Rie Oka

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.

Impacts of Visceral Adipose Tissue and Subcutaneous Adipose Tissue on Metabolic Risk Factors in Middle‐aged Japanese

Regional fat distribution rather than overall fat volume has been considered to be important to understanding the link between obesity and metabolic disorders. We aimed to evaluate the independent associations of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) with metabolic risk factors in apparently healthy middle‐aged Japanese. Participants were 1,119 men and 854 women aged 38–60 years who were not taking medications for diabetes, hypertension, or dyslipidemia. VAT and SAT were measured by use of computed tomography (CT) scanning. VAT and SAT were significantly and positively correlated with each other in men (r = 0.531, P < 0.001) and women (r = 0.589, P < 0.001). In multiple regression analyses, either measure of abdominal adiposity (VAT or SAT) was positively associated with blood pressure, fasting plasma glucose, and log triglyceride (P < 0.001) and inversely with high‐density lipoprotein (HDL)‐cholesterol (P < 0.001). When VAT and SAT were simultaneously included in the model, the association of VAT with triglycerides was maintained (P < 0.001) but that of SAT was lost. The same was true for HDL‐cholesterol in women. For fasting plasma glucose, the association with VAT was strong (P < 0.001) and the borderline association with SAT was maintained (P = 0.060 in men and P = 0.020 in women). Both VAT and SAT were independently associated with blood pressure (P < 0.001). Further adjustment for anthropometric indices resulted in the independent association only with VAT for all risk factors. In conclusion, impacts of VAT and SAT differed among risk factors. VAT showed dominant impacts on triglyceride concentrations in both genders and on HDL‐cholesterol in women, while SAT also had an independent association with blood pressure.

Comparison of waist circumference with body mass index for predicting abdominal adipose tissue

AIMS To compare waist circumference (WC) with body mass index (BMI) for the prediction of abdominal adipose tissues in Japanese men and women. METHODS 1432 men and 1038 women aged 38-60 years were recruited. WC, BMI, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) using CT scans were measured. RESULTS Women had a lower mean VAT than men (79.3 cm(2) vs. 132.3 cm(2); p<0.001) and a higher mean SAT (196.2 cm(2) vs. 139.7 cm(2); p<0.001). The correlation with WC or BMI was greatest for total adipose tissue (TAT), followed by SAT, and least for VAT. The correlation coefficients were not significantly different between WC and BMI for any adipose tissue except for VAT in men (p<0.05). Age was positively correlated with VAT in both genders (p<0.001). Using multiple regression analyses on VAT, R(2) values using WC and age were 0.45 in men and 0.48 in women. For SAT, the values were 0.57 in men and 0.59 in women. CONCLUSIONS The relationship with WC or BMI was greatest for TAT and SAT, and least for VAT. WC and BMI provided essentially similar estimates of TAT, VAT, and SAT in both genders.

Overexpression of Latent Transforming Growth Factor‐βl (TGF‐βl) Binding Protein 1 (LTBP‐1) in Association with TGF‐β1 in Ovarian Carcinoma

Using the differential display method, latent transforming growth factor‐β (TGF‐β1) binding protein 1 (LTBP‐1) mRNA was identified as one of the enriched mRNAs in ovarian carcinoma tissues after isolation of genes responsible for the development of ovarian cancer. Semi‐quantitative reverse transcription (RT)‐PCR analysis showed that expression of LTBP‐1 and TGF‐β1 mRNAs was much higher in both serous and mucinous adenocarcinomas than in their benign counterparts, including serous and mucinous cystadenomas and cystadenomas of low malignant potential (LMPs). Immunohistochemical analysis demonstrated that only proliferating benign adenoma cells were immunoreactive for both LTBP‐1 and TGF‐β1 proteins. In contrast, most serous and mucinous adenocarcinoma cells and their surrounding stroma were intensely immunoreactive for LTBP‐1 and TGF‐β1. LTBP‐1 and TGF‐β1 proteins, and their complex forms were identified in ovarian carcinoma cell lines and in their culture media by western blot analysis, suggesting these products were produced in ovarian carcinoma cells. RT‐PCR analysis demonstrated that LTBP‐1L, one of the LTBP‐1 transcripts that has a strong activity in targeting the latent form of TGF‐β1 to extracellular matrix (ECM), was predominantly expressed in ovarian carcinomas. Taken together, the results suggest that upregulation of LTBP‐1 in ovarian carcinoma cells may have an important role in distributing TGF‐β1 in the stromal tissues surrounding carcinoma cells.

Reduction in the local expression of complement component 6 (C6) and 7 (C7) mRNAs in oesophageal carcinoma.

Differential displays of tumour/normal pair specimens of human oesophagus identified complement component 7 (C7) as being enhanced in normal tissues, but remarkably reduced in carcinoma tissues. In situ hybridisation confirmed the localisation of C7 mRNA in normal oesophageal epithelial cells and its disappearance in tumour cells. When mRNA expressions of other components were examined by means of semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in 10 tumour/normal pair specimens, significant reductions in C6 and C7 mRNAs were observed, while C3 and C5 mRNAs were enhanced in both normal and tumour tissues. A similar reduction was observed in colon and kidney cancers using the tumour/normal expression array analysis. Gene deletion of C7 was not found in the cell lines by Southern blot analysis. Our findings suggest a possible relationship between oesophageal tumorigenesis and reduced expression of C6 and C7 mRNAs, which is probably caused by a change in gene expression regulation and not by genetic loss of the locus.

Behavioral abnormalities and apoptotic changes in neurons in mice brain following a single administration of allylnitrile

Abstract A single dose of allylnitrile in mice might induce persistent behavioral abnormalities, of which the mechanism is not yet known. The present study was undertaken to explore the relationship between behavioral abnormalities and pathological changes in the brain of mice following exposure to allylnitrile. Exposure to allylnitrile (63, 84, and 112 mg/kg, p.o.) resulted in dose-dependent changes in behavioral abnormalities, including increased locomotor activity, circling, retropulsion, head twitching, and alteration in reflexive behavior, which appeared at day 2 postdosing and were persistent throughout the experimental period (60 days) at the higher dose levels. Allylnitrile produced neuronal retraction including hyperchromasia of the nuclei in the raphe nuclei, cerebral cortex, hypothalamus, hippocampal CA1 and dentate gyrus later than 30 days. No gliosis was observed in these regions. Not all but a significant number of neurons in the hippocampal CA1, medial habenula and raphe nuclei were immunoreactive to CPP32 (Caspase-3) even at day 2. These neurons were also positive to Hoechst 33258 staining, indicating allylnitrile caused apoptotic changes in specific neurons when neuronal behaviors became apparent. These apoptotic changes were persistent even in the area without neuronal contraction such as medial habenula. However, almost all neurons in these areas were also positive to terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL). It is conceivable that allylnitrile caused apoptotic changes in neurons but did not always lead them to cell death immediately. Moreover, even when neuronal contraction resulted in retention of behavioral abnormalities, onset of these abnormalities seems to be associated with the impairment in the habenulo-raphe relay due to activation of apoptotic cascade in neurons.

One-hour plasma glucose as a predictor of the development of Type 2 diabetes in Japanese adults.

To test the hypothesis that 1‐h plasma glucose in an oral glucose tolerance test is a better predictor of the development of diabetes than 2‐h plasma glucose, independently of indices of insulin secretion or action in Japanese adults.

Contribution of visceral adiposity and insulin resistance to metabolic risk factors in Japanese men.

We investigated the relative impacts of visceral adiposity and insulin resistance on the metabolic risk profile in middle-aged Japanese men. A cross-sectional study was conducted in 636 nondiabetic Japanese men with a mean age of 51.6 years. Visceral adipose tissue (AT) was assessed using computed tomography, and insulin resistance was determined by the homeostasis model assessment of insulin resistance (HOMA-IR). Metabolic risk factors were diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome criteria: (1) hypertriglyceridemia, (2) low high-density lipoprotein cholesterol, (3) hypertension, (4) impaired fasting glucose, and (5) impaired glucose tolerance. Visceral AT and HOMA-IR were significantly and positively correlated with each other (r = 0.41, P < .001). Using the 75th percentile value as a cut point, those with isolated large visceral AT showed significantly greater odds ratios for each of the 5 risk factors measured except impaired fasting glucose, whereas those with isolated high HOMA-IR showed significantly greater odds ratios for each of the 5 risk factors except hypertriglyceridemia and impaired glucose tolerance, compared with the control group. The combined group (increased visceral AT and HOMA-IR) had the highest odds ratios for all studied risk factors. On logistic regression analysis using visceral AT and HOMA-IR as continuous independent variables, they were each independently associated with most of the metabolic risk factors and their clustering. In conclusion, neither visceral AT nor HOMA-IR stands out as the sole driving force of the risk profile; each makes a significant contribution to metabolic abnormalities in Japanese men.

Relationships of serum haptoglobin concentration with HbA1c and glycated albumin concentrations in Japanese type 2 diabetic patients

Abstract Background: The stable fractions of glycated hemoglobin (Hb), particularly HbA1c, and glycated albumin (GA) were measured to monitor chronic glycemic control. Haptoglobin (Hp) is a Hb-binding protein, which plays a major role in preventing free Hb-induced tissue oxidative damage. The aim of this study was to clarify the relationships of serum Hp concentration with HbA1c and GA concentrations. Methods: A cross-sectional study to determine the relationship of serum Hp concentration with GA and HbA1c concentrations was conducted. The subjects were 125 Japanese type 2 diabetic patients with stable HbA1c levels for more than 3 consecutive months. Patients with altered albumin and red blood cell turnover, which are observed in those with chronic renal failure, liver cirrhosis, and anemia among others, were excluded from the study. Results: Serum Hp concentration positively correlated with HbA1c concentration (r=0.30, p<0.001), but not with GA concentration (r=0.15, p=0.10). There was a weak inverse correlation between serum Hp concentration and GA/HbA1c ratio (r=−0.19, p=0.03). Moreover, GA /HbA1c ratio inversely correlated with body mass index (BMI) (r=−0.31, p<0.001). In contrast, there was no significant correlation between Hb concentration and HbA1c (r=0.01, p=0.88) or GA (r=0.12, p=0.21) concentrations. We also analyzed the correlation of serum Hp concentration with GA and HbA1c concentrations in patients with the Hp 2-1 and Hp 2-2 genotypes, separately. Hp concentration positively correlated with HbA1c concentration in patients with the Hp 2-1 (r=0.32, p=0.03) and Hp 2-2 (r=0.29, p=0.02) phenotypes. Multiple regression analysis revealed that the observed correlation between Hp and HbA1c concentrations was significant after adjustment for age, gender, and BMI. In contrast, there was no significant correlation between GA and Hp concentrations in patients with either phenotype. Then, we analyzed how Hp concentration affects GA/HbA1c ratio in patients with these Hp phenotypes. There was an inverse correlation between Hp concentration and GA/HbA1c ratio in patients with Hp 2-1 (r=−0.44, p=0.003), but not in those with Hp 2-2 (r=−0.03, p=0.75). Multiple regression analysis revealed that the inverse correlation between Hp concentration and GA/HbA1c ratio in patients with Hp 2-1 was independent of age, gender, and BMI. Conclusions: Hp phenotype and concentration should be considered in interpreting HbA1c and GA levels as glycemic control indicators in diabetic patients. We suggest that in type 2 diabetic patients with Hp 2-1 and high Hp concentrations, HbA1c level may be overestimated relative to GA level. Clin Chem Lab Med 2009;47:70–4.

Elevated liver enzymes are related to progression to impaired glucose tolerance in Japanese men

To investigate whether the elevation of liver enzymes is associated with the progression from normal to impaired glucose tolerance.