Tohru Nakagawa

Absolute value of visceral fat area measured on computed tomography scans and obesity-related cardiovascular risk factors in large-scale Japanese general population (the VACATION-J study)

Abstract Background. The management of cardiovascular risk factors is important for prevention of atherosclerotic cardiovascular diseases (ACVD). Visceral fat accumulation plays an important role in the clustering of cardiovascular risk factors, leading to ACVD. The present study investigated the gender- and age-specific relationship between obesity-related cardiovascular risk factor accumulation and computed tomography (CT)-measured fat distribution in a large-scale Japanese general population. Methods and results. Fat distribution was measured on CT scans in 12,443 subjects (males/females = 10,080/2,363), who underwent medical health check-up at 9 centers in Japan. The investigated obesity-related cardiovascular risk factors were hyperglycemia, dyslipidemia, and elevated blood pressure. Visceral fat area (VFA) for all males and old females showed almost symmetric distribution, while that of young females showed skewed distribution with a marked left shift. Only a small proportion of young females had large visceral fat and cardiovascular risk accumulation. The mean number of risk factors exceeded 1.0 at around 100 cm2 for VFA in all groups, irrespective of gender, age (cut-off age 55), and BMI (cut-off BMI 25 kg/m2). Conclusions. In this large-scale Japan-wide general population study, an absolute VFA value of about 100 cm2 equated with obesity-related cardiovascular risk factor accumulation, irrespective of gender, age, and BMI. Clinical trial registration information. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000002780&language=E.

High circulating levels of S100A8/A9 complex (calprotectin) in male Japanese with abdominal adiposity and dysregulated expression of S100A8 and S100A9 in adipose tissues of obese mice

S100A8/A9 complex, calprotectin, which serves as an endogenous ligand for immune pathways, is associated with atherosclerosis. These proteins are reported to have several functions such as activating NADPH oxidase, binding toll-like receptor 4 and associated with the receptor for advanced glycation end-products. We recently reported S100A8 mRNA was highly expressed in mouse white adipose tissues and differentiated 3T3-L1 adipocytes. However, regulation of S100A9 expression in murine adipose tissue remains to be elucidated. The results of our studies in male Japanese, obese and control mice and cultured cells showed: (1) serum levels of S100A8/A9 complex, calprotectin, correlated with visceral fat area, body mass index, subcutaneous fat area, and leukocyte count in 500 Japanese men, and (2) higher mRNA expression levels of S100A8 in mature adipocyte fraction and S100A9 in stromal vascular cell fraction of obese mice, compared with those of lean mice. Overexpression of S100A8 and S100A9 in obese adipose tissue may be involved, at least partly, in not only high circulating levels of S100A8/A9 complex in abdominal obesity but also adipose and systemic tissue inflammation.

Binding of adiponectin and C1q in human serum, and clinical significance of the measurement of C1q-adiponectin / total adiponectin ratio

OBJECTIVE Adiponectin and C1q have similar sequences, exist abundantly in blood, and are produced by adipose tissues. The aim of this study was to examine whether adiponectin and C1q form protein-complex in blood and to know the clinical significance of the C1q-adiponectin (C1q-APN) complex in serum. METHODS The direct interaction between adiponectin and C1q was investigated by far western blotting and co-immunoprecipitation. The relationship between serum C1q-APN and various clinical features was analyzed in 329 Japanese men who underwent health check-up, including measurements of visceral (VFA) and subcutaneous fat area (SFA) by computed tomography (Victor-J study). RESULTS Adiponectin bound to C1q in vitro and C1q-APN complex existed in human blood. C1q-APN complexes were identified in high- and middle-molecular weight forms of adiponectin in human serum by gel-filtration chromatography. Stepwise multiple regression analysis identified body mass index, VFA and SFA as significant determinants of serum C1q-APN level. Serum C1q-APN/Total-APN ratio correlated positively with cardiovascular risk factor accumulation in subjects with VFA ≥100 cm(2). CONCLUSIONS These results indicate that high- and middle-molecular forms of adiponectin partly consist of adiponectin-complex with other proteins including C1q and that the blood C1q-APN/Total-APN ratio may serve as a biomarker of the metabolic syndrome in general male subjects.

A decrease in lung cancer mortality following the introduction of low-dose chest CT screening in Hitachi, Japan

Recent US clinical trial demonstrated that CT screening prevents lung cancer death among high risk individuals. However, it remains unclear whether wide implementation of low-dose CT screening for lung cancer can decrease mortality in the community. Among residents in Hitachi City (Japan), where nearly 40% of inhabitants aged 50-69 years were estimated to have participated in the screening at least once from 1998 through 2009, the trend of lung cancer mortality was described in relation to the timing of implementation of the CT screening. Cancer mortality data were obtained from regional cancer registry and standardized mortality ratio (SMR) of lung cancer was calculated for each 5-year period during 1995-2009. In both men and women aged 60 years or older, age-specific lung cancer mortality rates were generally lower during 2005-2009 as compared with those during 1995-2004. For combined men and women aged 50-79 years, SMR was nearly unity prior to or during introductory phase of CT screening and during early period of implementation; however, it was significantly decreased during 2005-2009, well after the implementation of CT screening, with SMR (95% confidence interval) being 0.76 (0.67-0.86). Results suggest that wide implementation of low-dose chest CT screening may decrease lung cancer mortality in the community 4-8 years after introduction of the screening.

Prevalence of diabetes and pre-diabetes among workers: Japan Epidemiology Collaboration on Occupational Health Study.

AIMS Few studies have examined the prevalence of diabetes using glycated hemoglobin (HbA1c), a newly recommended diagnostic test. We examined the prevalence of diabetes and pre-diabetes using both HbA1c and fasting plasma glucose (FPG) and their associations with risk factors for type 2 diabetes in a large-scale Japanese working population. METHODS Participants were 47,172 men and 8280 women aged 20-69 years who received periodic health checkup in nine companies which participated in the Japan Epidemiology Collaboration on Occupational Health study. Participants were categorized into diabetes (HbA1c≥6.5% (≥48mmol/mol), FPG≥126mg/dl (≥7.0mmol/L), or medication for diabetes), pre-diabetes (HbA1c 6.0-6.4% (42-46mmol/mol) or FPG 110-125mg/dl (6.1-6.9mmol/L) among those without diabetes), and normal glucose regulation. RESULTS The prevalence of diabetes was 8.0% and 3.3% in men and women, respectively. Of individuals with diabetes, approximately 80% were defined by HbA1c≥6.5% (≥48mmol/mol) criterion. The prevalence of pre-diabetes was 14.1% in men and 9.2% in women. Prevalence of these glucose abnormalities increased with advancing age, especially during mid-40s and 50s. Higher body mass index and waist circumference, hypertension, dyslipidemia, and current smoking were each associated with higher prevalence of diabetes in both men and women. CONCLUSIONS Using HbA1c and FPG criteria or current medication, one in 13 men and one in 30 women had diabetes in the present Japanese working population. Interventions targeted for those in an early stage of impaired glucose metabolism would be required to prevent diabetes.

Long-term prognosis of patients with lung cancer detected on low-dose chest computed tomography screening

The effectiveness of lung cancer screening using low-dose chest computed tomography (CT) remains elusive. The present study examined the prognosis of patients with lung cancer detected on CT screening in Japanese men and women. Subjects were 210 patients with primary lung cancer identified on CT screening at two medical facilities in Hitachi, Japan, where a total of 61,914 CT screenings were performed among 25,385 screenees between 1998 and 2006. Prognostic status of these patients was sought by examining medical records at local hospitals, supplemented by vital status information from local government. The 5-year survival rate was estimated according to the characteristics of patients and lung nodule. A total of 203 (97%) patients underwent surgery. During a 5.7-year mean follow-up period, 19 patients died from lung cancer and 6 died from other causes. The estimated 5-year survival rate for all patients and for those on stage IA was 90% and 97%, respectively. Besides cancer stage, smoking and nodule appearance were independent predictors of a poor survival; multivariable-adjusted hazard ratio (95% confidence interval) was 4.7 (1.3, 16.5) for current and past smokers versus nonsmokers and 4.6 (1.6, 13.9) for solid nodule versus others. Even patients with solid shadow had a 5-year survival of 82% if the lesion was 20mm or less in size. Results suggest that lung cancers detected on CT screening are mostly curative. The impact of CT screening on mortality at community level needs to be clarified by monitoring lung cancer deaths.

Development of Risk Score for Predicting 3-Year Incidence of Type 2 Diabetes: Japan Epidemiology Collaboration on Occupational Health Study

Objective Risk models and scores have been developed to predict incidence of type 2 diabetes in Western populations, but their performance may differ when applied to non-Western populations. We developed and validated a risk score for predicting 3-year incidence of type 2 diabetes in a Japanese population. Methods Participants were 37,416 men and women, aged 30 or older, who received periodic health checkup in 2008–2009 in eight companies. Diabetes was defined as fasting plasma glucose (FPG) ≥126 mg/dl, random plasma glucose ≥200 mg/dl, glycated hemoglobin (HbA1c) ≥6.5%, or receiving medical treatment for diabetes. Risk scores on non-invasive and invasive models including FPG and HbA1c were developed using logistic regression in a derivation cohort and validated in the remaining cohort. Results The area under the curve (AUC) for the non-invasive model including age, sex, body mass index, waist circumference, hypertension, and smoking status was 0.717 (95% CI, 0.703–0.731). In the invasive model in which both FPG and HbA1c were added to the non-invasive model, AUC was increased to 0.893 (95% CI, 0.883–0.902). When the risk scores were applied to the validation cohort, AUCs (95% CI) for the non-invasive and invasive model were 0.734 (0.715–0.753) and 0.882 (0.868–0.895), respectively. Participants with a non-invasive score of ≥15 and invasive score of ≥19 were projected to have >20% and >50% risk, respectively, of developing type 2 diabetes within 3 years. Conclusions The simple risk score of the non-invasive model might be useful for predicting incident type 2 diabetes, and its predictive performance may be markedly improved by incorporating FPG and HbA1c.

Hba1c, Blood Pressure, and Lipid Control in People with Diabetes: Japan Epidemiology Collaboration on Occupational Health Study.

Aims The control of blood glucose levels, blood pressure (BP), and low-density lipoprotein cholesterol (LDL-C) levels reduces the risk of diabetes complications; however, data are scarce on control status of these factors among workers with diabetes. The present study aimed to estimate the prevalence of participants with diabetes who meet glycated hemoglobin (HbA1c), BP, and LDL-C recommendations, and to investigate correlates of poor glycemic control in a large working population in Japan. Methods The Japan Epidemiology Collaboration on Occupational Health (J-ECOH) Study is an ongoing cohort investigation, consisting mainly of employees in large manufacturing companies. We conducted a cross-sectional analysis of 3,070 employees with diabetes (2,854 men and 216 women) aged 20–69 years who attended periodic health examinations. BP was measured and recorded using different company protocols. Risk factor targets were defined using both American Diabetes Association (ADA) guidelines (HbA1c < 7.0%, BP < 140/90 mmHg, and LDL-C < 100 mg/dL) and Japan Diabetes Society (JDS) guidelines (HbA1c < 7.0%, BP < 130/80 mmHg, and LDL-C < 120 mg/dL). Logistic regression models were used to explore correlates of poor glycemic control (defined as HbA1c ≥ 8.0%). Results The percentages of participants who met ADA (and JDS) targets were 44.9% (44.9%) for HbA1c, 76.6% (36.3%) for BP, 27.1% (56.2%) for LDL-C, and 11.2% (10.8%) for simultaneous control of all three risk factors. Younger age, obesity, smoking, and uncontrolled dyslipidemia were associated with poor glycemic control. The adjusted odds ratio of poor glycemic control was 0.58 (95% confidence interval, 0.46–0.73) for participants with treated but uncontrolled hypertension, and 0.47 (0.33–0.66) for participants with treated and controlled hypertension, as compared with participants without hypertension. There was no significant difference in HbA1c levels between participants with treated but uncontrolled hypertension and those with treated and controlled hypertension. Conclusion Data from a large working population, predominantly composed of men, suggest that achievement of HbA1c, BP, and LDL-C targets was less than optimal, especially in younger participants. Uncontrolled dyslipidemia was associated with poor glycemic control. Participants not receiving antihypertensive treatment had higher HbA1c levels.

Smoking, Smoking Cessation, and the Risk of Type 2 Diabetes among Japanese Adults: Japan Epidemiology Collaboration on Occupational Health Study

Aims To examine the association of smoking status, smoking intensity, and smoking cessation with the risk of type 2 diabetes (T2D) using a large database. Methods The present study included 53,930 Japanese employees, aged 15 to 83 years, who received health check-up and did not have diabetes at baseline. Diabetes was defined as fasting plasma glucose ≥126 mg/dl, random plasma glucose ≥200 mg/dl, HbA1c ≥6.5% (≥48 mmol/mol), or receiving medication for diabetes. Cox proportional-hazards regression models were used to investigate the association between smoking and the risk of diabetes. Results During 3.9 years of median follow-up, 2,441 (4.5%) individuals developed T2D. The multivariable-adjusted hazard ratios (95% CI) for diabetes were 1 (reference), 1.16 (1.04 to 1.30) and 1.34 (1.22 to 1.48) for never smokers, former smokers, and current smokers, respectively. Diabetes risk increased with increasing numbers of cigarette consumption among current smokers (P for trend <0.001). Although the relative risk of diabetes was greater among subjects with lower BMIs (< 23 kg/m2), attributable risk was greater in subjects with higher BMIs (≥ 23 kg/m2). Compared with individuals who had never smoked, former smokers who quit less than 5 years, 5 to 9 years, and 10 years or more exhibited hazards ratios for diabetes of 1.36 (1.14 to 1.62), 1.23 (1.01 to 1.51), and 1.02 (0.85 to 1.23), respectively. Conclusions Results suggest that cigarette smoking is associated with an increased risk of T2D, which may decrease to the level of a never smoker after 10 years of smoking cessation.

Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy

This study aimed to evaluate various metabolic parameters in patients with spinal and bulbar muscular atrophy (SBMA), to investigate the association between those indices and disease severity, and to explore the underlying molecular pathogenesis. We compared the degree of obesity, metabolic parameters, and blood pressure in 55 genetically confirmed SBMA patients against those in 483 age- and sex-matched healthy control. In SBMA patients, we investigated the correlation between these factors and motor functional indices. SBMA patients had lower body mass index, blood glucose, and Hemoglobin A1c, but higher blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR, a marker of insulin resistance), total cholesterol, and adiponectin levels than the control subjects. There were no differences in visceral fat areas, high-density lipoprotein-cholesterol (HDL-C), or triglyceride levels in two groups. Revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) correlated positively with HDL-C, but negatively with HOMA-IR. Through stepwise multiple regression analysis, we identified HOMA-IR as a significant metabolic determinant of ALSFRS-R. In biochemical analysis, we found that decreased expressions of insulin receptors, insulin receptor substrate-1 and insulin receptor-β, in autopsied muscles and fibroblasts of SBMA patients. This study demonstrates that SBMA patients have insulin resistance, which is associated with the disease severity. The expressions of insulin receptors are attenuated in the skeletal muscle of SBMA, providing a possible pathomechanism of metabolic alterations. These findings suggested that insulin resistance is a metabolic index reflecting disease severity and pathogenesis as well as a potential therapeutic target for SBMA.