, such as cognitive impairment and epilepsy, regardless of the CMT subtype.

Birth weight was associated positively with gluteofemoral fat mass and inversely with 2-h postglucose insulin concentrations, a marker of insulin resistance, in young normal-weight Japanese women.

Introduction: We tested whether birth weight might be associated with gluteofemoral fat mass and insulin sensitivity later in life. Materials and methods: Body size trajectory since birth, body composition at age 20, and markers of insulin resistance were measured in 316 Japanese women. A subset of 148 women underwent a 75 g oral glucose tolerance test. Multiple linear regression analyses were used to identify most important determinants of birth weight. Results: Birth weight was correlated positively with height and weight at age 12, 15, and 20 years (all p < 0.001 except for weight at 12 years, p = 0.03). Although it showed no correlation with BMI at age 12 and 15, it was correlated positively with current BMI (p = 0.006). It showed positive correlations with lean mass in arms, legs, trunk, and the whole body at age 20 (all p < 0.001). Additionally, it was correlated positively with leg (gluteofemoral) fat mass (p = 0.007), although there was no correlation with total body and trunk fat mass. Furthermore, weight at birth showed inverse correlations with 2-h postglucose insulin concentrations (p = 0.008) whereas it was not correlated with fasting insulin and homeostasis model assessment-insulin resistance. In a multiple regression analysis, which included anthropometric and biochemical variables as independent variables, appendicular muscle mass (standardized ß 0.394, p < 0.001) emerged as a single determinant of birth weight (R 2 = 0.15). In a model which included gluteofemoral fat mass and 2-h postglucose insulin, birth weight was associated with gluteofemoral fat mass (standardized ß 0.240, p = 0.003) and 2-h postglucose insulin concentrations (standardized ß - 0.217, p = 0.007) (R 2 = 0.09). Conclusions: Birth weight was associated positively with gluteofemoral fat mass and inversely with 2-h postglucose insulin concentrations, a marker of insulin resistance.

Novel de novo POLR3B mutations responsible for demyelinating Charcot-Marie-Tooth disease in Japan.

BACKGROUND: Biallelic POLR3B mutations cause a rare hypomyelinating leukodystrophy. De novo POLR3B heterozygous mutations were recently associated with afferent ataxia, spasticity, variable intellectual disability, and epilepsy, and predominantly demyelinating sensorimotor peripheral neuropathy. METHODS: We performed whole-exome sequencing (WES) of DNA samples from 804 Charcot-Marie-Tooth (CMT) cases that could not be genetically diagnosed by DNA-targeted resequencing microarray using next-generation sequencers. Using WES data, we analyzed the POLR3B mutations and confirmed their clinical features. RESULTS: We identified de novo POLR3B heterozygous missense mutations in two patients. These patients presented with early-onset demyelinating sensorimotor neuropathy without ataxia, spasticity, or cognitive impairment. Patient 1 showed mild cerebellar atrophy and spinal cord atrophy on magnetic resonance imaging and eventually died of respiratory failure in her 50s. We classified these mutations as pathogenic based on segregation studies, comparison with control database, and in silico analysis. CONCLUSION: Our study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT-related gene panel for comprehensive genetic screening, particularly for patients with early-onset demyelinating CMT.