Institute for Adult Diseases

Tokyo, Japan

Institute for Adult Diseases

Tokyo, Japan

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Sone H.,University of Tsukuba | Tanaka S.,Kyoto University | Iimuro S.,University of Tokyo | Oida K.,Fukui Chuo Clinic | And 7 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Risk factors for cardiovascular complications in Japanese patients with diabetes have not been fully elucidated. Objective: Our objective was to determine incidence of and risk factors for coronary heart disease (CHD) and stroke in Japanese diabetic patients. Design and Settings: We conducted a prospective study at 59 hospitals throughout Japan. Patients: Patients included 940 men and 831 women with type 2 diabetes (mean age, 58.2 yr) without a history of cardiovascular complications who were followed for a median of 7.86 yr. Intervention: This was an observational study. Main Outcome Measures: Incidence of CHD and stroke was evaluated. Results: Incidences of CHD and stroke per 1000 person-years were 9.59 and 7.45, respectively, whereas those of myocardial and brain infarctions were 3.84 and 6.29, respectively. Multivariate Cox analysis revealed that the serum log-transformed triglyceride level was a potent and independent predictor of CHD [hazard ratio (HR) = 1.54;95% confidence interval (CI) = 1.22-1.94 per 1 SD increase), comparable to low-density lipoprotein (LDL) cholesterol (HR = 1.49; 95% CI = 1.25-1.78 per 1 SD increase). Triglycerides and LDL cholesterol linearly and continuously increased CHD risk, and subjects in the top third for both had markedly high risks of CHD, and their effects were possibly additive. However, serum triglycerides worked independently of blood pressure levels. Systolic blood pressure was the only significant predictor for stroke except for age (HR = 1.31; 95% CI = 1.04-1.65, per 1 SD increase). Conclusions: In Japanese patients with type 2 diabetes, the serum triglyceride level was a leading predictor of CHD, comparable to LDL cholesterol. Because the serum triglyceride level is not a leading predictor of CHD in diabetic subjects in Western countries, ethnic group-specific strategies for prevention of diabetic macroangiopathy may be indicated. Copyright © 2011 by The Endocrine Society.


Onishi Y.,Institute for Adult Diseases | Ono Y.,Takagi Hospital | Rabol R.,Novo Nordisk AS | Endahl L.,Novo Nordisk AS | Nakamura S.,Heiwadai Hospital
Diabetes, Obesity and Metabolism | Year: 2013

Aims: This phase 3, 26-week, open-label, treat-to-target trial investigated the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) in insulin-naïve Japanese adults with type 2 diabetes. Methods: Subjects were randomized to once-daily injections of IDegAsp (n=147) or insulin glargine (IGlar) (n=149), both ±≤2 oral antidiabetic treatments. IDegAsp was given before the largest meal at the discretion of each subject (and maintained throughout the trial); IGlar was dosed according to label. Both insulins were titrated to a target prebreakfast self-measured plasma glucose of 3.9 to <5.0mmol/l. Results: After 26weeks, mean HbA1c was 7% with IDegAsp and 7.3% with IGlar; superiority of IDegAsp to IGlar was shown (estimated treatment difference, ETD; IDegAsp-IGlar: -0.28% points [-0.46; -0.10]95% CI, p<0.01). At end-of-trial, mean fasting plasma glucose (FPG) was similar for IDegAsp and IGlar (5.7 vs. 5.6mmol/l; ETD IDegAsp-IGlar: 0.15mmol/l [-0.29; 0.60]95% CI, p=NS). IDegAsp was associated with numerically lower rates of overall confirmed (27%) and nocturnal confirmed hypoglycaemia (25%) versus IGlar (estimated rate ratio IDegAsp/IGlar: 0.73 [0.50; 1.08]95% CI, p=NS, and 0.75 [0.34; 1.64]95% CI, p=NS, respectively). Mean daily insulin doses were similar between groups at end-of-trial (both: 0.41U/kg) as were the increases in body weight from baseline (both: 0.7kg). Adverse event profiles were similar between groups. Conclusions: IDegAsp provided superior long-term glycaemic control compared to IGlar, with similar FPG and doses and numerically lower rates of overall and nocturnal hypoglycaemia (p=NS). © 2013 Blackwell Publishing Ltd.


Sakamoto K.,Institute for Adult Diseases | Hikiba Y.,Institute for Adult Diseases | Nakagawa H.,University of Tokyo | Hirata Y.,University of Tokyo | And 8 more authors.
Oncogene | Year: 2013

Ataxia-telangiectasia mutated (ATM) is one of the key molecules involved in the cellular response to DNA damage. A portion of activated ATM is exported from the nucleus into the cytoplasm, where it activates the I kappa B kinase/nuclear factor kappa B (IKK/NF-κB) signaling pathway. It has been thought that activated IKKβ, which is a critical kinase for NF-κB activation, generally resides in the cytoplasm and phosphorylates cytoplasmic downstream molecules, such as IκBα. Here, we identified a new role for IKKβ during the response to DNA damage. ATM phosphorylation in response to alkylating agents consisted of two phases: the early phase (up to 3 h) and late phase (after 6 h). A portion of the activated IKKβ generated during the DNA damage response was found to translocate into the nucleus and directly phosphorylate ATM in the late phase. Furthermore, the phosphorylation of ATM by nuclear IKKβ was suggested to promote DNA repair. In parallel, activated IKKβ induced classical NF-κB activation and was involved in anti-apoptosis. Our findings define the function of IKKβ during the response to DNA damage, which promotes cell survival and DNA repair, and maintains cellular homeostasis. © 2013 Macmillan Publishers Limited. All rights reserved.


Sone H.,University of Tsukuba | Tanaka S.,Kyoto University | Iimuro S.,University of Tokyo | Ishibashi S.,Jichi Medical College | And 6 more authors.
Diabetes Care | Year: 2012

OBJECTIVE - To determine the best lipid variable to predict coronary heart disease (CHD) in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS - Eligible Japanese men and women (1,771) aged 40-70 years with type 2 diabetes from59 institutes nationwide were followed for a planned 8-year period. The performance of eight conventional lipid variables, i.e., total cholesterol (TC), LDL-cholesterol (LDLC), HDL-cholesterol (HDLC), triglycerides (TGs), non-HDLC, TC/HDLC ratio, LDLC/HDLC ratio, and TG/HDLC ratio, as predictors of incident CHD were evaluated by four methods: hazard ratio (HR) per one SD increment by multivariate Cox analysis, χ 2 likelihood ratio test, area under the receiver operating characteristic curve (AUC), and tertile analysis. RESULTS - Although all variables significantly predicted CHD events inmen, non-HDLC (HR per one SD 1.78 [95% CI 1.43-2.21]; AUC 0.726) and TC/HDLC (HR 1.63 [1.36-1.95]; AUC 0.718) had the better predictive performances among the variables, including LDLC. In women, TGs (log-transformed; HR 1.72 [1.21-2.43]; AUC 0.708) were the best predictor according to results of tertile analysis (HR of the top tertile versus the bottom tertile 4.31 [1.53-12.16]). The associations with incident CHD were linear and continuous. CONCLUSIONS - For Japanese diabetic men, non-HDLC and TC/HDLC were the best predictors, whereas TGs were most predictive for women. These findings, which included prominent sex differences, should be considered among clinical approaches to risk reduction among East Asians with diabetes. © 2012 by the American Diabetes Association.


Tanaka S.,Kyoto University | Iimuro S.,University of Tokyo | Yamashita H.,Yamagata University | Katayama S.,Saitama University | And 4 more authors.
International Journal of Epidemiology | Year: 2014

The Japan Diabetes Complications Study, a randomised lifestyle intervention study of type 2 diabetes conducted at 59 institutes throughout Japan that enrolled 2033 eligible patients from January 1995 to March 1996, was directed at: (i) determining the incidence and progression rates of complications of diabetes; (ii) exploring clinical risk factors for complications of diabetes; and (iii) determining the association between lifestyle factors, including diet and physical activity, and complications of diabetes, in addition to comparing, in a randomised manner, the effects on type 2 diabetes of an extensive lifestyle intervention and conventional treatment. The protocol for the study originally specified four study populations according to primary outcomes, consisting of: (1) a macroangiopathy group (N=1771); (ii) a nephropathy group (N=1607); (iii) a retinopathy-incident group (N=1221); and (iv) a retinopathy-progression group (N=410). The primary outcomes were: (i) development of retinopathy; (ii) progression of retinopathy; (iii) development of overt nephropathy; and (iv) occurrence of macroangiopathic events including proven coronary heart disease and stroke. The study was originally planned to follow patients for 8 years, and an extended follow-up is ongoing. Information about primary outcomes, laboratory tests, and other clinical variables for each patient was collected at a central data centre through an annual report from each investigator. Additionally, extensive lifestyle surveys were conducted at baseline and 5 years after the beginning of the study intervention in both the intervention and conventional treatment groups. A description of the occurrence of complications of diabetes and of all-cause mortality, provided in this paper, demonstrated a clear gender-based difference in cardiovascular disease and all-cause mortality. The data set of the study is not freely available, but collaborative ideas are welcome. Potential collaborators should discuss ideas informally with the principal investigator by e-mail. © The Author 2013; Published by Oxford University Press on behalf of the International Epidemiological Association all rights reserved.


Tanaka S.,Kyoto University | Iimuro S.,University of Tokyo | Yamashita H.,Yamagata University | Katayama S.,Saitama University | And 6 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-To develop and validate a risk engine that calculates the risks of macro- and microvascular complications in type 2 diabetes. RESEARCH DESIGNANDMETHODS-We analyzed pooled data from two clinical trials on 1,748 Japanese type 2 diabetic patients without diabetes complications other than mild diabetic retinopathy with a median follow-up of 7.2 years. End points were coronary heart disease (CHD), stroke, noncardiovascular mortality, overt nephropathy defined by persistent proteinuria, and progression of retinopathy. We fit a multistate Cox regression model to derive an algorithm for prediction. The predictive accuracy of the calculated 5-year risks was cross-validated. RESULTS-Sex, age, HbA1c, years after diagnosis, BMI, systolic blood pressure, non-HDL cholesterol, albumin-to-creatinine ratio, atrial fibrillation, current smoker, and leisure-time physical activity were risk factors for macro- and microvascular complications and were incorporated into the risk engine. The observed-to-predicted (O/P) ratios for each event were between 0.93 and 1.08, and Hosmer-Lemeshow tests showed no significant deviations between observed and predicted events. In contrast, the UK Prospective Diabetes Study (UKPDS) risk engine overestimated CHD risk (O/P ratios: 0.30 for CHD and 0.72 for stroke). C statistics in our Japanese patients were high for CHD, noncardiovascular mortality, and overt nephropathy (0.725, 0.696, and 0.767) but moderate for stroke and progression of retinopathy (0.636 and 0.614). By combining macro- and microvascular risks, the classification of low- and high-risk patients was improved by a net reclassification improvement of 5.7% (P = 0.02). CONCLUSIONS-The risk engine accurately predictsmacro- and microvascular complications and would provide helpful information in risk classification and health economic simulations. © 2013 by the American Diabetes Association.


Tanaka S.,Kyoto University | Iimuro S.,University of Tokyo | Akanuma Y.,Institute for Adult Diseases | Ohashi Y.,University of Tokyo | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Previous studies on the association between body mass index (BMI) and mortality in diabetes do not necessarily provide a comprehensive view in terms of the global population because of the exclusion of individuals with a BMI less than 18.5 kg/m2. Objective: The objective of the study was to examine the association between BMI and mortality. Design, Setting, and Participants: We analyzed pooled data from 2 cohorts of 2620 Japanese patients with type 2 diabetes followed up for 6.3 years. Patients with a history of cardiovascular disease or cancer were excluded. Main Outcome Measure: The end point was all-cause mortality. Hazard ratios were estimated by Cox regression adjusted for age, smoking, leisure-time physical activity, and other confounders. Results: An analysis using BMI categories of 14.4-18.5 (5.2%), 18.5-22.4 (37.3%), 22.5-24.9 (31.0%), and 25.0-37.5 kg/m2 (26.6%) revealed no significant trend in mortality among patients with a BMI of 18.5 kg/m2 or greater (trend P = .69). In contrast, the hazard ratio of patients with a BMI less than 18.5 kg/m2 vs 22.5-24.9 kg/m2 was 2.58 (95% confidence interval 1.38-4.84; P < .01). Exclusion of deaths in the first 4 years of follow-up decreased the hazard ratio only slightly. Conclusions: The lowest mortality rate was observed among patients with a BMI of 18.5-24.9 kg/m2, and obesity hadnobenefits regarding mortality. Further research is needed in lean patients, especially among aging populations in East Asia. Copyright © 2014 by the Endocrine Society.


Takata A.,University of Tokyo | Otsuka M.,University of Tokyo | Yoshikawa T.,University of Tokyo | Kishikawa T.,University of Tokyo | And 11 more authors.
Hepatology | Year: 2013

MicroRNAs (miRNAs) are small RNAs that regulate the expression of specific target genes. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. We investigated whether deregulation of miRNA machinery components and subsequent functional impairment of miRNAs are involved in hepatocarcinogenesis. Among miRNA-containing ribonucleoprotein complex components, reduced expression of DDX20 was frequently observed in human hepatocellular carcinomas, in which enhanced nuclear factor-κB (NF-κB) activity is believed to be closely linked to carcinogenesis. Because DDX20 normally suppresses NF-κB activity by preferentially regulating the function of the NF-κB-suppressing miRNA-140, we hypothesized that impairment of miRNA-140 function may be involved in hepatocarcinogenesis. DNA methyltransferase 1 (Dnmt1) was identified as a direct target of miRNA-140, and increased Dnmt1 expression in DDX20-deficient cells hypermethylated the promoters of metallothionein genes, resulting in decreased metallothionein expression leading to enhanced NF-κB activity. MiRNA-140-knockout mice were prone to hepatocarcinogenesis and had a phenotype similar to that of DDX20 deficiency, suggesting that miRNA-140 plays a central role in DDX20 deficiency-related pathogenesis. Conclusion: These results indicate that miRNA-140 acts as a liver tumor suppressor, and that impairment of miRNA-140 function due to a deficiency of DDX20, a miRNA machinery component, could lead to hepatocarcinogenesis. (HEPATOLOGY 2013) © 2012 American Association for the Study of Liver Diseases.


Takao T.,Institute for Adult Diseases | Matsuyama Y.,University of Tokyo | Yanagisawa H.,Jikei University School of Medicine | Kikuchi M.,Institute for Adult Diseases | Kawazu S.,Institute for Adult Diseases
Journal of Diabetes and its Complications | Year: 2014

Aims We aimed to evaluate the association between HbA1c variability and mortality due to all causes, cancer, and non-cancer in patients with type 2 diabetes independently of mean HbA1c levels. Methods We enrolled 754 patients with type 2 diabetes who first visited our hospital between 1995 and 1996, had been followed for at least 2 years, and had undergone four or more HbA1c determinations. Patients were followed through June 2012. The standard deviation (SD) or coefficient of variation (CV) was used as a measure of HbA1c variability. Risk of death was evaluated by multivariate Cox proportional hazard models. Results Through June 2012, 63 patients died. Hazard ratios (HRs) for all-cause mortality and non-cancer mortality including cardiovascular diseases (CVD) increased across tertiles of both HbA1cSD and HbA1cCV. HRs for cancer mortality did not increase across tertiles of either HbA1cSD or HbA1cCV. Using a stepwise regression method, both HbA1cSD and HbA1cCV predicted all-cause mortality, especially non-cancer mortality. In contrast, mean HbA1c predicted cancer mortality. Conclusions HbA1c variability is a predictor of all-cause mortality, especially non-cancer mortality including CVD, in patients with type 2 diabetes, independent of mean HbA1c level. In contrast, mean HbA1c, but not HbA1c variability, might predict cancer mortality. © 2014 Elsevier Inc.


Takao T.,Institute for Adult Diseases | Matsuyama Y.,University of Tokyo | Yanagisawa H.,Jikei University School of Medicine | Kikuchi M.,Institute for Adult Diseases | Kawazu S.,Institute for Adult Diseases
Journal of Diabetes and its Complications | Year: 2014

Objective To investigate whether visit-to-visit variability in systolic blood pressure (SBP) can predict development and progression of diabetic nephropathy and retinopathy in patients with type 2 diabetes mellitus (T2DM). Methods From 1995 through 1996, 664 T2DM patients visited our hospital for the first time and were subsequently examined 4 times or more and at least once annually. At first visit, 326 had normoalbuminuria, 644 had an estimated glomerular filtration rate (eGFR) of ≥ 45 ml/min/1.73 m2, 526 had no diabetic retinopathy and 609 had no severe non-proliferative diabetic retinopathy (NPDR). They were followed through June 2012, at the latest. Results Ninety patients developed microalbuminuria, 76 showed decrease of eGFR to < 45 ml/min/1.73 m2, 113 developed mild-moderate NPDR and 50 progression to severe NPDR. The unadjusted, age- and sex-adjusted and multivariate-adjusted hazard ratios for development and progression of nephropathy, but not retinopathy, increased across tertiles of the standard deviation (SD) of SBP. Both the SD and coefficient of variation (CV) of SBP were significant predictors of development and progression of nephropathy, but not retinopathy, independently of mean SBP. Conclusion Visit-to-visit SBP variability is an independent predictor of development and progression of diabetic nephropathy, but not retinopathy, in T2DM patients. © 2014 Elsevier Inc. All rights reserved.

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