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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. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this study was to examine the association between HbA 1c variability and the development of microalbuminuria as defined by an albumin/creatinine ratio ≥3.4 mg/mmol (≥30 mg/g) in at least two of three consecutive urine samples in Japanese patients with type 2 diabetes. Methods: HbA 1c level was measured in 812 serially registered normoalbuminuric adults aged 21–79 years with type 2 diabetes. After registration, a 1-year period to establish baseline values for mean HbA 1c and HbA 1c variability (measured as the intrapersonal SD of serially collected HbA 1c) was decided upon. The association between HbA 1c variability and the development of microalbuminuria was determined by Cox regression analysis after adjustment for other risk factors for microalbuminuria. Results: Microalbuminuria occurred in 193 patients during the observation period of (mean ± SD) 4.3 ± 2.7 years. Even after adjustment for mean HbA 1c, HbA 1c variability was a significant predictor of microalbuminuria independently of the mean HbA 1c; the HR for every 1% (95% CI) increase in mean HbA 1c was 1.22 (1.06, 1.40) ( p = 0.005), and that for HbA 1c variability was 1.35 (1.05, 1.72) ( p = 0.019). The effects of these two variables were quite similar when 1 SD was used; the HR for every 1 SD increase (95% CI) in HbA 1c was 1.23 (1.07, 1.43) ( p = 0.005), and that for HbA 1c variability was 1.20 (1.03, 1.39) ( p = 0.019). Conclusions/interpretation: HbA 1c variability affects the development of microalbuminuria independently of mean HbA 1c in type 2 diabetes. Further studies should be performed to evaluate the influence of HbA 1c variability on other complications and in individuals of other ethnicities with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: In type 2 diabetic patients at low risk for cardiovascular disease (CVD), the relationship between the clinical course of nephropathy by stage of chronic kidney disease (CKD) and onset of CVD remains unclear. Clarification of this relationship is important for clinical decision-making for both low- and high-risk diabetic patients. Methods: This 4 year prospective study enrolled 2,954 type 2 diabetic patients with no prevalent CVD, and serum creatinine <176.8 μmol/l. The risk for CVD onset (non-fatal and fatal CVD and stroke, and peripheral arterial disease) was assessed according to CKD stage categorised by urinary albumin-to-creatinine ratio (ACR; mg/mmol) and estimated GFR (eGFR; ml min 1.73 m). Association of progression from 'no CKD' stage (ACR <3.5 mg/mmol and eGFR ≥90 ml min 1.73 m) with risk for CVD onset was also evaluated. Results: During follow-up (median 3.8 years), 89 CVD events occurred. Compared with patients with 'no CKD' as reference, those with ACR ≥ 35.0 mg/mmol with co-existing eGFR 60-89 ml min 1.73 m or <60 ml min 1.73 m showed increased risk for CVD onset, whereas those with eGFR ≥90 ml min 1.73 m did not. Those with ACR <3.5 mg/mmol and eGFR <60 ml min 1.73 m did not show any increased risk. Among patients with 'no CKD' stage at baseline, those who progressed to ACR ≥3.5 mg/mmol during follow-up showed an increased risk compared with those who did not, whereas those who progressed to eGFR <90 ml min 1.73 m did not have increased risk. Conclusions/interpretation: The risk for CVD was associated with progression of albuminuria stage rather than eGFR stage in type 2 diabetic patients at relatively low risk for CVD. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this study was to determine the incidence and progression rates of diabetic retinopathy and their associations in Japanese individuals with type 2 diabetes. Methods: This is a part of the Japan Diabetic Complications Study (JDCS), a multi-centred randomised trial of type 2 diabetes patients aged 40-70 years with an 8 year follow-up. There were 1,221 patients without diabetic retinopathy at baseline; incidence of diabetic retinopathy was defined as the development of any diabetic retinopathy. There were 410 patients with mild non-proliferative diabetic retinopathy at baseline; progression of diabetic retinopathy was defined as the development of severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy. We used multivariate proportional Cox hazard models, and generalised additive models were also applied to identify potential threshold effect. Results: The incidence and progression rate of diabetic retinopathy was 38.3/1,000 person-years and 21.1/1,000 person-years, respectively. Higher HbA (adjusted HR [aHR] per 1% [10.9 mmol/mol] 1.36 [95% CI 1.28-1.45]), longer duration of diabetes (aHR per 5 year period 1.26 [95% CI 1.17-1.35]), higher systolic blood pressure (aHR per +10 mmHg 1.01 [95% CI 1.00-1.02]) and higher body mass index (aHR per 1 kg/m 1.05 [95% CI 1.00-1.09]) were associated with incident diabetic retinopathy. The association between HbA and incident diabetic retinopathy was linear; the association with duration of diabetes increased rapidly between 5 and 10 years. Higher HbA was also associated with progression of diabetic retinopathy (aHR per 1% [10.9 mmol/mol] 1.66 [95% CI 1.41-1.96]). Conclusions: Observed incidence and progression rates of diabetic retinopathy seemed lower than that in western populations. HbA was the only factor associated with both incidence and progression of diabetic retinopathy. The strength of the association between duration of diabetes and incidence of diabetic retinopathy increased rapidly during a period of 5 to 10 years duration of diabetes. Trial registration:: C000000222 () Funding:: This study is supported by the Ministry of Health, Labour and Welfare, Japan. [ABSTRACT FROM AUTHOR]

ims/hypothesis: The aim of the study was to determine the transition rate and factors associated with the progression of normo- and low microalbuminuria to diabetic nephropathy (overt proteinuria). Methods: For 8 years we prospectively observed 1,558 Japanese patients with type 2 diabetes mellitus whose basal urinary albumin:creatinine ratio (UACR) had been measured as <17.0 mg/mmol at entry. The incidence of nephropathy (UACR >33.9 mg/mmol) was determined by measuring UACR twice a year. Results: Progression to nephropathy occurred in 74 patients. The annual transition rate was 0.67%, and was substantially higher for the low-microalbuminuric group than for the normoalbuminuric group (1.85% and 0.23%, respectively; hazard ratio for the low-microalbuminuric group 8.45, p < 0.01). The hazard ratio for an HbA of 7-9% or ≥9% was 2.72 ( p < 0.01) or 5.81 ( p < 0.01) relative to HbA <7.0%, respectively. In comparison with individuals with a systolic blood pressure (SBP) of <120 mmHg, the hazard ratios for patients with an SBP of 120-140 mmHg or ≥140 mmHg were 2.31 ( p = 0.06) and 3.54 ( p < 0.01), respectively. Smoking also affected progression to proteinuria (hazard ratio 1.99, p < 0.01). In contrast, 30.3% of the low-microalbuminuric group returned to normoalbuminuria (i.e. were in remission). Conclusions/interpretation: These results suggest that if patients with type 2 diabetes mellitus are receiving treatment from diabetologists for hyperglycaemia and hypertension when they are in the early stages of nephropathy (i.e. normo- or low microalbuminuria), their rate of transition to proteinuria is considerably lowered, and that differentiating patients with low microalbuminuria from those with high microalbuminuria might be clinically useful. Trial registration: UMIN Clinical Trials Registry C000000222 Funding: The study was funded by the Ministry of Health, Labour and Welfare, Japan. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: During the pathogenesis of type 2 diabetes insulin resistance causes compensatory proliferation of beta cells. As beta cells have a limited replication potential, this compensatory proliferation might accelerate cellular senescence and lead to diabetes. We examined the cellular senescence of beta cells after proliferation during lipoglucotoxicity., Methods: Senescence-associated markers in beta cells were examined in nutrient-induced diabetic C57BL/6J mice that were fed a high-fat diet. After 4 and 12 months of the high-fat diet, intraperitoneal glucose tolerance tests (IPGTTs) and histochemical analyses of Ki-67, p38, senescence-associated beta-galactosidase, and beta cell mass were performed., Results: At 4 months, the AUC for plasma insulin levels during the IPGTT (AUC(insulin)) was higher, beta cell mass was 3.1-fold greater, and the proliferation of beta cells was 2.2-fold higher than in the control group. However, at 12 months, AUC(insulin) declined, the frequency of Ki-67-positive beta cells decreased to one-third that of the control group, and the senescence-associated, beta-galactosidase-positive area increased to 4.7-fold that of the control group. Moreover, small amounts of p38, which is induced by oxidative stress and mediates cellular senescence, were found in beta cells from the high-fat diet group, but not in beta cells from the control group. Furthermore, the senescence-associated, beta-galactosidase-positive area in the high-fat diet group had a highly significant negative correlation with AUC(insulin) (r=-0.852, p<0.01)., Conclusions/interpretation: Beta cell senescence occurred in diet-induced type 2 diabetes and led to insufficient insulin release. These findings suggest that cellular senescence contributes to the pathogenesis of diet-induced diabetes.