Search

Objective. The aim of this study was to evaluate the relationships between the composition of free fatty acids (FFAs) and metabolic parameters, including body fat distribution, in Japanese. Methods. The study subjects were 111 Japanese patients (54 males, 57 females). Metabolic parameters and visceral and subcutaneous fat areas as determined by CT scanning at the umbilical level were measured. Glucose tolerance test (GTT) was performed by administering 75 g glucose orally. Results. The percentage of linoleic acid (C18:2), the greatest constituent among FFAs, was negatively correlated with visceral fat area (r=−0.411, p<0.0001), fasting glucose (r=−0.330, p<0.0001), HbA1c (r=−0.231, p=0.0146), and systolic blood pressure (r=−0.224, p=0.0184). Linoleic acid percentage was also significantly negatively correlated with HOMA-IR (r=−0.416, p<0.0001) by simple correlation. Based on the findings of OGTT, the 111 subjects were classified into three groups: 33 with normal glucose tolerance, 71 with impaired glucose tolerance (IGT), and 7 diabetic subjects. The percentage of serum linoleic acid in diabetic subjects was significantly lower than that in normal subjects. Conclusion. We conclude that serum linoleic acid level is negatively correlated with the accumulation of visceral fat in relation to a reduction of insulin resistance in Japanese subjects. [ABSTRACT FROM AUTHOR]

Aim: We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and six susceptibility loci (TMEM154, SSR1, FAF1, POU5F1, ARL15, and MPHOSPH9) originally identified by a transethnic meta-analysis of genome-wide association studies (GWAS) in 2014. Methods: We genotyped 7,620 Japanese participants (5,817 type 2 diabetes patients and 1,803 controls) for each of the single nucleotide polymorphisms (SNPs) using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using logistic regression analysis. Results: Of the six SNPs examined in this study, four (rs6813195 near TMEM154, rs17106184 in FAF1, rs3130501 in POU5F1 and rs4275659 near MPHOSPH9) had the same direction of effect as in the original reports, but two (rs9505118 in SSR1 and rs702634 in ARL15) had the opposite direction of effect. Among these loci, rs3130501 and rs4275659 were nominally associated with type 2 diabetes (rs3130501; p = 0.017, odds ratio [OR] = 1.113, 95% confidence interval [CI] 1.019–1.215, rs4275659; p = 0.012, OR = 1.127, 95% CI 1.026–1.238, adjusted for sex, age and body mass index), but we did not observe a significant association with type 2 diabetes for any of the six evaluated SNP loci in our Japanese population. Conclusions: Our results indicate that effects of the six SNP loci identified in the transethnic GWAS meta-analysis are not major among the Japanese, although SNPs in POU5F1 and MPHOSPH9 loci may have some effect on susceptibility to type 2 diabetes in this population. [ABSTRACT FROM AUTHOR]

Aim: We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and 7 susceptibility loci originally identified by European genome-wide association study (GWAS) in 2012: ZMIZ1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, and BCAR1. We also examined the association of 3 additional loci: CCND2 and GIPR, identified in sex-differentiated analyses, and LAMA1, which was shown to be associated with non-obese European type 2 diabetes. Methods: We genotyped 6,972 Japanese participants (4,280 type 2 diabetes patients and 2,692 controls) for each of the 10 single nucleotide polymorphisms (SNPs): rs12571751 in ZMIZ1, rs10842994 near KLHDC5, rs2796441 near TLE1, rs459193 near ANKRD55, rs10401969 in CILP2, rs12970134 near MC4R, rs7202877 near BCAR1, rs11063069 near CCND2, rs8108269 near GIPR, and rs8090011 in LAMA1 using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using a logistic regression analysis. Results: All SNPs examined in this study had the same direction of effect (odds ratio > 1.0, p = 9.77 × 10-4, binomial test), as in the original reports. Among them, rs12571751 in ZMIZ1 was significantly associated with type 2 diabetes [p = 0.0041, odds ratio = 1.123, 95% confidence interval 1.037–1.215, adjusted for sex, age and body mass index (BMI)], but we did not observe significant association of the remaining 9 SNP loci with type 2 diabetes in the present Japanese population (p ≥ 0.005). A genetic risk score, constructed from the sum of risk alleles for the 7 SNP loci identified by un-stratified analyses in the European GWAS meta-analysis were associated with type 2 diabetes in the present Japanese population (p = 2.3 × 10-4, adjusted for sex, age and BMI). Conclusions: ZMIZ1 locus has a significant effect on conferring susceptibility to type 2 diabetes also in the Japanese population. [ABSTRACT FROM AUTHOR]

Aims: To clarify predictive values of C-reactive protein (CRP) and high-molecular-weight (HMW) adiponectin for development of metabolic syndrome. Research Design and Methods: We conducted a prospective cohort study of Japanese workers who had participated in an annual health checkup in 2007 and 2011. A total of 750 subjects (558 men and 192 women, age 46±8 years) who had not met the criteria of metabolic syndrome and whose CRP and HMW-adiponectin levels had been measured in 2007 were enrolled in this study. Associations between CRP, HMW-adiponectin and development of metabolic syndrome after 4 years were assessed by logistic regression analysis and their predictive values were compared by receiver operating characteristic analysis. Results: Among 750 subjects, 61 (8.1%) developed metabolic syndrome defined by modified National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria and 53 (7.1%) developed metabolic syndrome defined by Japan Society for the Study of Obesity (JASSO) in 2011. Although CRP and HMW-adiponectin were both significantly correlated with development of metabolic syndrome, multivariate logistic regression analysis revealed that HMW-adiponectin but not CRP was associated with metabolic syndrome independently of BMI or waist circumference. Adding these biomarkers to BMI or waist circumference did not improve the predictive value for metabolic syndrome. Conclusion: Our findings indicate that the traditional markers of adiposity such as BMI or waist circumference remain superior markers for predicting metabolic syndrome compared to CRP, HMW-adiponectin, or the combination of both among the Japanese population. [ABSTRACT FROM AUTHOR]

By an association mapping for the candidate locus in chromosome 21q, rs3746876 within KCNJ15 was shown to be associated with type 2 diabetes in Japanese populations. However, the association of rs3746876 with type 2 diabetes has not been validated in an independent cohort. The aim of the present study was to ascertain the association of rs3746876 with type 2 diabetes in an independent larger Japanese sample. We genotyped 7885 Japanese participants (4967 individuals with type 2 diabetes and 2918 control individuals) for rs3746876 with polymerase-chain reaction-invader assay. The association of rs3746876 with type 2 diabetes was examined by using logistic regression analysis. Quantitative traits analyses for homeostasis model assessment (HOMA) of β-cell function, HOMA of insulin resistance, fasting plasma glucose, fasting immunoreactive insulin and body mass index (BMI) were performed in control individuals by using multiple-linear regression analysis. We observed a significant association of rs3746876-T with type 2 diabetes (P=0.0281, odds ratio (OR)=0.82, 95% confidence interval (CI, 0.68-0.98)), but the direction of effect was opposite to that in the original report. The association of rs3746876 with type 2 diabetes was more significant in obese patients (BMI25 kg m−2, P=0.0025, OR=0.62, 95% CI, 0.45-0.84). We did not observe significant association of rs3746876 with any of the quantitative traits in the control individuals. We could not replicate the original finding for the association of rs3746876 with type 2 diabetes, although rs3746876 was significantly associated with obese type 2 diabetes in the present Japanese population. [ABSTRACT FROM AUTHOR]

Aims: The DUSP9 locus on chromosome X was identified as a susceptibility locus for type 2 diabetes in a meta-analysis of European genome-wide association studies (GWAS), and GWAS in South Asian populations identified 6 additional single nucleotide polymorphism (SNP) loci for type 2 diabetes. However, the association of these loci with type 2 diabetes have not been examined in the Japanese. We performed a replication study to investigate the association of these 7 susceptibility loci with type 2 diabetes in the Japanese population. Methods: We genotyped 11,319 Japanese participants (8,318 with type 2 diabetes and 3,001 controls) for each of the 7 SNPs-rs5945326 near DUSP9, rs3923113 near GRB14, rs16861329 in ST6GAL1, rs1802295 in VPS26A, rs7178572 in HMG20A, rs2028299 near AP3S2, and rs4812829 in HNF4A-and examined the association of each of these 7 SNPs with type 2 diabetes by using logistic regression analysis. Results: All SNPs had the same direction of effect (odds ratio [OR].1.0) as in the original reports. One SNP, rs5945326 near DUSP9, was significantly associated with type 2 diabetes at a genome-wide significance level (p = 2.21x10-8; OR 1.39, 95% confidence interval [CI]: 1.2421.56). The 6 SNPs derived from South Asian GWAS were not significantly associated with type 2 diabetes in the Japanese population by themselves (p≥0.007). However, a genetic risk score constructed from 6 South Asian GWAS derived SNPs was significantly associated with Japanese type 2 diabetes (p = 8.69x10-4, OR 1.06. 95% CI; 1.0321.10). Conclusions/interpretation: These results indicate that the DUSP9 locus is a = common susceptibility locus for type 2 diabetes across different ethnicities, and 6 loci identified in South Asian GWAS also have significant effect on susceptibility to Japanese type 2 diabetes. [ABSTRACT FROM AUTHOR]

Losartan, an angiotensin II receptor blocker (ARB), has been reported to increase serum level of high-molecular weight (HMW) adiponectin, which has beneficial effects on insulin resistance and atherosclerosis. On the other hand, treatment with diuretics was reported to decrease the adiponectin level. In the present study, we investigated the effects of changing the treatment to losartan//hydrochlorothiazide (HCTZ) on blood pressure (BP) and various metabolic parameters in Japanese male hypertensive subjects. This study included 15 subjects whose therapy was changed from a usual dosage of ARB to losartan 50mg//HCTZ 12.5mg daily, and also 14 subjects who continued losartan treatment (50mg//day). Serum HMW-adiponectin concentration was assayed using a commercially available HMW-specific ELISA kit. In the losartan//HCTZ patient group, systolic//diastolic BP decreased from 146//95 to 130//84 mmHg (P == 0.0012 for both). The HbA1c level tended to increase from 5.44 ±± 0.39 to 5.55 ±± 0.44%% (P == 0.0554) and serum creatinine level slightly increased from 0.82 ±± 0.12 to 0.87 ±± 0.12 mg//dl (P == 0.0015). In contrast, serum TG (125 ±± 77 to 149 ±± 112 mg//dl), uric acid, and HMW-adiponectin levels (3.24 ±± 2.97 to 3.36 ±± 2.43 μμg//ml) were unchanged. In the 14 patients who continued losartan treatment, systolic//diastolic BP was unchanged from 134//86 to 129//80 mmHg. The HbA1c level tended to increase from 5.26 ±± 0.63 to 5.39 ±± 0.71%% (P == 0.0880), serum creatinine and uric acid levels were unchanged, serum lipids tended to improve, and serum HMW-adiponectin levels increased from 3.03 ±± 1.06 to 3.46 ±± 1.28 μμg//ml (P == 0.0105). In summary, changing treatment to losartan//HCTZ, when changed from a usual dosage of ARB, exerted good BP control, while the HMW-adiponectin level was unchanged in male hypertensive subjects. [ABSTRACT FROM AUTHOR]

Abstract: Adiponectin is an adipocyte-specific secretory protein, which possesses antidiabetic and antiatherosclerotic properties. Adiponectin exists as multimers in serum, and high-molecular-weight (HMW) adiponectin is particularly considered to be the active form of the protein. The objective of the present study was to examine whether decreased HMW adiponectin is a predictor of progression to metabolic syndrome during a 6-year follow-up period in Japanese men. The study subjects were 416 Japanese men without metabolic syndrome, aged 30 to 59 years at baseline, who had participated in annual health checkups in both 2000 and 2006. Low concentration of HMW adiponectin (≤2.65 μg/mL) was associated with substantially higher hazard ratio of the progression to metabolic syndrome after adjustment for age and body mass index (hazard ratio, 1.561; 95% confidence interval, 1.051-2.292; P = .028). The number of subjects with the progression to metabolic syndrome in each tertile based on baseline HMW adiponectin concentration was significantly different among the 3 groups (HMW adiponectin: χ 2 = 7.473, P = .0238; total adiponectin: χ 2 = 4.477, P = .1066; HMW-total adiponectin ratio: χ 2 = 1.676, P = .4325). It was suggested that decreased HMW adiponectin is a predictor of the progression to metabolic syndrome in a 6-year follow-up study of Japanese men. Furthermore, it was suggested longitudinally that measuring HMW adiponectin is efficient to predict the progression to metabolic syndrome compared with measuring total adiponectin or HMW-total adiponectin ratio. [Copyright &y& Elsevier]

Purpose: Some reports have shown that the cause of type 1 diabetes is associated with dysfunction of regulatory T cells (Tregs). The FOXP3/Scurfin gene is known to be a master gene of Tregs. Therefore, we tried to analyze the relation between the gene polymorphism and adult onset type 1 diabetes and its subtype in the Japanese population. Methods: In this study, we recruited 316 Japanese patients with type 1 diabetes (155 male and 161 female, mean onset age 35.4 years) and 432 healthy Japanese controls (263 male and 169 female, mean age 44.4 years). Then we subdivided the patients by onset type, sex, and islet-associated autoantibody positivity. Results: The genotype frequency of (GT)16/(GT)16 in female patients with overall type 1 diabetes was especially lower than that in controls (19.9% vs. 38.5%, p = 0.0002). Moreover, the genotype frequency of (GT)16/(GT)16 in female patients with slowly progressive type 1 diabetes was significantly lower than that in controls (15.4% vs. 38.5%, p = 0.002). Conclusion: Our data showed that the (GT)n microsatelloite polymorphism in the FOXP3/Scrufin gene was associated with Japanese adult onset type 1 diabetes, especially in females, and slowly progressive type 1 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Adiponectin is an adipocyte-specific secretory protein that possesses antidiabetic and antiatherosclerotic properties. Recent studies have demonstrated that the high molecular weight (HMW) multimer form is the active form of this protein. In patients with type 2 diabetes mellitus, HMW-total adiponectin ratio was reported to be a more useful marker than total adiponectin in the prediction of insulin resistance and metabolic syndrome. In the present study of healthy Japanese male subjects without any medication, we investigated the hypothesis that measuring only HMW adiponectin may be as effective as HMW-total ratio to predict insulin resistance and/or metabolic syndrome. This was a working community–based cross-sectional study of 637 male subjects aged 30 to 65 years. Total and HMW adiponectin concentrations in serum were measured by enzyme-linked immunosorbent assay using commercially available kits. Serum HMW adiponectin level was inversely correlated with homeostasis model assessment of insulin resistance (HOMA-IR) (r = −0.375, P < .0001) even after adjustment for age and body mass index (r′ = −0.245, P < .0001). When we divided the study subjects into quartile groups with equal numbers of subjects, HOMA-IR in the 4 groups based on serum HMW adiponectin level was significantly different (P < .01). Metabolic syndrome score in the 4 groups based on serum HMW adiponectin level was also significantly different (P < .01). Area under the curve of receiver operator characteristic curves of HMW adiponectin (0.73) to evaluate the presence of insulin resistance (HOMA-IR >2.5) was larger than that of total adiponectin (0.68) or HMW-total ratio (0.70). Area under the curve of receiver operator characteristic curves of HMW adiponectin (0.70) to evaluate the presence of metabolic syndrome (body mass index–based modified criteria) was also larger than that of total adiponectin (0.65), but equal to that of HMW-total ratio (0.70). These results suggest that simply measuring HMW adiponectin may be as effective as HMW-total ratio to evaluate the presence of insulin resistance and metabolic syndrome, at least in nondiabetic subjects who are not receiving any medication. [Copyright &y& Elsevier]

Aims:East Asian genome-wide association studies (GWAS) for type 2 diabetes identified 8 loci with genome-wide significance, and 2 loci with a borderline association. However, the associations of these loci except MAEA locus with type 2 diabetes have not been evaluated in independent East Asian cohorts. We performed a replication study to investigate the association of these susceptibility loci with type 2 diabetes in an independent Japanese population. Methods:We genotyped 7,379 Japanese participants (5,315 type 2 diabetes and 2,064 controls) for each of the 9 single nucleotide polymorphisms (SNPs), rs7041847 in GLIS3, rs6017317 in FITM2−R3HDML−HNF4A, rs6467136 near GCCI−PAX4, rs831571 near PSMD6, rs9470794 in ZFAND3, rs3786897 in PEPD, rs1535500 in KCNK16, rs16955379 in CMIP, and rs17797882 near WWOX. Because the sample size in this study was not sufficient to replicate single SNP associations, we constructed a genetic risk score (GRS) by summing a number of risk alleles of the 9 SNPs, and examined the association of the GRS with type 2 diabetes using logistic regression analysis. Results:With the exception of rs1535500 in KCNK16, all SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. The GRS constructed from the 9 SNPs was significantly associated with type 2 diabetes in the Japanese population (p = 4.0 × 10-4, OR = 1.05, 95% confidence interval: 1.02–1.09). In quantitative trait analyses, rs16955379 in CMIP was nominally associated with a decreased homeostasis model assessment of β-cell function and with increased fasting plasma glucose, but neither the individual SNPs nor the GRS showed a significant association with the glycemic traits. Conclusions:These results indicate that 9 loci that were identified in the East Asian GWAS meta-analysis have a significant effect on the susceptibility to type 2 diabetes in the Japanese population. [ABSTRACT FROM AUTHOR]