Risk of the development of Type 2 diabetes in relation to overall obesity, abdominal obesity and the clustering of metabolic abnormalities in Japanese individuals: does metabolically healthy overweight really exist? The Niigata Wellness Study.

AIMS: We investigated the risk of developing diabetes across various metabolic phenotypes by considering the presence of overall adiposity or abdominal adiposity and the number of metabolic abnormalities and aimed to clarify whether a 'healthy overweight' phenotype, that is, overweight with no metabolic abnormalities, was protective of the development of diabetes. METHODS: We studied 29 564 Japanese individuals without diabetes. The 5-year incidence of diabetes was assessed according to a combination of either overweight (BMI ≥ 25.0 kg/m(2) ) or abdominal obesity (waist circumference ≥ 90 cm in men and ≥ 80 cm in women) and the number of metabolic factors present (hypertension, elevated triglyceride concentration, low HDL cholesterol concentration and impaired fasting glucose). RESULTS: A total of 1188 individuals developed diabetes. Compared with normal weight individuals with none of the four metabolic abnormalities, in overweight individuals with none of the four abnormalities there was an odds ratio (OR) of 2.32 [95% confidence interval (CI) 1.50, 3.59] for diabetes; having any one metabolic abnormality increased the risk of developing diabetes among normal weight individuals [OR 3.23 (2.55, 4.10)] and overweight individuals [OR 5.00 (3.77, 6.63)]. Among overweight individuals, the presence of impaired fasting glucose alone substantially elevated the risk of diabetes by 8.98-fold (5.52, 14.6) in comparison with the absence of the four metabolic factors. CONCLUSIONS: Being 'healthy overweight' was associated with a higher OR of developing future diabetes among Japanese individuals than normal weight individuals with no metabolic abnormalities, and being overweight with one or more abnormalities had a further elevated OR compared with 'healthy overweight' people.

Role of sleep duration as a risk factor for Type 2 diabetes among adults of different ages in Japan: the Niigata Wellness Study.

AIM: To compare the role of short sleep duration as a risk factor for diabetes among adults of different ages. METHODS: The study enrolled 38987 Japanese individuals without diabetes, and the 8-year risk of developing diabetes attributable to different sleep durations (< 5.5 h, 5.5 to < 6.5 h, 6.5 to < 7.0 h, 7.0-7.5 h, > 7.5-8.0 h, or > 8.0 h) was assessed among individuals aged ≤ 45, 46-59 or ≥ 60 years. RESULTS: During the 8-year follow-up period, 2085 individuals developed diabetes. Overall, individuals with a short sleep duration of < 5.5 h or 5.5 to < 6.5 h had, respectively, a 1.53-fold (95% CI 1.19, 1.97) or 1.25-fold (95% CI 1.10, 1.42) increased risk of diabetes as compared with those who had 7.0-7.5 h of sleep. A sleep duration of < 5.5 h or 5.5 to < 6.5 h was predictive of the development of diabetes among individuals aged ≤ 45 years, but not among those aged ≥ 60 years. With increasing age, the effect of short sleep duration on the risk of diabetes was attenuated. CONCLUSIONS: Short sleep duration was predictive of diabetes among young or middle-aged Japanese adults but not among elderly individuals after age was considered. Managing habitual short sleep and the possible reasons for having such short sleep duration could be particularly important for young or middle-aged adults in the development of future diabetes.

Comparison of different aspects of BMI history to identify undiagnosed diabetes in Japanese men and women: Toranomon Hospital Health Management Center Study 12 (TOPICS 12).

AIMS: To examine current BMI and various aspects of BMI history as pre-screening tools for undiagnosed diabetes in Japanese individuals. METHODS: This cross-sectional study included 16 226 men and 7026 women aged 30-75 years without a self-reported history of clinician-diagnosed diabetes. We estimated the probability of having undiagnosed diabetes (fasting glucose ≥ 7.0 mmol/l and/or HbA1c ≥ 48 mmol/mol (≥ 6.5%) for the following variables: current BMI, BMI in the early 20s (BMI(20y)), lifetime maximum BMI (BMI(max)), change between BMI in the early 20s and current BMI (ΔBMI(20y-cur)), change between BMI in the early 20s and maximum BMI (ΔBMI(20y-max)), and change between lifetime maximum and current BMI (ΔBMI(max-cur)). RESULTS: The prevalence of undiagnosed diabetes was 3.3% (771/23252) among participants. BMI(max) , ΔBMI(20y-max) and current BMI (1-sd increments) were more strongly associated with diabetes than the other factors (multivariate odds ratio 1.58 [95% CI 1.47-1.70] in men and 1.65 [95% CI 1.43-1.90] in women for BMI(max) ; multivariate odds ratio 1.47 [95% CI 1.37-1.58] in men and 1.61 [95% CI 1.41-1.84] in women for ΔBMI(20y-max) ; multivariate odds ratio 1.47 [95% CI 1.36-1.58] in men and 1.63 [95% CI 1.40-1.89] in women for current BMI). The probability of having diabetes was markedly higher in those with both the highest tertile of BMI(max) and greatest ΔBMI(20y-max) ; however, a substantially lower likelihood of diabetes was observed among individuals with the lowest and middle tertiles of current BMI (< 24.62 kg/m² in men and < 22.54 kg/m² in women). CONCLUSIONS: Lifetime maximum BMI and BMI changes from early adulthood were strongly associated with undiagnosed diabetes. Adding BMI history to people's current BMI would improve the identification of individuals with a markedly higher probability of having undiagnosed diabetes.

Quantitative relationship between body weight gain in adulthood and incident type 2 diabetes: a meta-analysis.

This meta-analysis quantified the risk of type 2 diabetes mellitus (T2DM) preceded by body weight (BW) gain in the general population. Systematic literature searches retrieved 15 eligible studies. The BW gain was divided into early weight-gain, which was defined as BW gain from early adulthood (18-24 years of age) to cohort entry (≥25 years of age), and late weight-gain, which was defined as BW gain from cohort entry. The pooled relative risk (RR; 95% confidence interval [CI]) of T2DM for an increment of BW gain standardized into a 5-kg m(-2) increment in the body mass index (BMI) was 3.07 (2.49-2.79) for early weight-gain and 2.12 (1.74-2.58) for late weight-gain. When limiting analysis to studies that concurrently examined T2DM risk for current BMI (defined in both groups as BMI at cohort entry), a larger magnitude of T2DM risk was revealed for early weight-gain compared with current BMI (RR [95% CI], 3.38 [2.20-5.18] vs. 2.39 [1.58-3.62]), while there was little difference between late weight-gain (RR [95% CI], 2.21 [1.91-2.56]) and current BMI (RR [95% CI], 2.47 [1.97-3.30]). The meta-analysis suggested that BW gain was a quantifiable predictor of T2DM, as well as current obesity in adults. Particularly, BW gain in early rather than middle-to-late adulthood played an important role in developing T2DM.

Leisure-time physical activity is a significant predictor of stroke and total mortality in Japanese patients with type 2 diabetes: analysis from the Japan Diabetes Complications Study (JDCS).

AIMS/HYPOTHESIS: Our aim was to clarify the association between leisure-time physical activity (LTPA) and cardiovascular events and total mortality in a nationwide cohort of Japanese diabetic patients. METHODS: Eligible patients (1,702) with type 2 diabetes (mean age, 58.5 years; 47% women) from 59 institutes were followed for a median of 8.05 years. A comprehensive lifestyle survey including LTPA and occupation was performed using standardised questionnaires. Outcome was occurrence of coronary heart disease (CHD), stroke and total mortality. The adjusted HR and 95% CI were calculated by Cox regression analysis. RESULTS: A significant reduction in HR in patients in the top (≥ 15.4 metabolic equivalents [MET] h/week) vs the bottom tertile (≤ 3.7 MET h/week) of LTPA, adjusted by age, sex and diabetes duration, was observed in stroke (HR 0.55, 95% CI 0.32, 0.94) and total mortality (HR 0.49, 95% CI 0.26, 0.91) but not in CHD (HR 0.77, 95% CI 0.48, 1.25). The HR for stroke became borderline significant or nonsignificant after adjustment for lifestyle or clinical variables including diet or serum lipids. The significantly reduced total mortality by LTPA was independent of these variables and seemed not to be, at least mainly, attributed to reduced cardiovascular disease. CONCLUSIONS/INTERPRETATION: In Japanese persons with type 2 diabetes, LTPA of 15.4 MET h/week or more was associated with a significantly lower risk of stroke partly through ameliorating combinations of cardiovascular risk factors. It was also associated with significantly reduced total mortality but independently of cardiovascular risk factors or events. These findings, implying differences from Western diabetic populations, should be considered in the clinical management of East Asians with diabetes.

Brain-derived neurotrophic factor modulates glucagon secretion from pancreatic alpha cells: its contribution to glucose metabolism.

AIM: Brain-derived neurotrophic factor (BDNF) reduces plasma glucose levels in obese db/db diabetic mice and is speculated to produce its effects via the hypothalamus, the regulatory centre of satiety and the autonomic nervous system. The potential effect of BDNF directly on peripheral endocrine organs, however, remains to be clarified. Here we report the effects of BDNF on hormonal secretion from pancreatic islets of Langerhans using their isolated culture. METHODS AND RESULTS: In an immunohistochemical study, mouse pancreatic alpha cells were stained specifically with the anti-TrkB (a specific receptor for BDNF) antibody. After 7 days culture of isolated islets of the normal mouse pancreas, 10 ng/ml BDNF decreased the secretion of glucagon per 6 h significantly less than that of the control (p = 0.016). In contrast, there were no significant changes in insulin secretion or glucagon and insulin contents in the islets cultured under the same conditions. In vivo administration of BDNF (10 mg/kg/day) to normal mice for 7 days significantly decreased their food consumption (p < 0.05). The fasting plasma glucose levels were decreased on day 7 compared with day 1 more significantly in BDNF-treated mice (p = 0.043) than in pair-fed control mice (p = 0.14). In newborn BDNF-knockout mice, fasting plasma glucose levels increased in the order of homozygote, heterozygote and wild type (p = 0.033). No apparent immunohistochemical abnormality was observed for pancreatic glucagon in the BDNF-knockout mice. CONCLUSION: These data suggest that BDNF affects glucose metabolism not only with its anorectic effect but also with modulated glucagon secretion from pancreatic alpha cells.

Left ventricular mass index increases in proportion to the progression of diabetic nephropathy in Type 2 diabetic patients.

The aim of our cross-sectional case-control study was to evaluate the mechanism of increased cardiac morbidity and mortality in Type 2 diabetic patients with normo-, micro-, and macroalbuminuria. Twenty-nine Type 2 diabetic patients with normoalbuminuria (group N), 19 patients with microalbuminuria (group M1), and seven patients with macroalbuminuria (group M2) were investigated. Groups were not significantly different concerning age, sex and diabetes duration. All patients took their normal medication throughout the study and had no clinical evidence of heart disease. Left ventricular mass index (LVMI) and systolic function were determined by echocardiography. As to the elevation of urinary albumin excretion levels, LVMI was significantly elevated, 101.4+/-20 gm(-2) of group N, 119.5+/-29 gm(-2) of group M1, and 141.9+/-27 gm(-2) of group M2. The prevalence of left ventricular hypertrophy (LVH) was significantly higher in group M2 (100%), and M1 (58%), as compared with group N (24%), but was not significantly different between groups M1 and M2. The body mass index and systolic blood pressure were significant independent predictors of LVMI by multiple regression analysis. In conclusion, the mechanism of the link between albuminuria and cardiovascular mortality was suggested to be LVH.

No association of glutathione S-transferase M1 gene polymorphism with diabetic nephropathy in Japanese type 2 diabetic patients.

Oxidative stress possibly contributes to the development of diabetic nephropathy. Therefore, the levels of endogenous antioxidants may be one of determinants of the susceptibility to diabetic nephropathy. Glutathione S-transferases (GSTs) can work as one of endogenous antioxidants to protect cells from oxidative stress. The M1 member of GST mu class (GSTM1) is polymorphic and only expressed in 55-60% of Caucasians because of the homozygous deletion of the gene (null genotype). Recent studies have provided evidence that the GSTM1 null genotype, i.e. lack of the GSTM1 activity, is associated with an increased susceptibility to lung cancer and colorectal cancer. The present study was conducted to determine whether the genetic polymorphism influences the development of diabetic nephropathy. We examined 105 patients with diabetic nephropathy and 69 patients without diabetic nephropathy in Japanese type 2 diabetic patients with proliferative diabetic retinopathy. GSTM1 genotyping was performed by polymerase chain reaction. The two patient groups were well matched with regard to age, body mass index and HbAlc. GSTM1 null genotype was observed in 48.6% of patients with nephropathy versus 55.1% of patients without nephropathy. The frequency of GSTM1 null genotype was not significantly higher in the patient group with nephropathy than in the patient group without nephropathy. This study is the first to investigate the association of GSTM1 gene polymorphism with the development of diabetic nephropathy. The present results suggest that GSTM1 null genotype does not contribute to the development of diabetic nephropathy in Japanese type 2 diabetic patients.

Lack of association between an ecNOS gene polymorphism and diabetic nephropathy in type 2 diabetic patients with proliferative diabetic retinopathy.

The development of diabetic nephropathy shows remarkable variation among individuals. Therefore, not only hyperglycemia but also genetic factors may contribute to the development of diabetic nephropathy. The aim of the present study was to examine the contribution of the 27-bp repeat polymorphism in intron 4 of the endothelial constitutive nitric oxide synthase gene (ecNOS4) to the development of diabetic nephropathy. For this purpose, we analyzed this polymorphism in 167 Japanese type 2 diabetic patients with proliferative diabetic retinopathy consisting of 102 patients with diabetic nephropathy (with macroalbuminuria) and 65 patients without diabetic nephropathy (with normoalbuminuria). The genotype and allele frequencies were not significantly different between patients with diabetic nephropathy and those without diabetic nephropathy (ecNOS4 "b/b" 79.4% vs. 84.6%, ecNOS4 "b/a" 20.6% vs. 15.4%, "b" allele 89.7% vs. 92.3%, "a" allele 10.3% vs. 7.7%). We conclude that the ecNOS4 polymorphism does not contribute to the development of diabetic nephropathy.

Lack of association between the heparan sulfate proteoglycan gene polymorphism and diabetic nephropathy in Japanese NIDDM with proliferative diabetic retinopathy.

The development of diabetic nephropathy shows remarkable variation among individuals. Therefore, not only hyperglycemia but also genetic factors may contribute to the development of diabetic nephropathy Heparan sulfate proteoglycan (HSPG) is thought to play an important role as a component of the charge selectivity barrier in the glomerular basement membrane. Recently, a BamHI restriction fragment length polymorphism (RFLP) in the HSPG gene (HSPG2) was reported to be associated with diabetic nephropathy in Caucasian insulin-dependent diabetes mellitus (IDDM). The aim of the present study was to examine the contribution of the BamHI HSPG2 polymorphism to the development of diabetic nephropathy in Japanese non-insulin-dependent diabetes mellitus (NIDDM). For this purpose, we recruited 102 patients with diabetic nephropathy and 64 age-matched patients without diabetic nephropathy from Japanese NIDDM patients. Since all the subjects had proliferative diabetic retinopathy, it seems likely that they would be exposed to hyperglycemia for a long time. In the present study, the BamHI HSPG2 genotype and allele frequencies were not significantly different between the patients with nephropathy and the patients without nephropathy. Therefore, we conclude that the BamHI HSPG2 polymorphism is not associated with the development of diabetic nephropathy in Japanese NIDDM.

No association between MTHFR gene polymorphism and diabetic nephropathy in Japanese type II diabetic patients with proliferative diabetic retinopathy.

The development of diabetic nephropathy shows marked variation among individuals. Not only hyperglycemia, but also genetic factors may contribute to the development of diabetic nephropathy. Methylenetetrahydrofolate reductase (MTHFR) is involved in remethylation of homocysteine to methionine. Decreased activity of MTHFR which can result in hyperhomocysteinemia may lead to cerebrovascular disease and coronary artery disease. Recently, a common C to T mutation at nucleotide position 677 of the MTHFR gene (MTHFR677CT) has been reported to be correlated with hyperhomocysteinemia and the severity of coronary artery disease as macroangiopathy. In the present study, we recruited 173 of Japanese type II diabetic patients with proliferative diabetic retinopathy who would be exposed to long-term hyperglycemia, and examined the contribution of the MTHFR gene polymorphism to the development of diabetic nephropathy as microangiopathy. The frequency of the mutated allele was 43.3% in patients with nephropathy (n = 105) versus 41.9% in those without nephropathy (n = 68). The genotype frequencies were +/+, 16.2%; +/-, 54.3%; -/-, 29.5% in patients with nephropathy versus +/+, 13.2%; +/-, 57.4%; -/-, 29.4% in those without nephropathy (+ indicates the presence of the mutation). The MTHFR genotype and allele frequencies were not significantly different between patients with and without nephropathy. Therefore, we conclude that the MTHFR gene polymorphism is not associated with the development of diabetic nephropathy in Japanese type II diabetic patients.

Polymorphism of the angiotensin I-converting enzyme gene in diabetic nephropathy in type II diabetic patients with proliferative retinopathy.

Recently, deletion (D)/insertion (I) polymorphism in the Angiotensin I-converting enzyme (ACE) gene has been suggested to be related to the development of diabetic nephropathy in type I diabetes mellitus. This hypothesis, however, remains controversial. Differences in clinical states between patients, especially in glycemic control or duration of diabetes, could be responsible for these contradictory results. In this study we examined the relationship between D/I polymorphism of the ACE gene and diabetic nephropathy in type II diabetic patients who had already developed proliferative retinopathy (n = 45), and were thought to have been in a hyperglycemic state for long enough to develop microangiopathy. The patients were divided into two subgroups: 24 with nephropathy (albumin excretion rate: AER > or = 20 micrograms/min) and 21 without (AER < 20 micrograms/min). There was no difference in the duration of diabetes, HbA1c levels or average blood pressure over the previous year between these subgroups and other clinical characteristics were comparable. Patients without nephropathy exhibited allele I more often than those with nephropathy (p = .025). AER was lowest in genotype II and highest in genotype DD patients but the difference was not statistically significant (p = .07). From these findings, it was concluded that genotype II for the ACE gene could be a marker for reduced risk of diabetic nephropathy.

Urinary excretion rate of ceruloplasmin in non-insulin-dependent diabetic patients with different stages of nephropathy.

The level of ceruloplasmin, which is a more negatively charged protein than albumin, was measured by an immunoradiometric assay in timed overnight urine and serum samples from patients with non-insulin-dependent diabetes mellitus and healthy controls. None of the plasma proteins examined showed any cross-reactivity in this assay. A linear correlation was seen between the ceruloplasmin level and the serial dilution of the sample. Western blot analysis using concentrated urine samples showed that the molecular weight of ceruloplasmin in the urine sample was the same as that of ceruloplasmin in the serum and standard samples. These findings indicated that the substance detected by this assay was truly ceruloplasmin. The urinary ceruloplasmin excretion rate (CER) and clearance of ceruloplasmin increased in parallel with the progression of albuminuria. The highest CER was found in macroalbuminuric patients, followed by micro- and normoalbuminuric patients and the healthy control subjects, the differences between the groups being significant. In view of the fact that the isoelectric point of ceruloplasmin (4.4) is more acidic than that of albumin, the present findings suggested that an enhanced CER was due either to the alteration of charge selectivity in the glomerular basement membrane with unaltered tubular function or to a defect of the non-discriminatory pores (shunt pathway) with unaltered tubular function.

Female siblings with Pendred's syndrome.

Female siblings with Pendred's syndrome were admitted to our clinic. The abnormality of the acoustic structure was examined by MRI. Bilateral enlargement of the vestibular aqueduct and a prominently marked endolymphatic sac were found on MRI. These findings seemed likely to represent a Mondini deformity. Acoustic structure in Pendred's syndrome was examined here by MRI for the first time. We examined their HLA-DR locus as a genetic marker using the affected sib-pair method preliminary. HLA typing might be a diagnostic criteria of Pendred's syndrome, although the present siblings possessed 2 HLA genes in common.