Comparison of urethral sling surgery and non-ablative vaginal Erbium:YAG laser treatment in 327 patients with stress urinary incontinence: a case-matching analysis.

Stress urinary incontinence (SUI) occurs when abdominal pressure, such as from coughing or sneezing, causes urine leakage. We retrospectively compared tension-free vaginal tape (TVT) and non-ablative vaginal Erbium:YAG laser treatment (VEL) by propensity score (PS) analysis in women with SUI. No PS analysis studies have investigated urethral sling surgery using polypropylene TVT and VEL for SUI. Data from patients aged 35-50 years who were treated for SUI and registered at several institutions were selected. Patients with medical records covering 1 year for the 1-h pad test, who completed the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) and the Overactive Bladder Symptom Score (OABSS), were included. We analyzed 102, 113, and 112 patients in the TVT, VEL, and control groups, respectively. Compared with the control group, the TVT and VEL groups exhibited significant improvement in the 1-h pad test and ICIQ-SF. In the PS analysis, the TVT and VEL groups similarly improved in the 1-h pad test and ICIQ-SF. As for the OABSS, the VEL group showed significantly greater improvement than the TVT group. In the odds ratio analysis for the 1-h pad test, no differences in any of the parameters were observed between TVT and VEL. VEL may be considered an alternative to TVT for SUI treatment.

Risk Classification for Metabolic Syndrome and the Incidence of Cardiovascular Disease in Japan With Low Prevalence of Obesity: A Pooled Analysis of 10 Prospective Cohort Studies.

Background It is uncertain whether risk classification under the nationwide program on screening and lifestyle modification for metabolic syndrome captures well high-risk individuals who could benefit from lifestyle interventions. We examined the validity of risk classification by linking the incidence of cardiovascular disease (CVD). Methods and Results Individual-level data of 29 288 Japanese individuals aged 40 to 74 years without a history of CVD from 10 prospective cohort studies were used. Metabolic syndrome was defined as the presence of high abdominal obesity and/or overweight plus risk factors such as high blood pressure, high triglyceride or low high-density lipoprotein cholesterol levels, and high blood glucose levels. The risk categories for lifestyle intervention were information supply only, motivation-support intervention, and intensive support intervention. Sex- and age-specific hazard ratios and population attributable fractions of CVD, which were also further adjusted to consider non-high density lipoprotein cholesterol levels, were estimated with reference to nonobese/overweight individuals, using Cox proportional hazard regression. Since the reference category included those with risk factors, we set a supernormal group (nonobese/overweight with no risk factor) as another reference. We documented 1023 incident CVD cases (565 men and 458 women). The adjusted CVD risk was 60% to 70% higher in men and women aged 40 to 64 years receiving an intensive support intervention, and 30% higher in women aged 65 to 74 years receiving a motivation-support intervention, compared with nonobese/overweight individuals. The population attributable fractions in men and women aged 40 to 64 years receiving an intensive support intervention were 17.7% and 6.6%, respectively, while that in women aged 65 to 74 years receiving a motivation-support intervention was 9.4%. Compared with the supernormal group, nonobese/overweight individuals with risk factors had similar hazard ratios and population attributable fractions as individuals with metabolic syndrome. Conclusions Similar CVD excess and attributable risks among individuals with metabolic syndrome components in the absence and presence of obesity/overweight imply the need for lifestyle modification in both high-risk groups.

Increased cancer mortality among Japanese individuals with hyperinsulinemia.

AIMS: To evaluate the effect of hyperinsulinemia on cancer death, we clarified the association between hyperinsulinemia and cancer mortality among Japanese individuals. METHODS: All the participants (5586 men and 6652 women) lived in Hiroshima City, underwent a 75 g oral glucose tolerance test between 1994 and 2012, and were followed for mortality until August 2013. A systematic review of death certificates was used to confirm the cause of death. RESULTS: During the follow-up period (median, 10.0 years), 587 participants died of cancer. Lung cancer was the most common cause of organ-specific death. We divided the participants into 3 groups according to the tertiles of fasting immunoreactive insulin (FIRI) levels (low, middle, and high groups). The high group had the highest mortality rate (5.5 per 1000 person-years). The hazard ratio (HR) for cancer mortality of the high group after adjustment for possible confounders, such as age, sex, body mass index, smoking status, alcohol intake, and radiation effects (model 1), was significantly higher than that of the low group (HR, 1.55; 95% confidence interval (CI), 1.23-1.95). In model 2 (model 1 plus fasting plasma glucose) and model 3 (model 1 plus HbA1c), the multivariate HRs for cancer mortality were 1.46 (95% CI, 1.15-1.85) and 1.48 (95% CI, 1.17-1.87), respectively.The HR for cancer death at high FIRI levels (per 1 µU/mL) was 1.04 (95% CI, 1.02-1.05) in all participants after adjusting for fasting plasma glucose level and other confounders. In the subgroup analysis, the HRs were 1.03 (95% CI, 0.98-1.09), 1.05 (95% CI, 1.02-1.08), and 1.04 (95% CI, 1.02-1.06) in the normal, prediabetes, and diabetes group, respectively. CONCLUSIONS: Hyperinsulinemia was associated with a high risk of cancer mortality and may be an important link between cancer mortality and diabetes or prediabetes.

Association between a biomarker of glucose spikes, 1,5-anhydroglucitol, and cancer mortality.

INTRODUCTION: 1,5-Anhydroglucitol (1,5-AG) is a biomarker of glucose spikes. To evaluate the effect of acute glucose excursions on cancer death, we clarified the association between 1,5-AG and cancer mortality among Japanese individuals with normal glucose tolerance. RESEARCH DESIGN AND METHODS: We measured 1,5-AG in 6783 (2842 men, 3941 women) individuals with normal fasting and 2-hour plasma glucose who received a 75 g oral glucose tolerance test between 1994 and 2012. They were followed for mortality until August 2013. A systematic review of death certificates was used to confirm the cause of death. We divided the participants into four groups according to the quartile of 1,5-AG level at registration. We used Cox regression to clarify the association between 1,5-AG levels and cancer mortality with multivariate adjustment for possible confounders. RESULTS: During the follow-up period (median, 10.0 years), 140 men and 109 women died of cancer. The HR for cancer mortality of the lowest quartile group was higher than that of the highest quartile group in men (HR, 2.62; 95% CI, 1.60 to 4.41) and in women (HR, 1.47; 95% CI, 0.88 to 2.47). These associations were not attenuated with further adjustment for HbA1c. CONCLUSIONS: 1,5-AG was associated with high risk of cancer mortality in Japanese men after adjustment for HbA1c.

Longitudinal examination of pancreatic ß-cell function in Japanese individuals.

AIMS/INTRODUCTION: We carried out a retrospective, longitudinal analysis of ß-cell function between a diabetes mellitus group, including those that progressed to diabetes mellitus during the follow-up period, and a diabetic type with glycated hemoglobin (HbA1c) <6.5 group, including those that progressed to a diabetic type during the follow-up period. ß-Cell function was assessed using homeostasis model of assessment of ß-cell function. MATERIALS AND METHODS: The relationship between the duration of diabetes mellitus or the diabetic type and pancreatic ß-cell function was compared between the diabetes mellitus group (1,817) and diabetic type with HbA1c <6.5 group (1,843) using results from an oral glucose tolerance test. Linear mixed effects models were used to analyze repeated measurements of oral glucose tolerance tests. RESULTS: The slope of the regression line of ß-cell function for the duration of the diabetes mellitus group was -2.2%/year before the diagnosis. The slope differed after the diagnosis, and the difference was 1.3. The slope of the diabetic type group was -1.2%/year, and no significant difference was observed in the slope before and after the diagnosis. ß-Cell function at the onset was 54.3% in the diabetic type group and 40.6% in the diabetes mellitus group, and the slope of the regression line was significantly higher in the diabetes mellitus group. We divided the diabetes mellitus and diabetic type with HbA1c <6.5 groups into obese and non-obese participants. ß-Cell function declined more with obesity. CONCLUSIONS: Subsequent declines in ß-cell function were faster in the diabetes mellitus group than that in the diabetic type with HbA1c <6.5 group, and increased with obesity.

Second derivative of the finger photoplethysmogram and cardiovascular mortality in middle-aged and elderly Japanese women.

The second derivative of the digital photoplethysmogram (SDPTG) is an indicator of arterial stiffness. The ratio of the height of the d wave to the a wave of the SDPTG (d/a) is associated with functional peripheral vascular tension and represents aortic-blood pressure (BP) augmented by reflection waves from the periphery. This longitudinal study aimed to investigate the relationship between SDPTG and cardiovascular mortality in middle-aged and elderly Japanese women. From 1998 to 2008, we recruited 4373 women (50-79 years old at baseline) who underwent medical check-ups and SDPTG measurement. The SDPTG index (d/a) was calculated from the wave component height, and was divided into quartiles (Q) according to the d/a value. The median follow-up period was 9.0 years. The d/a value was negatively associated with age and BP, and positively associated with heart rate and body height. Using the Cox proportional hazards model, the hazard ratios for cardiovascular mortality for Q2, Q3 and Q4 were significantly higher than that of Q1. In multivariate analysis, the hazard ratio was 2.30 for Q3 (95% confidence interval (CI): 1.06-4.99, P<0.05) and 2.60 for Q4 (95% CI: 1.21-5.60, P<0.05), after adjustment for age, height, body mass index, BP levels, heart rate and other atherosclerosis-related factors. The hazard ratios of cardiovascular mortality for Q3 and Q4 were significantly higher compared with the reference (Q1). Thus, the SDPTG d/a is an independent predictor of cardiovascular mortality in middle-aged and elderly Japanese women.

Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes.

Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (P<5 × 10(-8)), rs1116357 near CCDC85A, rs147538848 in FAM60A, rs1575972 near DMRTA1, rs9309245 near ASB3, rs67156297 near ATP8B2, rs7107784 near MIR4686 and rs67839313 near INAFM2. Of these, the association of 4 loci with T2D is replicated in multi-ethnic populations other than Japanese (up to 65,936 T2Ds and 158,030 controls, P<0.007). These results indicate that expansion of single ethnic GWAS is still useful to identify novel susceptibility loci to complex traits not only for ethnicity-specific loci but also for common loci across different ethnicities.

Evaluation of the new criteria of 2010 for diabetes mellitus: Japan Diabetes Society.

We investigated the characteristics of the new criteria for diabetes mellitus (DM) issued by the Japan Diabetes Society in 2010, which include HbA1C measurement, and differences between 1999 criteria, in order to indicate clinical caution points. If a person with fasting plasma glucose (FPG) ≥126 mg/dl or an oral glucose tolerance test (OGTT) 2-h value ≥200 and HbA1C ≥6.5 % is determined as having DM, the disease can be detected at a rate of ≥70 % in persons <60 years and at no more than 40-50 % in elderly persons. In longitudinal examination, we observed that individuals with DM with FPG ≥126 mg/dl and HbA1C ≥6.5 % obtained the same determination over time at a rate of nearly 90 %. The percentage of persons whose result shifted from normal type to DM was 3- to 4-fold lower than that of persons whose result shifted from normal type to diabetic type. Based on these results, measurement of FPG and HbA1C at the same time may be extremely effective in identifying DM, although we should pay attention to a higher likelihood that mild glucose metabolism disorders will be overlooked.

Association between the Postprandial Glucose Levels and Arterial Stiffness Measured According to the Cardio-ankle Vascular Index in Non-diabetic Subjects.

OBJECTIVE: Although a relationship between post-challenge hyperglycemia and arterial stiffness has been reported, the relationship between the postprandial glucose levels and cardio-ankle vascular index (CAVI) in non-diabetic subjects is not clear. This study thus evaluated the association between the postprandial glucose levels after a composite meal and the degree of arterial stiffness measured according to CAVI in non-diabetic subjects. METHODS: The subjects included 1,291 individuals (655 men and 636 women; mean age, 48.6 years; range, 23-85 years) who underwent medical examinations, including blood tests and CAVI assessments, between October 2005 and April 2012. The 1-hour postprandial glucose levels were determined after a 600-kcal traditional Japanese meal. RESULTS: The CAVI values were significantly higher in the subjects with higher 1-hour postprandial glucose levels (≥140 mg/dL in men; ≥158 mg/dL in women). A simple regression analysis indicated that the CAVI values were significantly correlated with the 1-hour postprandial glucose levels in men (r=0.286, p<0.0001) and women (r=0.228, p<0.0001). After adjusting for age, BMI, systolic blood pressure, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, 1-hour postprandial glucose, homeostatis model assessment of insulin resistance, estimated glemerular filtration rate, and high sensitive C-reactive protein, stepwise multiple regression analysis demonstrated that the 1-hour postprandial glucose level was an independent predictor associated with the CAVI in men (p=0.003) and older women 50 years of age or older (p=0.003). CONCLUSION: This study demonstrated that the 1-hour postprandial glucose levels are associated with increased CAVI values in non-diabetic men and older women 50 years of age or older.

Genome-wide association study identifies three novel loci for type 2 diabetes.

Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.

A single-nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations.

To identify a novel susceptibility locus for type 2 diabetes, we performed an imputation-based, genome-wide association study (GWAS) in a Japanese population using newly obtained imputed-genotype data for 2 229 890 single-nucleotide polymorphisms (SNPs) estimated from previously reported, directly genotyped GWAS data in the same samples (stage 1: 4470 type 2 diabetes versus 3071 controls). We directly genotyped 43 new SNPs with P-values of <10(-4) in a part of stage-1 samples (2692 type 2 diabetes versus 3071 controls), and the associations of validated SNPs were evaluated in another 11 139 Japanese individuals (stage 2: 7605 type 2 diabetes versus 3534 controls). Combined meta-analysis using directly genotyped data for stages 1 and 2 revealed that rs515071 in ANK1 and rs7656416 near MGC21675 were associated with type 2 diabetes in the Japanese population at the genome-wide significant level (P < 5 × 10(-8)). The association of rs515071 was also observed in European GWAS data (combined P for all populations = 6.14 × 10(-10)). Rs7656416 was in linkage disequilibrium to rs6815464, which had recently been identified as a top signal in a meta-analysis of East Asian GWAS for type 2 diabetes (r(2) = 0.76 in stage 2). The association of rs7656416 with type 2 diabetes disappeared after conditioning on rs6815464. These results indicate that the ANK1 locus is a new, common susceptibility locus for type 2 diabetes across different ethnic groups. The signal of association was weaker in the directly genotyped data, so the improvement in signal indicates the importance of imputation in this particular case.

A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B.

We conducted a genome-wide association study of type 2 diabetes (T2D) using 459,359 SNPs in a Japanese population with a three-stage study design (stage 1, 4,470 cases and 3,071 controls; stage 2, 2,886 cases and 3,087 controls; stage 3, 3,622 cases and 2,356 controls). We identified new associations in UBE2E2 on chromosome 3 and in C2CD4A-C2CD4B on chromosome 15 at genome-wide significant levels (rs7612463 in UBE2E2, combined P = 2.27 × 10⁻9; rs7172432 in C2CD4A-C2CD4B, combined P = 3.66 × 10⁻9). The association of these two loci with T2D was replicated in other east Asian populations. In the European populations, the C2CD4A-C2CD4B locus was significantly associated with T2D, and a combined analysis of all populations gave P = 8.78 × 10⁻¹4, whereas the UBE2E2 locus did not show association to T2D. In conclusion, we identified two new loci at UBE2E2 and C2CD4A-C2CD4B associated with susceptibility to T2D.

Report of the committee on the classification and diagnostic criteria of diabetes mellitus.

CONCEPT OF DIABETES MELLITUS: Diabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its pathogenesis involves both genetic and environmental factors. The long-term persistence of metabolic disorders can cause susceptibility to specific complications and also foster arteriosclerosis. Diabetes mellitus is associated with a broad range of clinical presentations, from being asymptomatic to ketoacidosis or coma, depending on the degree of metabolic disorder. CLASSIFICATION TABLES 1 AND 2 AND FIGURE 1: [Table: see text] [Table: see text] Figure 1 A scheme of the relationship between etiology (mechanism) and patho-physiological stages (states) of diabetes mellitus. Arrows pointing right represent worsening of glucose metabolism disorders (including onset of diabetes mellitus). Among the arrow lines, indicates the condition classified as 'diabetes mellitus'. Arrows pointing left represent improvement in the glucose metabolism disorder. The broken lines indicate events of low frequency. For example, in type 2 diabetes mellitus, infection can lead to ketoacidosis and require temporary insulin treatment for survival. Also, once diabetes mellitus has developed, it is treated as diabetes mellitus regardless of improvement in glucose metabolism, therefore, the arrow lines pointing left are filled in black. In such cases, a broken line is used, because complete normalization of glucose metabolism is rare.imageThe classification of glucose metabolism disorders is principally derived from etiology, and includes staging of pathophysiology based on the degree of deficiency of insulin action. These disorders are classified into four groups: (i) type 1 diabetes mellitus; (ii) type 2 diabetes mellitus; (iii) diabetes mellitus due to other specific mechanisms or diseases; and (iv) gestational diabetes mellitus. Type 1 diabetes is characterized by destruction of pancreatic ß-cells. Type 2 diabetes is characterized by combinations of decreased insulin secretion and decreased insulin sensitivity (insulin resistance). Glucose metabolism disorders in category (iii) are divided into two subgroups; subgroup A is diabetes in which a genetic abnormality has been identified, and subgroup B is diabetes associated with other pathologic disorders or clinical conditions. The staging of glucose metabolism includes normal, borderline and diabetic stages depending on the degree of hyperglycemia occurring as a result of the lack of insulin action or clinical condition. The diabetic stage is then subdivided into three substages: non-insulin- requiring, insulin-requiring for glycemic control, and insulin-dependent for survival. The two former conditions are called non-insulin-dependent diabetes and the latter is known as insulin-dependent diabetes. In each individual, these stages may vary according to the deterioration or the improvement of the metabolic state, either spontaneously or by treatment. DIAGNOSIS TABLES 3­7 AND FIGURE 2: [Table: see text] [Table: see text] [Table: see text] [Table: see text] [Table: see text] Figure 2 Flow chart outlining steps in the clinical diagnosis of diabetes mellitus. *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%).imageCategories of the State of Glycemia: Confirmation of chronic hyperglycemia is essential for the diagnosis of diabetes mellitus. When plasma glucose levels are used to determine the categories of glycemia, patients are classified as having a diabetic type if they meet one of the following criteria: (i) fasting plasma glucose level of ≥126 mg/dL (≥7.0 mmol/L); (ii) 2-h value of ≥200 mg/dL (≥11.1 mmol/L) in 75 g oral glucose tolerance test (OGTT); or (iii) casual plasma glucose level of ≥200 mg/dL (≥11.1 mmol/L). Normal type is defined as fasting plasma glucose level of <110 mg/dL (<6.1 mmol/L) and 2-h value of <140 mg/dL (<7.8 mmol/L) in OGTT. Borderline type (neither diabetic nor normal type) is defined as falling between the diabetic and normal values. According to the current revision, in addition to the earlier listed plasma glucose values, hemoglobin A1c (HbA1c) has been given a more prominent position as one of the diagnostic criteria. That is, (iv) HbA1c≥6.5% is now also considered to indicate diabetic type. The value of HbA1c, which is equivalent to the internationally used HbA1c (%) (HbA1c [NGSP]) defined by the NGSP (National Glycohemoglobin Standardization Program), is expressed by adding 0.4% to the HbA1c (JDS) (%) defined by the Japan Diabetes Society (JDS). Subjects with borderline type have a high rate of developing diabetes mellitus, and correspond to the combination of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) noted by the American Diabetes Association (ADA) and WHO. Although borderline cases show few of the specific complications of diabetes mellitus, the risk of arteriosclerosis is higher than those of normal type. When HbA1c is 6.0-6.4%, suspected diabetes mellitus cannot be excluded, and when HbA1c of 5.6-5.9% is included, it forms a group with a high risk for developing diabetes mellitus in the future, even if they do not have it currently. Clinical Diagnosis: 1 If any of the criteria for diabetic type (i) through to (iv) is observed at the initial examination, the patient is judged to be 'diabetic type'. Re-examination is conducted on another day, and if 'diabetic type' is reconfirmed, diabetes mellitus is diagnosed. However, a diagnosis cannot be made only by the re-examination of HbA1c alone. Moreover, if the plasma glucose values (any of criteria [i], [ii], or [iii]) and the HbA1c (criterion [iv]) in the same blood sample both indicate diabetic type, diabetes mellitus is diagnosed based on the initial examination alone. If HbA1c is used, it is essential that the plasma glucose level (criteria [i], [ii] or [iii]) also indicates diabetic type for a diagnosis of diabetes mellitus. When diabetes mellitus is suspected, HbA1c should be measured at the same time as examination for plasma glucose.2 If the plasma glucose level indicates diabetic type (any of [i], [ii], or [iii]) and either of the following conditions exists, diabetes mellitus can be diagnosed immediately at the initial examination.• The presence of typical symptoms of diabetes mellitus (thirst, polydipsia, polyuria, weight loss)• The presence of definite diabetic retinopathy3 If it can be confirmed that the above conditions 1 or 2 existed in the past, diabetes mellitus can be diagnosed or suspected regardless of the current test results.4 If the diagnosis of diabetes cannot be established by these procedures, the patient is followed up and re-examined after an appropriate interval.5 The physician should assess not only the presence or absence of diabetes, but also its etiology and glycemic stage, and the presence and absence of diabetic complications or associated conditions. Epidemiological Study: For the purpose of estimating the frequency of diabetes mellitus, 'diabetes mellitus' can be substituted for the determination of 'diabetic type' from a single examination. In this case, HbA1c≥6.5% alone can be defined as 'diabetes mellitus'. Health Screening: It is important not to misdiagnose diabetes mellitus, and thus clinical information such as family history and obesity should be referred to at the time of screening in addition to an index for plasma glucose level. Gestational Diabetes Mellitus: There are two hyperglycemic disorders in pregnancy: (i) gestational diabetes mellitus (GDM); and (ii) diabetes mellitus. GDM is diagnosed if one or more of the following criteria is met in a 75 g OGTT during pregnancy: 1 Fasting plasma glucose level of ≥92 mg/dL (5.1 mmol/L)2 1-h value of ≥180 mg/dL (10.0 mmol/L)3 2-h value of ≥153 mg/dL (8.5 mmol/L) However, diabetes mellitus that is diagnosed by the clinical diagnosis of diabetes mellitus defined earlier is excluded from GDM. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00074.x, 2010).

The impact of visceral adipose tissue and high-molecular weight adiponectin on cardio-ankle vascular index in asymptomatic Japanese subjects.

Few studies addressed the relation of visceral adiposity and high-molecular weight (HMW) adiponectin to arterial stiffness. We investigated the impact of visceral adipose tissue (VAT) and HMW adiponectin on cardio-ankle vascular index (CAVI) in asymptomatic Japanese subjects. We studied 487 consecutive subjects (271 men and 216 women) who underwent general health examination between October 2005 and May 2008. The abdominal, visceral, and subcutaneous adipose tissue areas were determined by low-dose x-ray computed tomography. Serum levels of total and HMW adiponectin were measured using the enzyme-linked immunosorbent assay system based on a monoclonal antibody to humans. Cardio-ankle vascular index was positively correlated with VAT area and negatively correlated with HMW adiponectin levels. We also found the positive association of the number of metabolic syndrome components with CAVI in both sexes. A stepwise multiple regression analysis revealed that age, VAT area, serum HMW adiponectin levels, and homeostasis model assessment of insulin resistance were independent determinants of CAVI. Receiver operating characteristic analyses demonstrated that the predictive value of the VAT area for the extent of CAVI (mild: <25th percentile vs severe: >75th percentile) exceeded that of total or HMW adiponectin levels in both sexes. In conclusion, increased CAVI is associated with both amounts of VAT measured by computed tomography and serum HMW adiponectin levels in asymptomatic Japanese subjects. Receiver operating characteristic analysis indicates that the VAT area is a lot better predictor of arterial stiffness than adiponectin levels.

Aortic pulse wave velocity predicts cardiovascular mortality in middle-aged and elderly Japanese men.

BACKGROUND: Aortic pulse wave velocity (PWV) is widely used as a noninvasive index of arterial stiffness and was used in the present study to investigate the relationship between PWV and cardiovascular mortality in the middle-aged and elderly Japanese population using a longitudinal study design. METHODS AND RESULTS: From 1988 to 2003, a total of 3,960 men (50-69 years old at baseline) who underwent medical check-ups and measurement of PWV, which was standardized for diastolic blood pressure, were recruited and divided into 4 groups according to the PWV values. The average follow-up period was 8.2 years. Mortality from all-causes and from cardiovascular disease significantly increased as PWV increased in the entire follow-up period. Multivariate-adjusted relative risks of all-cause and cardiovascular disease mortality for the highest quartile of PWV (>9.0 m/s) were 1.28 (95% confidence interval (CI) 0.97-1.68) and 1.83 (95%CI 1.02-3.29), respectively, compared with the lowest quartile (<7.5 m/s). CONCLUSIONS: An increased PWV can predict cardiovascular mortality in middle-aged and elderly Japanese men.

Is there any association between subcutaneous adipose tissue area and plasma total and high molecular weight adiponectin levels?

This study was conducted for the purpose of clarifying the correlations between the subcutaneous adipose tissue area and plasma total and high-molecular weight (HMW) adiponectin levels. The subjects of this study comprised 359 men and 142 women who underwent general health examinations from October 2005 to December 2006. The abdominal subcutaneous and visceral adipose tissue areas were measured using low-dose x-ray computed tomography. Total and HMW adiponectin levels were measured using the enzyme-linked immunosorbent assay system based on a monoclonal antibody to humans. There were negative correlations between the plasma total and HMW adiponectin levels and visceral and subcutaneous adipose tissue areas using simple correlation analysis. Multiple linear regression analysis clearly indicated that the subcutaneous adipose tissue area was independently correlated with the HMW adiponectin levels in men and closely related in women. Many studies reported that only the visceral adipose tissue area showed a significant correlation with metabolic syndrome. However, these results clearly indicate that it is also important to consider the subcutaneous adipose tissue area in metabolic syndrome.

Hepatocyte nuclear factor-4alpha P2 promoter haplotypes are associated with type 2 diabetes in the Japanese population.

Hepatocyte nuclear factor (HNF)-4alpha is a transcription factor known as a key molecule in the development and functions of the beta-cells. In a previously performed genome-wide scan of Japanese type 2 diabetic sibpairs, we observed linkage of type 2 diabetes to chromosome 20q12-q13, a region in which the HNF4A gene is located. Recent studies have reported associations between type 2 diabetes and polymorphisms in the P2 promoter region specific to beta-cells. In this study, we attempted to assess whether the HNF4A gene plays a role in the genetic susceptibility to type 2 diabetes in the Japanese population by analyzing polymorphisms and haplotypes of the HNF4A gene. Linkage disequilibrium across the P2 promoter region was preserved in the Japanese population, consistent with previous reports. Although none of the individual polymorphisms examined showed any significant association with type 2 diabetes, we found very strong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene (P = 3.82 x 10(-4)). In contrast, there was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The association was replicated using two additional cohorts (P = 1.51 x 10(-4) and 0.019, respectively). The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as-yet-unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene that directly influences susceptibility to type 2 diabetes.

A polymorphism in the AMPKalpha2 subunit gene is associated with insulin resistance and type 2 diabetes in the Japanese population.

AMP-activated protein kinase (AMPK) acts as a fuel gauge for glucose and lipid metabolism. The gene encoding the alpha2 isoform of the catalytic subunit of AMPK (PRKAA2) is located at one of the Japanese type 2 diabetes loci mapped by our previous genome scan (1p36-32). PRKAA2 is, therefore, a good candidate gene for insulin resistance and type 2 diabetes. We screened all nine exons, their exon-intron boundaries, and the 5' and 3' flanking regions of PRKAA2 to identify single nucleotide polymorphisms (SNPs), and we genotyped 192 type 2 diabetic patients and 272 nondiabetic subjects to assess possible associations between genotypes or haplotypes and type 2 diabetes. None of the 10 SNPs genotyped was associated with type 2 diabetes, but the haplotype analysis, consisting of six representative SNPs, revealed one haplotype, with the A (minor) allele for rs2051040 and a major allele for the other five SNPs, to be associated with type 2 diabetes (P = 0.009). This finding was confirmed in two larger replication samples (657 case and 360 control subjects, P = 0.021; and 356 case and 192 control subjects from the same area in Japan, P = 0.007) and a significant P value was obtained in the joint haplotype analysis of all samples (1,205 case and 824 control subjects, P = 0.0001). Furthermore, insulin resistance was associated with rs2051040 in nondiabetic subjects, and those with the A (minor) allele had a higher homeostasis model assessment of insulin resistance index than those who did not (initial control subjects [n = 272], P = 0.002; and joint replication control subjects [n = 552], P = 0.037). We speculate that the PRKAA2 gene influences insulin resistance and susceptibility to type 2 diabetes in the Japanese population.