Lower physical activity is a risk factor for a clustering of metabolic risk factors in non-obese and obese Japanese subjects: the Takahata study.

In several countries including Japan, people without obesity but with a clustering of metabolic risk factors (MetRFs) were not considered to have the metabolic syndrome (MetS). Here, we examined whether lifestyle characteristics differed between non-obese and obese subjects with or without a clustering of MetRFs. From a population-based cross-sectional study of Japanese subjects aged ≥ 40 years, 1,601 subjects (age: 61.9 ± 10.3 years; 710/891 men/women) were recruited. Physical activity status and daily nutritional intake were estimated using questionnaires. A clustering of MetRFs was defined based on the presence of at least two non-essential risk factors for the diagnosis of the MetS in Japan. Energy intake was not higher in subjects with a clustering of MetRFs compared with those without. Among men, energy expenditure at work was significantly lower in non-obese (9.0 ± 8.2 vs. 11.3 ± 9.3 metabolic equivalents (METs), P = 0.025) and obese (9.0 ± 7.9 vs. 11.6 ± 9.4 METs, P = 0.017) subjects with a clustering of MetRFs than in those without. Multiple logistic regression analysis showed that energy expenditure at work was significantly associated with a clustering of MetRFs after adjusting for possible confounding factors including total energy intake. The ORs (per 1 METs) were 0.970 (95% CI, 0.944-0.997; P = 0.032) in non-obese men and 0.962 (0.926- 0.999; P = 0.043) in obese men. Similar associations were not observed in women. In Japanese males, lower physical activity, but not excessive energy intake, is a risk factor for a clustering of MetRFs independent of their obesity status.

Thyroid dysfunction in patients treated with tyrosine kinase inhibitors, sunitinib, sorafenib and axitinib, for metastatic renal cell carcinoma.

OBJECTIVE: Targeted drugs are generally associated with a lower toxicity than conventional systemic cytotoxic drugs and, thus, are administered for long periods. As a result, unusual adverse effects, including thyroid dysfunction, have become important clinical issues. METHODS: We retrospectively collected the data and compared the incidence and the time of onset of thyroid dysfunction in 33 patients (M/F: 26/7, age: 34-77) with metastatic renal cell carcinoma treated with the small-molecule tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib and axitinib in Yamagata University Hospital, Japan, from 2005 to 2010. RESULTS: The incidence of thyroid dysfunction tended to be higher in patients treated with axitinib (6 of 6: 100%) than in those treated with sunitinib (9 of 15: 60%) or sorafenib (6 of 12: 50%) (P= 0.1113). The median thyroid dysfunction-free survival evaluated using the Kaplan-Meier product-limit method with the log-rank test was significantly shorter in patients treated with axitinib than in those treated with sunitinib/sorafenib (3 vs. 16 weeks, P=0.0198). A multivariate Cox regression model for thyroid dysfunction-free survival with several probable confounding factors as co-variables showed that patients treated with axitinib were more likely to have thyroid dysfunction than the others (hazard ratio: 4.53, 95% confidence interval: 1.40-14.63, P=0.0116). CONCLUSIONS: Patients treated with the tyrosine kinase inhibitors developed thyroid dysfunction frequently. Furthermore, those treated with axitinib developed thyroid dysfunction significantly more and at a faster rate than the others. Therefore, when the tyrosine kinase inhibitors, especially axitinib, are used, close monitoring of thyroid function is recommended, at least for the initial 1-2 months, to avoid clinical symptoms derived from thyroid dysfunction.

Association of the common fat mass and obesity associated (FTO) gene polymorphism with obesity in a Japanese population.

The association of the FTO gene polymorphism, rs9939609, with obesity was examined using the population of the Takahata study (n (M/F): 2,639 (1,168 / 1,470); age: 63.0 +/- 10.2 years), a Japanese community-based study. The effects of lifestyle-related factors, including nutritional intake and physical activities, on the association were also examined. Body mass index (BMI) was significantly associated with the FTO gene polymorphism (p<0.001). A case-control association study of the FTO gene polymorphism with obesity using multiple logistic regression analysis showed a significant association of the genotype AA (odds ratio, 1.53 [95% confidential interval, 1.04-2.24]) after adjustment for age and gender. Analysis to examine the differences in lifestyle-related factors among the genotype groups showed a significant difference in the energy expenditure for moderate to high-intensity physical activity (PA) (> or = 3.0 METs) (p=0.012) with a significant decrease toward the genotype AA (p=0.027). The effect of energy expenditure for moderate to high-intensity PA on the association of the polymorphism with obesity was then examined using study groups stratified based on the energy expenditure for moderate to high-intensity PA (Low-PA and High-PA). The BMI was significantly higher in the genotype AA in the Low-PA group (p=0.016) but not in the High-PA group (p=0.103). Furthermore, the genotype AA was significantly associated with obesity (odds ratio, 2.39 [95% confidential interval, 1.19-4.80]) in the Low-PA group but not in the High- PA group (p=0.650). The FTO gene, rs9939609, was associated with obesity, and the association was evident in subjects with low-PA, suggesting a PA-dependent association.

Association of the Ser326Cys polymorphism in the OGG1 gene with type 2 DM.

The association of the Ser326Cys polymorphism of the 8-oxoguanine glycosylase 1 (OGG1) gene with type 2 diabetes was examined using a Japanese population (n (M/W): 4585 (2085/2500); age: 62.6 +/- 10.9 years). HbA1c levels and frequency of diabetic subjects were significantly higher in subjects with genotypes with Cys allele than in those without (p = 0.032 and 0.037, respectively). Multiple logistic regression analysis showed that genotypes with Cys allele were significantly associated with diabetes (OR: 1.32, p = 0.0289). In subjects whose glucose tolerance was classified by FPG and 2-h PG (n = 1.634), the association was more substantial (genotypes with Cys allele vs. without, OR: 1.70, p = 0.0059; genotypes Cys/Cys vs. Ser/Ser, OR: 2.19, p = 0.0008). In subjects with genotype Ser/Ser, the insulin secretion index, HOMA-beta, increased in the subjects with glucose intolerance and decreased in the subjects with diabetes, while, in subjects with genotypes Ser/Cys + Cys/Cys, HOMA-beta decreased as the glucose tolerance progressed (p for trend = 0.010).

Expression of BAFF-R and TACI in reactive lymphoid tissues and B-cell lymphomas.

AIMS: The receptor for B-cell-activating factor belonging to the tumour necrosis factor family (BAFF-R) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) have been established as binding molecules to BAFF. The aim of this study was to determine the pathological diagnostic roles and clinical significance of these BAFF-binding receptors in B-cell neoplasms. METHODS AND RESULTS: Expression of BAFF-R and TACI was examined immunohistochemically in reactive lymphoid tissues and B-cell lymphomas including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (MZBCL) and plasma cell myeloma (PCM). In reactive tissues BAFF-R was expressed exclusively in the cells of the mantle zone and within the germinal centres (GCs), whereas TACI appeared positive in the scattered cells in extrafollicular areas. There were variable patterns of expression of BAFF-R and TACI amongst the different types of B-cell lymphomas (MCL and FL: BAFF-R+TACI-; PCM: BAFF-R-TACI+; DLBCL and MZBCL: variable expression). Reverse transcriptase-polymerase chain reaction studies supported these results. The overall survival of the BAFF-R+ DLBCL group was significantly better than that of the BAFF-R- group. CONCLUSIONS: These results indicate that the assessment of expression of BAFF-binding receptors aids subclassification and prognostication of DLBCL.

A functional polymorphism of the TNF-alpha gene that is associated with type 2 DM.

To examine the association of the tumor necrosis factor-alpha (TNF-alpha) gene region with type 2 diabetes (DM), 11 single-nucleotide polymorphisms (SNPs) of the region were analyzed. The initial study using a sample set (148 cases vs. 227 controls) showed a significant association of the SNP IVS1G+123A of the TNF-alpha gene with DM (p=0.0056). Multiple logistic regression analysis using an enlarged sample set (225 vs. 716) revealed the significant association of the SNP with DM independently of any clinical traits examined (OR: 1.49, p=0.014). The functional relevance of the SNP were examined by the electrophoretic mobility shift assays using nuclear extracts from the U937 and NIH3T3 cells and luciferase assays in these cells with Simian virus 40 promoter- and TNF-alpha promoter-reporter gene constructs. The functional analyses showed that YY1 transcription factor bound allele-specifically to the SNP region and, the IVS1+123A allele had an increase in luciferase expression compared with the G allele.

Association of the PIK3C2G gene polymorphisms with type 2 DM in a Japanese population.

The associations of five SNPs (SNPs1-5: A-5468G, A-3333G, C-1794T, C437T and T9148C) of the class II phosphoinositide 3-kinase gamma-subunit (PIK3C2G) gene with type 2 diabetes were examined using a population of the Takahata Study (n (M/W): 2930 (1328/1602); age: 63.3+/-10.2 years), a Japanese community-based study. Quantitative association study of the SNPs with HbA1c levels showed significant association for SNPs 2 and 4 (p=0.018 and 0.004, respectively). A case-control association study of SNP 4 with diabetes by multiple logistic regression analysis showed a significant association of the genotype TT of the SNP with an odds ratio of 2.21 (p=0.001) independently of age, gender and BMI. In the NGT subjects, serum fasting insulin levels in the at-risk genotype group of SNP 4 were significantly lower than those in the others (TT, TC, and CC, 4.9+/-2.6, 5.4+/-3.0, and 5.6+/-3.4muU/ml, respectively; p=0.029).

Salt consumption-dependent association of the GNB3 gene polymorphism with type 2 DM.

The associations of the C825T polymorphism (rs5443) of the G-protein beta3 subunit (GNB3) gene and eight adjacent single nucleotide polymorphisms (SNPs) with diabetes were examined using a Japanese population (n (M/W): 2956 (1335/1621); age: 63.0+/-10.2 years). Fasting plasma glucose (FPG) levels were significantly associated with the C825T polymorphism and two flanking SNPs (rs2301339 and rs5446) (p=0.002, 0.001, and 0.008, respectively). A case-control association study of the C825T polymorphism with diabetes using multiple logistic regression analysis showed a significant association of the genotypes TT+TC with an odds ratio of 0.62 (p=0.008) independent of age, gender, and BMI. The effects of salt consumption on the association were then examined (n=1635). The FPG levels were significantly associated with the C825T polymorphism only in subjects with low salt consumption (<12.44 g/day) (p=0.002). A case-control association study also showed a significant association with diabetes only in subjects with low salt consumption (p=0.006).

Impaired glucose tolerance is a risk factor for stroke in a Japanese sample--the Funagata study.

Impaired glucose tolerance (IGT) is a known risk factor for cardiovascular disease, which includes stroke as well as coronary heart disease (CHD). We investigated whether IGT is a risk factor for stroke. The incidence of stroke and CHD in a cohort population (n = 2938) consisting of participants of the 1990-1997 Funagata study was assessed through interviews with the participants and their family members and reviews of death certificates and residence transfer documents through 2002. Glucose tolerance at the baseline was classified according to the criteria of the 1998 World Health Organization (normal glucose tolerance, n = 2189; IGT, n = 320; and diabetes, n = 286). The cumulative incidences among the groups were compared using the Kaplan-Meier product-limit method, and the risks of these conditions were evaluated by person-year and Cox proportional hazard methods. During the 147-month (mean, 116.5 months) follow-up, 158 (normal glucose tolerance, IGT, and diabetes: 94, 35, and 29, respectively) participants experienced a stroke and 94 (54, 16, and 24, respectively) experienced CHD. By the person-year method, IGT and diabetes were shown to be significant risk factors for stroke and CHD (odds ratio, 1.87 [95% confidence interval, 1.73-2.03] and 3.57 [3.21-3.98] for stroke; 1.53 [1.31-1.78] and 3.47 [2.91-4.14] for CHD, respectively). Cox proportional hazard analysis showed that IGT was a risk factor for stroke (age-, sex-, and hypertension-adjusted hazard ratio: 1.51 [95% confidence interval, 1.02-2.24], P = .039) but not for CHD (1.21 [0.69-2.313], .509). Impaired glucose tolerance is a risk factor for future stroke in a Japanese population.

Transient Worsening of Photosensitivity due to Cholelithiasis in a Variegate Porphyria Patient.

Variegate porphyria (VP) is an autosomal dominant disease caused by mutations of the protoporphyrinogen oxidase (PPOX) gene. This porphyria has unique characteristics which can induce acute neurovisceral attacks and cutaneous lesions that may occur separately or together. We herin report a 58-years-old VP patient complicated with cholelithiasis. A sequencing analysis indicated a novel c.40G>C mutation (p.G14R) in the PPOX gene. His cutaneous photosensitivity had been worsening for 3 years before the emergence of cholecystitis and it then gradually improved after cholecystectomy and ursodeoxycholic acid treatment with a slight decline in the porphyrin levels in his blood, urine and stool. In VP patients, a worsening of photosensitivity can thus be induced due to complications associated with some other disease, thereby affecting their porphyrin-heme biosynthesis.

A case of primary biliary cirrhosis accompanied with fibrinogen storage disease.

We report the first case of primary biliary cirrhosis (PBC) accompanied by fibrinogen storage disease (FSD). A 50-year-old Japanese woman had been treated for numbness of her right-side extremities for 5 years. Mildly elevated serum levels of alkaline phosphatase and gamma-glutamyl transferase were detected. The titers of both anti-mitochondrial (x 320) and anti-mitochondrial M2 (x 84) antibodies were elevated. The biopsied liver specimen showed mononuclear cell infiltrate densely encircling the bile ducts, poorly developed epithelioid cell granuloma, and loss of integrity of bile duct organization, which permitted a diagnosis of stage I PBC according to Scheuer's histologic classification. In addition, round to oval, eosinophilic, homogenous intracytoplasmic inclusions, several microm in average size, with a surrounding halo were found in the vast majority of hepatocytes. These inclusions were negative for the periodic acid-Schiff reaction. In immunohistochemistry, the inclusions were positive for fibrinogen and complement C3c, but not for HBs antigen and alpha1-antitrypsin. These findings were identical to FSD. To investigate the mechanism(s) of abnormal fibrinogen storage, immunostaining for heat shock protein 70 and ubiquitin was performed. The former was detected in all intracytoplasmic inclusions, whereas the latter was detected in only some inclusions, suggesting a partial loss of ubiquitin expression.

Higher plasma renin activity is a risk factor for total mortality in older Japanese individuals: the Takahata study.

Plasma renin activity (PRA) is accepted as a marker for increased risk of cardiovascular diseases. However, the association between PRA and total mortality has not been fully explored in a general population. We here examined whether PRA is associated with increased total mortality in a general Japanese population. The participants of the Takahata study (3502 subjects; age, 62.5 ± 10.4 years), a population-based, longitudinal study of Japanese held from 2004 to 2006, were enrolled and followed up for up to 7 years. The incidence of death and causes of death were monitored annually to the end of 2010 (median follow-up, 2280 days). During the follow-up period, 143 subjects died. Kaplan-Meier analysis showed a significantly increased risk for total mortality in subjects with higher PRA (log-rank P < .001). Cox proportional hazard model analyses with adjustment for factors correlated with PRA (age, sex, weight, diastolic blood pressure, high-density lipoprotein cholesterol, uric acid, B-type natriuretic peptide, serum total protein, antihypertensive treatment, and diabetes) showed that higher PRA was associated with increased total mortality in linear regression models (per 1 increase in log 10 × PRA [nanograms per milliliter per hour]: hazard ratio, 2.12; 95% confidence interval, 1.47-3.06), between groups of patients stratified by quartiles of PRA (highest vs lowest quartile: 2.63, 1.57-4.41) and in subjects with high (≥ 2.0 ng/[mL h]) vs low (<2.0 ng/[mL h]) PRA (1.97, 1.37-2.83). Higher PRA was a significant and independent risk factor for increased total mortality in this Japanese population and may be a marker for subjects at an increased risk of total mortality.

Serum glycerophosphate levels are increased in Japanese men with type 2 diabetes.

OBJECTIVE: To identify metabolites showing changes in serum levels among Japanese male with diabetes. METHODS: We performed metabolite profiling by coupling capillary electrophoresis with electrospray ionization time-of-flight mass spectrometry using fasting serum samples from Japanese male subjects with diabetes (n=17), impaired glucose tolerance (IGT; n=5) and normal glucose tolerance (NGT; n=14). RESULTS: Other than the expected differences in characteristics related to abnormal glucose metabolism, the percent body fat was significantly different among subjects with diabetes, IGT and NGT (27.3±6.2, 22.2±4.5 and 19.2±6.0%, respectively, p=0.0022). Therefore, percent body fat was considered as a possible confounding factor in subsequent analyses. Of 560 metabolites detected using our platform, the levels of 74 metabolites were quantified in all of the serum samples. Significant differences between diabetes and NGT were observed for 24 metabolites. The top-ranked metabolite was glycerol-3-phophate (glycerophosphate), which was significantly higher in subjects with diabetes than in those with NGT, even after Bonferroni correction for multiple testing (11.7±3.6 vs. 6.4±1.9 µM, respectively; corrected p=0.0222). Stepwise multiple regression analyses revealed that serum glycerophosphate levels were significantly correlated with 2-h plasma glucose after a 75-g oral glucose tolerance test (r=0.553, p=0.0005), independently of other characteristics, including FPG and HbA1c. CONCLUSION: Serum glycerophosphate levels were found to be elevated in Japanese men with diabetes, and correlated with 2-h PG, independent of FPG and HbA1c. Namely, serum glycerophosphate level at fasting condition can be a marker for predicting glucose intolerance. These results warrant further studies to evaluate the relevance of glycerophosphate in the pathophysiology of diabetes.

Association of the clusterin gene polymorphisms with type 2 diabetes mellitus.

The association of the clusterin (CLU) gene polymorphism (single nucleotide polymorphisms [SNPs] 1-4: rs1532278, rs1532277, rs2279590, and rs2279591, respectively) with type 2 diabetes mellitus was examined using a population of the Funagata study (n [male-female] = 1631 [741:884]; age, 62.0 ± 12.1 years), a Japanese community-based study. Single nucleotide polymorphisms 1 to 3 were significantly associated with hemoglobin A(1c) levels (P = .0154, .0021, and .0006, respectively) and diabetes (.0310, .0170, and .0021, respectively). A case-control association study of SNP 3 with diabetes by multiple logistic regression analysis showed a significant association of genotype AA (the at-risk genotype) with an odds ratio (OR) of 2.33 (P = .0039) independently of age and sex. The association was marginally validated by a study with another Japanese community-based sample, the Takahata Study (n [male-female] = 2.948 [1333:1615]; age, 63.0 ± 10.2 years) (OR, 1.59; P = .0595; χ(2)P = .0264). When the 2 samples were combined, the association became more significant (OR, 1.75; P = .0025). In subjects with the non-at-risk genotypes, the insulin resistance index--homeostasis model assessment of insulin resistance (HOMA-R)--increased significantly (P < .0001) and the insulin secretion index--HOMA-ß--appeared to decrease (P = .1803 and .0097, respectively, for the genotypes AG and GG) as the glucose tolerance progressed toward diabetes (normal glucose tolerance to glucose intolerance to diabetes). However, in subjects with the at-risk genotype, HOMA-R and HOMA-ß showed a significant increase already in the subjects with normal glucose tolerance (P = .0239 and .0305, respectively); and as the glucose tolerance progressed toward diabetes, HOMA-R stayed approximately the same, whereas HOMA-ß decreased significantly (P = .0332). The CLU gene was associated with diabetes, probably through an increase in insulin resistance primarily and through an impairment of insulin secretion secondarily.

Hemoglobin A1c in predicting progression to diabetes.

The predictive value of hemoglobin A1c (HbA1c) in comparison to fasting plasma glucose (FPG) is evaluated for 5-year incident diabetes (DM), as HbA1c may be more practical than FPG in the screening for DM in the future. Of 1189 non-DM subjects aged 35-89 years old from the Funagata Study, 57 subjects (4.8%) had developed DM on the WHO criteria at 5-year follow-up. The odds ratio (95% confidence interval: CI) for a one standard deviation increase in FPG/HbA1c was 3.40 (2.44-4.74)/3.49 (2.42-5.02). The area under the receiver operating characteristic curve for FPG/HbA1c was 0.786 (95% CI: 0.719-0.853)/0.785 (0.714-0.855). The HbA1c corresponding to FPG 5.56 mmol/l was HbA1c 5.3%. There was no statistical difference in sensitivity between FPG 5.56 mmol/l and HbA1c 5.3% (61.4% vs. 56.1%), while specificity was higher in HbA1c 5.3% than FPG 5.56 mmol/l (87.8% vs. 82.5%, p-value<0.001). The fraction of incident case from those with baseline IGT was similar between the groups, however the fraction of people above the cut-off was significantly lower in HbA1c 5.3% than FPG 5.56 mmol/l (14.3% vs. 19.6%, p-value<0.001). HbA1c is similar to FPG to evaluate DM risk, and HbA1c could be practical and efficient to select subjects for intervention.

Raised fasting plasma glucose a better predictor of diabetes than the IDF definition of the metabolic syndrome.

Raised FPG was better at identifying future diabetes than either IDF MetS or a constellation of risk factors except for raised FPG with and without abdominal adiposity. This should shed light on a screening program for future DM in Japan.