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Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (P

Background O-linked β- N -acetylglucosamine modification O-GlcNAcylation) is a post-translational modification of intracellular proteins, serving as a nutrient sensor. Growing evidence has demonstrated its physiological and pathological importance in various mammalian tissues. This study examined the physiological role of O-GlcNAcylation in podocyte function and development. Methods O-GlcNAc transferase (Ogt) is a critical enzyme for O-GlcNAcylation and resides on the X chromosome. To abrogate O-GlcNAcylation in podocytes, we generated congenital and tamoxifen (TM)-inducible podocyte-specific Ogt knockout mice (Podo-Ogt y/- and TM-Podo-Ogt y/- , respectively) and analyzed their renal phenotypes. Results Podo-Ogt y/- mice showed normal podocyte morphology at birth. However, they developed albuminuria at 8 weeks of age, increasing progressively until age 32 weeks. Glomerular sclerosis, proteinuria-related tubulointerstitial lesions and markedly altered podocyte foot processes, with decreased podocin expression, were observed histologically in 32-week-old Podo-Ogt y/- mice. Next, we induced adult-onset deletion of the Ogt gene in podocytes by TM injection in 8-week-old TM-Podo-Ogt y/- mice. In contrast to Podo-Ogt y/- mice, the induced TM-Podo-Ogt y/- mice did not develop albuminuria or podocyte damage, suggesting a need for O-GlcNAcylation to form mature foot processes after birth. To test this possibility, 3-week-old Podo-Ogt y/- mice were treated with Bis-T-23, which stimulates actin-dependent dynamin oligomerization, actin polymerization and subsequent foot process elongation in podocytes. Albuminuria and podocyte damage in 16-week-old Podo-Ogt y/- mice were prevented by Bis-T-23 treatment. Conclusions O-GlcNAcylation is necessary for maturation of podocyte foot processes, particularly after birth. Our study provided new insights into podocyte biology and O-GlcNAcylation.

Aims:Conflicting evidence exists regarding whether obesity is independently associated with coronary artery calcium (CAC), a measure of coronary atherosclerosis. We examined an independent association of obesity with prevalent CAC among samples of multi-ethnic groups whose background populations have varying levels of obesity and coronary heart disease (CHD)., Methods and results:We analysed a population-based sample of 1212 men, aged 40-49 years free of clinical cardiovascular disease recruited in 2002-06; 310 Japanese in Japan (JJ), 294 Koreans in South Korea (KN), 300 Japanese Americans (JA), and 308 Whites in the USA (UW). We defined prevalent CAC as an Agatston score of ≥10. Prevalent CAC was calculated by tertile of the body mass index (BMI) in each ethnic group and was plotted against the corresponding median of tertile BMI. Additionally, logistic regression was conducted to examine whether an association of the BMI was independent of conventional risk factors. The median BMI and crude prevalence of CAC for JJ, KN, JA, and UW were 23.4, 24.4, 27.4, and 27.1 (kg/m2); 12, 11, 32, and 26 (%), respectively. Despite the absolute difference in levels of BMI and CAC across groups, higher BMI was generally associated with higher prevalent CAC in each group. After adjusting for age, smoking, alcohol, hypertension, lipids, and diabetes mellitus, the BMI was positively and independently associated with prevalent CAC in JJ, KN, UW, but not in JA., Conclusion:In this multi-ethnic study, obesity was independently associated with subclinical stage of coronary atherosclerosis among men aged 40-49 years regardless of the BMI level.

Protein-tyrosine phosphatase 1B (PTP1B) is a major regulator of insulin sensitivity. We have described a novel action of PTP1B in the induction of sterol regulatory element-binding protein-1 (SREBP-1) gene expression through activation of protein phosphatase 2A (PP2A). PTP1B is anchored to the endoplasmic reticulum membrane via its C-terminal tail. We have previously reported that membrane localization of PTP1B is essential for PP2A activation, which is crucial for enhancing SREBP-1 gene expression in in vitro experiments. In this study, we further investigated the physiological importance of membrane localization of PTP1B in vivo. We found that transient liver-specific overexpression of wild-type PTP1B (PTP1B-WT) using adenovirus-mediated gene transfer was associated with hypertriglyceridaemia and enhanced hepatic SREBP-1 gene expression in mice. However, overexpression of the C-terminal truncated PTP1B (PTP1BDeltaCT) failed to increase hepatic SREBP-1 expression or serum triglyceride levels, despite causing insulin resistance. Our results indicate that activation of PTP1B in the liver could induce hypertriglyceridaemia and that anchoring of PTP1B to the membrane is crucial for its action.

Background: In Caucasian populations, adult height is inversely associated with cardiovascular disease (CVD) risk and positively related to some cancers. However, there are few data from Asian populations and from women. We sought to determine the sex- and region-specific associations between height and cardiovascular outcomes, and deaths due to cancer, respiratory and injury in populations from the Asia-Pacific region. Methods: Thirty-nine studies from the Asia Pacific Cohort Studies Collaboration database were included. We used Cox proportional hazard regression models to estimate the associations between height and pre-specified outcomes. Results: A total of 510 800 participants with 21 623 deaths were included. Amongst men, inverse linear associations were observed between height and coronary heart disease (CHD), stroke, CVD, injury and total mortality. The hazard ratios [95% confidence intervals, (CI)] for a 1-SD (= 6 cm) increment in height ranged from 0.85 (0.80-0.91) for injury to 0.97 (0.95-0.98) for total mortality. Similar trends were found between height and CHD, haemorrhagic stroke and CVD in women. A positive linear association was observed between height and cancer mortality. For each standard deviation greater height, the risk of cancer was increased by 5% (2-8%) and 9% (5-14%) in men and women, respectively. No regional difference was observed between Asian and Australasian cohorts. Adjusting for markers of education did not alter the results. Conclusions: The opposing relationships of height with CVD and cancer suggest that care is required in setting national policies on childhood nutrition lest they have unintended consequences on the incidence of major non-communicable diseases. Published by Oxford University Press on behalf of the International Epidemiological Association

Since World War II (WWII), exposures to westernized lifestyle have occurred in many non-Western countries, including Japan. The man born after WWII in Japan have had major changes in diet and other lifestyle factors, including heavy cigarette smoking, increase in the levels of total and low density lipoprotein cholesterol (LDL-C), increase in cholesterol intake in diet which is higher than in the United States (US), increase in body weight and obesity, substantial increase in alcohol consumption, and increase in western foods 1. Comparing the survey data from national representative samples around 1990, risk factor profiles for coronary heart disease (CHD): total cholesterol, and systolic and diastolic blood pressure, were very similar in men in the post WWII birth cohorts in the US and Japan, except for much higher prevalence of cigarette smoking in Japan and much higher prevalence of obesity in the US 2. We compared CHD mortality in men aged 35-44 between the US and Japan and found that CHD mortality in Japan is still considerably lower than in the US: 23.7/100,000 for the US and 8.7/100,000 for Japan 3. After careful review, the differences do not appear to be explained by differences in potential misclassification of causes of death 3. These observations imply that there may be important protective factors that reduce risk of CHD in Japan. Differences in genetic factors are unlikely to fully explain the difference in CHD mortality because studies of Japanese migrants to the US clearly illustrated the increase in CHD morbidity and mortality in Japanese men in the US 4. Epidemiological investigations monitoring and comparing CHD morbidity and mortality in the post WWII birth cohorts, i.e. age

Background Few prospective data from the Asia-Pacific region are available relating body mass index (BMI) to the risks of stroke and ischaemic heart disease (IHD). Our objective was to assess the age-, sex-, and region-specific associations of BMI with cardiovascular disease using individual participant data from prospective studies in the Asia-Pacific region. Methods Studies were identified from literature searches, proceedings of meetings, and personal communication. All studies had at least 5000 person-years of follow-up. Hazard ratios were calculated from Cox models, stratified by sex and cohort, and adjusted for age at risk and smoking. The first 3 years of follow-up were excluded in order to reduce confounding due to disease at baseline. Results A total of 33 cohort studies, including 310 283 participants, contributed 2 148 354 person-years of follow-up, during which 3332 stroke and 2073 IHD events were observed. There were continuous positive associations between baseline BMI and the risks of ischaemic stroke, haemorrhagic stroke, and IHD, with each 2 kg/m(2) lower BMI associated a 12% (95% CI: 9, 15%) lower risk of ischaemic stroke, 8% (95% CI: 4, 12%) lower risk in haemorrhagic stroke, and 11% (95% CI: 9, 13%) lower risk of IHD. The strengths of all associations were strongly age dependent, and there was no significant difference between Asian and Australasian cohorts. Conclusions This overview provides the most reliable estimates to date of the associations between BMI and cardiovascular disease in the Asia-Pacific region, and the first direct comparisons within the region. Continuous relationships of approximately equal strength are evident in both Asian and Australasian populations. These results indicate considerable potential for cardiovascular disease reduction with population-wide lowering of BMI.

To investigate the difference in signaling between insulin and insulin-like growth factor I (IGF-I), we studied the effects of these hormones on the phosphorylation state of Crk-associated substrate (Cas) in cells expressing human insulin receptor (HIRc). In the basal state, Cas was heavily tyrosine-phosphorylated, and insulin dephosphorylated Cas in a time- and dose-dependent manner. On the other hand, IGF-I phosphorylated rather than dephosphorylated Cas in HIRc cells. In HIRY/F2 cells expressing a mutant insulin receptor lacking a binding site of SHP-2, a protein-tyrosine phosphatase containing src homology 2 (SH2) regions, insulin accelerated phosphorylation of Cas, as did IGF-I. In HIRc cells expressing a mutant SHP-2 lacking a PTPase domain (DeltaPTP), which interfered with SHP-2 function, insulin failed to dephosphorylate Cas. In whole cell lysate obtained in the basal state, Cas bound to a glutathione-S transferase fusion protein containing SH2 domains of SHP-2 and dissociated from this GST protein in response to insulin. These results indicate that the opposite regulation of Cas phosphorylation by insulin and IGF-I may be mediated through different properties of their receptors, and that the interaction of the insulin receptor with SHP-2 may play an important role in determining the tyrosine-phosphorylation state of Cas.

We have reported that high glucose conditions (27 mM for 4 days) induces activation of protein tyrosine phosphatases (PTPases) which are associated with impaired insulin signaling in Rat 1 fibroblasts expressing human insulin receptors [Maegawa, H. et al. (1995) J. Biol. Chem. 270, 7724-7730]. In this study, we found increased mRNA-levels of a non-receptor type PTPase, protein tyrosine phosphatase 1B (PTP1B), and receptor type PTPases, leukocyte common antigen-related phosphatase (LAR), and LAR-related phosphatase (LRP), under high glucose conditions. In accordance with these results, LAR content was significantly increased, whereas LRP content was not increased. Cytosolic PTP1B content was increased, but membrane-associated PTP1B content showed no detectable change. Pioglitazone, a thiazolidinedione, normalized increased cytosolic PTPase activity through reduction of cytosolic PTP1B content, but it had no effect on mRNA levels of these PTPases. Under the high glucose condition, we also found that epidermal growth factor (EGF)-stimulated signaling, including tyrosine-phosphorylation of EGF receptor and phosphatidylinositol 3'-kinase activities, was attenuated. Nevertheless, pioglitazone failed to restore the attenuated EGF-signaling. These results indicate that the high glucose conditions cause dysfunction of EGF receptor. However, the increased cytosolic PTP1B content is not involved in the abnormal regulation of EGF-signaling, in contrast to insulin-signaling.

The in vitro effect of glucocorticoid on insulin binding and glucose transport was studied with rat adipocytes. Isolated rat adipocytes were incubated with or without 0.70 microgram/ml (1.9 mumol) of hydrocortisone in TCM 199 medium at 37 degrees C, 5% CO2/95% air (v/v), pH 7.4, for 2, 4, and 8 h, and then fat cell insulin binding and insulin-stimulated 3-O-methylglucose transport were measured. Hydrocortisone did not affect insulin binding in terms of affinity or receptor number. Glucose transport in the absence of insulin was significantly decreased at the incubation time of 2 h and continued to decrease up to 8 h of incubation with hydrocortisone. Decreased insulin sensitivity of glucose transport (i.e., a right-ward shift of the dose response curve) was also demonstrated after 2 h incubation with hydrocortisone, and the ED50 of insulin was maximally increased at 4 h of incubation (0.53 ng/ml for treated vs. 0.22 ng/ml for control cells). Maximal insulin responsiveness was also significantly decreased in treated cells after 8 h incubation with hydrocortisone. When percent maximum glucose transport was expressed relative to receptor-bound insulin, the ED50 values of treated and control cells were 10.5 and 7.2 pg of bound insulin, per 2 X 10(5) cells, respectively. Thus, it was evident that glucocorticoid induced a post-receptor coupling defect in the signal transmission of insulin-receptor complex.