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Background: Serum gamma-glutamyltransferase has been recognized as the risk factor of cardiovascular and metabolic diseases. However, the association between serum gamma-glutamyltransferase and the risk of chronic kidney disease is not well known, and no prospective studies have examined separately the relationship of serum gamma-glutamyltransferase with the risk of proteinuria versus that of low estimated glomerular filtration rate (eGFR). Methods: We prospectively followed 9,341 Japanese men who did not have low eGFR, proteinuria, or diabetes, and did not take antihypertensive medications at entry for the analysis of proteinuria, and we followed 9,299 men for the analysis of low eGFR. We defined “persistent proteinuria” as proteinuria detected two or more times consecutively and persistently as ≥1+ on urine dipstick at the annual check-up until the end of follow-up. Low eGFR was defined as eGFR

AIMS: We examined the longitudinal association between change in body composition directly measured by computed tomography (CT) and future insulin sensitivity. METHODS: This was a prospective study with 10 years of follow-up with 297 Japanese-American without diabetes. Intra-abdominal fat area (IAFA) and abdominal subcutaneous fat area (SCFA), and thigh SCFA were measured by CT. Insulin sensitivity was calculated by HOMA-IR and the Matsuda index. RESULTS: Baseline and change in IAFA were significantly and independently associated with change in HOMA-IR and Matsuda index during follow-up. In multivariate analysis, IAFA and 10-year change in IAFA (Δ IAFA) was significantly and positively associated with 10-year HOMA-IR (p

Although glomerular hyperfiltration (GHF) is a major risk of diabetic nephropathy and it is important to prevent GHF in subjects with prediabetes, it is not known which factors are associated with the risk of GHF. We prospectively examined the relationship of alcohol consumption and smoking habits to the risk of GHF in subjects with impaired fasting glucose (IFG). Study population was 2811 middle-aged Japanese men who had IFG, no proteinuria, no GHF, and no low estimated glomerular filtration rate (eGFR) at baseline, and who did not have low eGFR before the onset of GHF during the follow-up period. GHF was defined as eGFR ≥117 mL/min/1.73 m2, which was the upper 2.5th percentile value of eGFR in the all study population of our cohort. Low eGFR was defined as eGFR In conclusion, high daily alcohol consumption and current smoking increased the risk of GHF in subjects with IFG. Disclosure M. Shibata: None. T. Hayashi: None. K. K. Sato: None. S. Uehara: None. N. Nishida: None. K. Okamura: None. I. Shibata: None. H. Koh: None. K. Oue: None. M. Morimoto: None.

Leptin and adiponectin are two major adipocytokines reported to be associated with type 2 diabetes. However, it is unknown whether their associations with the risk of incident type 2 diabetes are independent of visceral adiposity and liver fat in a prospective cohort study. We included 787 Japanese men aged 28 to 77 years without type 2 diabetes at baseline. The subjects were classified into four groups based on leptin-adiponectin profile at baseline, with the median concentration value as the cut-off point (median levels of leptin and adiponectin were 4.8 ng/dL and 5.7 µg/mL, respectively): low-high, low-low, high-high, and high-low group. Visceral fat was measured by computed tomography (CT) as intra-abdominal fat area at the umbilicus level. Liver fat was assessed by liver-to-spleen attenuation ratio measured by CT. Type 2 diabetes was diagnosed as fasting plasma glucose level ≥126 mg/dL, HbA1c ≥6.5%, or taking oral hypoglycemic medications or insulin. Cox proportional hazard models were used to estimate hazard ratios (HR) for developing type 2 diabetes. During 5215 person-years of follow-up, 72 subjects developed type 2 diabetes. Incidence rates of type 2 diabetes per 1000 person-years were 3.2, 9.2, 18.6, and 26.1 for the low-high, low-low, high-high, and high-low group, respectively. After adjustment for age, smoking status, alcohol consumption, regular physical activity, family history of diabetes, visceral fat, and liver fat, multiple-adjusted HRs (95% CI) of incident type 2 diabetes were 1.87 (0.63-5.50), 2.90 (1.02-8.21), and 3.41 (1.23-9.47) for the low-low, high-high, and high-low group compared with the low-high group. In conclusion, leptin and adiponectin were associated with incident type 2 diabetes independent of both visceral fat and liver fat. Disclosure I. Shibata: None. W. Y. Fujimoto: None. E. J. Boyko: None. T. Hayashi: None. M. Shibata: None. K. K. Sato: None. S. Uehara: None. N. Nishida: None. K. Okamura: None. Y. Yuyama: None. H. Koh: None. Y. Hikita: None.

Prediabetes is a key risk for type 2 diabetes and its remission to normal glucose regulation has been shown to prevent or delay the onset of diabetes. However, which factors play roles in remission is not fully understood. We prospectively examined the relationships between liver enzymes at baseline and future remission from impaired fasting glucose (IFG) to normal fasting glucose (NFG). We included 3334 middle-aged Japanese men with IFG and not taking diabetic medications at baseline. They were followed for up to 11 years. IFG was defined as fasting plasma glucose level 100-125 mg/dL and HbA1c In conclusion, elevated ALT was inversely associated with future remission from IFG to NFG, but AST was not. Disclosure I. Shibata: None. K.K. Sato: None. M. Shibata: None. H. Koh: None. S. Uehara: None. K. Oue: None. H. Kambe: None. M. Morimoto: None. T. Hayashi: None.

Decline in kidney function is a major concern for patients with type 2 diabetes. The importance of serum uric acid level as the risk factor for chronic kidney disease (CKD) remains unconfirmed. We therefore evaluated the relationship between baseline serum uric acid level and the risk of incident CKD among men with untreated type 2 diabetes at baseline examination in a 10-11 years prospective cohort study. We included 717 middle-aged Japanese subjects with fasting plasma glucose level ≥126 mg/dL or HbA1c ≥6.5% at baseline who were not taking hypoglycemic medications nor insulin, who had an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, who did not have proteinuria nor malignant tumors, and who were not taking anti-hypertensive medications nor urate-lowering medications at baseline. CKD was defined as eGFR During the 5961 person-years follow-up period, 87 subjects developed CKD. Higher serum uric acid level was associated with an increased risk of CKD after adjustment for age, body mass index, systolic blood pressure, diastolic blood pressure, HbA1c, smoking habits (nonsmokers, past smokers, and current smokers), regular leisure-time physical activity (yes/no), daily alcohol consumption (g ethanol/day), and eGFR at baseline. Multiple-adjusted hazard ratios of CKD for quintile 4 (6.2-6.9 mg/dL) and quintile 5 (≥7.0 mg/dL) of serum uric acid levels were 1.30 (95% CI, 0.73-2.30) and 1.80 (95% CI, 1.04-3.11), respectively, compared with quintile 1 to 3 (0.7-6.1 mg/dL). Moreover, when we modeled serum uric acid level as a continuous variable, serum uric acid level per 1.0 mg/dL increase was significantly associated with a 25% increased risk of incident CKD. In conclusion, higher serum uric acid level is independently and significantly associated with an increased risk of CKD in patients with untreated type 2 diabetes. Disclosure Y. Okada: None. K.K. Sato: None. M. Shibata: None. S. Uehara: None. H. Koh: None. K. Oue: None. H. Kambe: None. M. Morimoto: None. T. Hayashi: None.

Aims We compared 20 previously reported indices of insulin sensitivity derived from samples during an oral glucose tolerance test (OGTT) to determine which was best in predicting incident type 2 diabetes. Methods We prospectively followed 418 Japanese Americans without diabetes for 10–11 years. We compared ability to predict incident diabetes of 20 insulin sensitivity indices—9 based on fasting samples, 7 based on 2-h and/or fasting samples, and 4 based on multiple samples (0, 30, 60, 120 min) during an OGTT—by integrated discrimination improvement, category free net reclassification improvement, and area under the receiver operator characteristic curve. Results There were 95 incident cases of diabetes. The Cederholm and Gutt indices, requiring more than only fasting samples, were the best to predict incident diabetes as judged by integrated discrimination improvement (0.187, 0.184), category free net reclassification improvement (0.962, 1.030), and area under the receiver operator characteristic curve (0.864, 0.863, respectively). Fasting indices were clearly inferior to both the Cederholm and Gutt indices. Conclusions Among the 20 indices, the Cederholm and Gutt indices predicted diabetes best but the Gutt index may be preferable because it requires fewer samples during an OGTT.

Background We examined prospectively which of the four blood pressure (BP) components (systolic BP [SBP], diastolic BP [DBP], pulse pressure [PP], and mean arterial pressure [MAP]) was best in predicting the risk of proteinuria. Methods This prospective study included 9341 non-diabetic Japanese middle-aged men who had no proteinuria and an estimated glomerular filtration rate ≥60 mL/min/1.73 m2 and were not taking antihypertensive medications at entry. Persistent proteinuria was defined if proteinuria was detected two or more times consecutively and persistently at the annual examination until the end of follow-up. We calculated the difference in values of Akaike's information criterion (ΔAIC) in comparison of the BP components-added model to the model without them in a Cox proportional hazards model. Results During the 84,587 person-years follow-up period, we confirmed 151 cases of persistent proteinuria. In multiple-adjusted models that included a single BP component, the hazard ratios for persistent proteinuria for the highest quartile of SBP, PP, and MAP were 3.11 (95% confidence interval [CI], 1.79–5.39), 1.87 (95% CI, 1.18–2.94), and 2.21 (95% CI, 1.33–3.69) compared with the lowest quartile of SBP, PP, and MAP, respectively. The hazard ratio for the highest quartile of DBP was 2.69 (95% CI, 1.65–4.38) compared with the second quartile of DBP. Of all models that included a single BP component, those that included SBP alone or DBP alone had the highest values of ΔAIC (14.0 and 13.1, respectively) in predicting the risk of persistent proteinuria. Conclusions Of all BP components, SBP and DBP were best in predicting the risk of persistent proteinuria in middle-aged Japanese men., Highlights • We examined which blood pressure (BP) components increased risk of proteinuria. • We used systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. • Systolic and diastolic BP were the best predictors of persistent proteinuria.

The β-cell plays a major role in type 2 diabetes (T2DM). HOMA-β reflects fasting β-cell activity. Insulin responses during an OGTT reflect β-cell activity during glucose loading, which has two phases, early and late. HOMA-β, early, and late β-cell activity have different pathophysiologies. However, no research has examined whether HOMA-β and early and late phase β-cell activity during an OGTT are independently associated with the risk of T2DM. In a prospective cohort study, 415 nondiabetic Japanese-American men and women were followed for 10-11 years. β-cell activity was assessed by HOMA-β [fasting insulin × 360/(fasting glucose − 63)] as fasting activity, the insulinogenic index (IGI) [?insulin (30-0 min)/?glucose (30-0 min)] during an OGTT as early phase activity, and (area under the curve (AUC) of insulin 60-120 min)/(AUC glucose 60-120 min) as late phase activity. Insulin sensitivity was estimated by Matsuda index [10000/square root of ((fasting glucose) × (fasting insulin) × (AUC glucose 0-120 min/120) × (AUC insulin 0-120 min/120))]. T2DM was diagnosed as fasting plasma glucose level ≥126 mg/dL, 2-hour glucose level ≥200 mg/dL, or taking glucose-lowering medications. During the 10-11 year follow-up, 95 cases of T2DM occurred. HOMA-β, IGI, and late phase β-cell activity were all independently associated with the risk of T2DM. Multiple-adjusted odds ratios of T2DM for tertile 1, 2, and 3 of HOMA-β were 1.00 (reference), 0.25 (95% CI, 0.11-0.57), and 0.14 (0.05-0.37), respectively; those of IGI were 1.00, 0.35 (0.17-0.75), and 0.19 (0.07-0.47), respectively; and those of late phase β-cell activity were 1.00, 0.34 (0.14-0.82), and 0.16 (0.05-0.53), respectively, in the model that included HOMA-β, IGI, late phase β-cell activity, Matsuda index, age, BMI, sex, and family history of T2DM. In conclusion, higher β-cell activity while fasting and in both the early and late phase during an OGTT were all independently associated with a lower risk of T2DM. Disclosure T. Shimojo: None. C. Izumi: None. K.K. Sato: None. D.L. Leonetti: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. W.Y. Fujimoto: None. E.J. Boyko: None. T. Hayashi: None.

Background: Previous studies showed that higher serum uric acid levels increased the risk of chronic kidney disease (CKD), but moderate alcohol consumption decreased it. The comparative importance of serum uric acid levels and habitual alcohol consumption as risk factors for CKD remain undefined. We therefore evaluated the relationship of baseline serum uric acid level in combination with daily alcohol consumption to the incidence of CKD. Methods: A prospective cohort study of 9,116 middle-aged nondiabetic ­Japanese men without CKD nor proteinuria who were not taking antihypertensive medications nor urate-lowering medications at entry. CKD was defined as estimated glomerular filtration rate 2. We investigated the relationship of baseline serum uric acid level in combination with daily alcohol consumption to the incidence of CKD during an 11-year observation period. Daily alcohol consumption was classified into 4 groups: nondrinkers, light drinkers (0.1–23.0 g ethanol/day), moderate drinkers (23.1–46.0 g ethanol/day), and heavy drinkers (≥46.1 g ethanol/day). Cox proportional hazards models were used in multivariate analysis. Results: During the 79,361 person-years follow-up period, a total of 1,230 subjects developed CKD. In multivariate models, higher serum uric acid levels increased risk of CKD; and moderate daily alcohol consumption decreased the risk. Multiple-adjusted hazard ratios of CKD were 1.38 (95% CI 1.11–1.70), 1.58 (95% CI 1.28–1.95), 2.27 (95% CI 1.86–2.77), and 3.12 (95% CI 2.56–3.81) for quintile 2, quintile 3, quintile 4, and quintile 5 of serum uric acid levels, respectively, compared with quintile 1, and that for moderate drinkers was 0.55 (95% CI 0.46–0.66) compared with nondrinkers. In the joint analysis of alcohol consumption and serum uric acid, moderate drinkers with the lowest tertile of serum uric acid levels had the lowest risk of CKD, but nondrinkers with the highest tertile of serum uric acid levels had the highest risk of CKD. Conclusions: Serum uric acid level and daily alcohol consumption were independently associated with the risk of CKD. Nondrinkers with the highest serum uric acid level had the highest risk of CKD.

Objective To examine cross-sectionally whether intraabdominal fat area (IAFA), i.e., visceral fat, and liver fat assessed by computed tomography (CT) are independently associated with hyperuricemia. Methods Subjects were 801 Japanese men not taking antidiabetic, antihypertensive, or urate-lowering medications, without any history of renal disease, cardiovascular disease, or cancer, and with serum creatinine 7.0 mg/dl. Its association with adiposity was tested using logistic regression. Results The prevalence of hyperuricemia was 19.6% (157 men). Both greater IAFA and lower L/S ratio were independently associated with hyperuricemia in models that simultaneously included IAFA and L/S ratio: multiple-adjusted odds ratios of hyperuricemia for quintiles 3, 4, and 5 of IAFA were 2.16 (95% confidence interval [95% CI] 1.02–4.59), 2.41 (95% CI 1.13–5.16), and 4.00 (95% CI 1.81–8.85), respectively, compared to quintile 1, and the L/S ratios for quintiles 3, 2, and 1 were 2.34 (95% CI 1.16–4.75), 2.15 (95% CI 1.06–4.34), and 2.79 (95% CI 1.35–5.76), respectively, compared to quintile 5. Both IAFA and L/S ratio remained significant even after adjusting for abdominal subcutaneous fat area, TFA, TSFA, body mass index, or waist circumference. Of all fat measurements, IAFA had the strongest association with hyperuricemia by Akaike's information criteria. Conclusion Greater amounts of both visceral fat and liver fat were independently associated with hyperuricemia.

Background: In 2013, an unusually high incidence of biliary tract cancer among current or former workers of the offset color proof printing department of a printing company in Osaka, Japan, was reported. The purpose of this study was to examine whether distance from the printing factory was associated with incidence of biliary tract cancer and whether incident biliary tract cancer cases clustered around the printing factory in Osaka using population-based cancer registry data. Methods: We estimated the age-standardized incidence ratio of biliary tract cancer according to distance from this printing factory. We also searched for clusters of biliary tract cancer incidence using spatial scan statistics. Results: We did not observe statistically significantly high or low standardized incidence ratios for residents in each area categorized by distance from the printing factory for the entire sample or for either sex. The scan statistics did not show any statistically significant clustering of biliary tract cancer incidence anywhere in Osaka prefecture in 2004–2007. Conclusions: There was no statistically significant clustering of biliary tract cancer incidence around the printing factory or in any other areas in Osaka, Japan, between 2004 and 2007. To date, even if some substances have diffused outside this source factory, they do not appear to have influenced the incidence of biliary tract cancer in neighboring residents.

Aims Visceral adiposity measured by computed tomography (CT) as intra-abdominal fat area (IAFA) predicts metabolic diseases. Existing adiposity surrogates have not been systematically compared to a regression-based model derived in individuals of Japanese ancestry. We developed and validated a method to estimate IAFA in individuals of Japanese ancestry and compared it to existing adiposity surrogates. Methods We assessed age, BMI, waist circumference (WC), fasting lipids, glucose, smoking status, grip strength, mid-thigh circumference (MTC), humeral length, leg length, and IAFA by single-slice CT at the umbilicus for 622 Japanese Americans. We used stepwise linear regression to predict IAFA and termed the predicted value the Estimate of Visceral Adipose Tissue Area (EVA). For men, the final model included age, BMI, WC, high-density lipoprotein cholesterol (HDLc), glucose, and MTC; for women, age, BMI, WC, HDLc, low-density lipoprotein cholesterol, glucose, and MTC. We compared goodness-of-fit (R2) from linear regression models and mean-squared errors (MSE) from k-fold cross-validation to compare the ability of EVA to estimate IAFA compared to an estimate by Despres et al., waist-to-height ratio, WC, deep abdominal adipose tissue index, BMI, lipid accumulation product, and visceral adiposity index (VAI). We classified low/high IAFA using area under receiver-operating characteristic curves (AUROC) for IAFA dichotomized at the 75th percentile. Results EVA gave the least MSE and greatest R2 (men: 1244, 0.61; women: 581, 0.72). VAI gave the greatest MSE and smallest R2 (mean 2888, 0.08; women 1734, 0.14). Conclusions EVA better predicts IAFA in Japanese-American men and women compared to existing surrogates for adiposity.

Lipid profile abnormalities have been reported to be associated with cardiometabolic diseases, but it is not fully known whether lipid profile abnormalities are prospectively associated with the risk of proteinuria in subjects with impaired fasting glucose (IFG) or type 2 diabetes. Study subjects included 3801 Japanese men aged 40-55 years who had fasting plasma glucose ≥100 mg/dL, no proteinuria, eGFR ≥60 mL/min/1.73 m2, and no history of cancer and were not taking antihypertensive, lipid-lowering, and hypoglycemic medications at baseline. The incidence of proteinuria was defined as “consecutive proteinuria” if it was detected twice consecutively as 1+ or higher on urine dipstick during the follow-up periods to exclude chance proteinuria as much as possible. Triglycerides, HDL-cholesterol, non HDL-cholesterol, and LDL-cholesterol levels were obtained at baseline. During the 11-year follow-up period, we confirmed 221 cases of proteinuria. In Cox proportional-hazards analysis, higher level of triglycerides increased the risk of proteinuria and higher level of HDL-cholesterol decreased the risk of proteinuria. After adjustment for age, eGFR, fasting plasma glucose, hypertension status, alcohol consumption, regular physical activity, and smoking status, hazard ratios (HRs) for triglycerides levels of 100-149, 150-199, and ≥200 mg/dL were 1.07 (95% CI, 0.73-1.55), 1.22 (0.80-1.84), and 1.47 (1.01-2.13), respectively, compared with In conclusion, higher level of triglycerides increased the risk of incident consecutive proteinuria and higher level of HDL-cholesterol decreased it in the middle-aged Japanese men with IFG or type 2 diabetes. Disclosure S. Uehara: None. K. Sato: None. M. Shibata: None. K. Oue: None. H. Kambe: None. M. Morimoto: None. T. Hayashi: None.

Both diet and visceral adiposity play key roles in cardiometabolic disease. However, the association between dietary fat and subsequent visceral fat accumulation is not known. Thus, we prospectively examined future visceral fat accumulation in relation to dietary intake of animal and plant fats, or saturated and polyunsaturated fats in 312 nondiabetic Japanese-American men and women. Visceral adiposity was measured as intra-abdominal fat (IAF) area at the umbilicus by computed tomography at baseline and 10-11 years. Detailed dietary information was assessed at baseline using a food frequency questionnaire and 24-hour recall. Insulin sensitivity was evaluated by homeostasis model assessment for insulin resistance (HOMA-IR) and insulin response by the insulinogenic index (IGI) [Δinsulin/Δglucose (30-0 minutes)]. After adjustment for baseline IAF, age, sex, smoking habits (non-smokers, past-smokers, current smokers), physical activity, alcohol consumption, HOMA-IR, IGI, total protein intake, and total carbohydrate intake in multiple linear regression models, baseline log transformed animal fat intake [coefficient=15.319 (P=0.002)], but not plant fat intake [0.163 (P=0.270)], was associated with future IAF change. In the model that included saturated and polyunsaturated fat substituted for animal and plant fat intake, saturated fat was associated with future IAF change in both men [0.892 (P=0.030)] and women [1.121 (P=0.022)], but a statistically significant interaction was present between sex and polyunsaturated fat, such that polyunsaturated fat intake was inversely associated with future IAF change in men [-1.290 (P=0.003)], but not women [-0.058 (P=0.905)]. In conclusion, in both men and women, higher intake of animal fat and saturated fat, not plant fat, precede more visceral fat accumulation, while in men only, higher polyunsaturated fat intake precedes less visceral fat accumulation. Disclosure T. Hayashi: None. K. Sato: None. D.L. Leonetti: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim GmbH, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Research & Development, Merck & Co., Inc., Novo Nordisk A/S. S. Uehara: None. W.Y. Fujimoto: None. E.J. Boyko: None.

Visceral fat, liver, and skeletal muscle are all major target organs of insulin and play key roles in the pathophysiology of type 2 diabetes. Not known is whether visceral fat, liver fat, and thigh skeletal muscle area or fat directly measured by computed tomography (CT) are independently associated with the incidence of type 2 diabetes. In a prospective cohort study, 1228 nondiabetic Japanese men and women were included. Intra-abdominal fat area (IAFA), liver-to-spleen (L/S) attenuation ratio to assess liver fat, and mid-thigh muscle area and attenuation were measured by CT. Low CT attenuation of liver and muscle reflects greater liver and intramuscular lipid content. Insulin resistance was assessed by HOMA-IR. Type 2 diabetes was diagnosed as fasting plasma glucose level ≥126 mg/dL, HbA1c ≥6.5%, or taking oral hypoglycemic medications or insulin. Discrete-time logistic hazard model was used. During the 7686 person-years of follow-up (median follow-up period, 7 years), 95 subjects developed type 2 diabetes. IAFA and L/S ratio, not thigh muscle area, were independently associated with the risk of type 2 diabetes. In multiple-adjusted models that included IAFA, L/S ratio, thigh muscle area, age, gender, family history of diabetes, HOMA-IR, smoking habit, daily alcohol consumption, and regular physical activity, odds ratios of type 2 diabetes for tertile 2 and 3 of IAFA were 2.23 (95% CI, 0.94-5.31) and 3.16 (1.33-7.52), respectively, compared to tertile 1, and those for tertile 1 and 2 of L/S ratio were 2.01 (1.01-3.97) and 2.(1.04-4.08), respectively, compared to tertile 3. However, those of tertile 2 and 3 of thigh muscle area were 0.76 (0.32-1.78) and 0.64 (0.24-1.69), respectively, compared to tertile 1. When thigh muscle attenuation was substituted for its area, results was identical to the above model. In conclusion, both greater amounts of visceral and liver fat, not thigh muscle area nor attenuation, were independently associated with the risk of type 2 diabetes. Disclosure K. Sato: None. S. Uehara: None. M. Shibata: None. Y. Hikita: None. W.Y. Fujimoto: None. E.J. Boyko: None. T. Hayashi: None.

Background Metabolically healthy obesity seems to be a unique phenotype for the risk of cardiometabolic diseases. However, it is not known whether this phenotype is associated with the risk of proteinuria. Methods Study subjects were 9,185 non-diabetic Japanese male workers aged 40-55 years who had no proteinuria, an estimated glomerular filtration rate ≥60 mL/min/1.73 m2, no history of cancer, and no use of antihypertensive or lipid-lowering medications at baseline. Obesity was defined as body mass index ≥25.0 kg/m2. Metabolic health was defined as the presence of no Adult Treatment Panel III components of the metabolic syndrome criteria, excluding waist circumference, and metabolic unhealth was defined as the presence of one or more metabolic syndrome components, excluding waist circumference. "Consecutive proteinuria" was considered positive if proteinuria was detected twice consecutively as 1+ or higher on urine dipstick at annual examinations to exclude chance proteinuria as much as possible. Results During the 81,660 person-years follow-up period, we confirmed 390 cases of consecutive proteinuria. Compared with metabolically healthy non-obesity, metabolically healthy obesity was not associated with the risk of consecutive proteinuria (multiple-adjusted hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.37-1.99), but metabolically unhealthy non-obesity with ≥2 metabolic syndrome components (HR 1.77; 95% CI, 1.30-2.42), metabolically unhealthy obesity with one component (HR 1.71; 95% CI, 1.12-2.61), and metabolically unhealthy obesity with ≥2 metabolic syndrome components (HR 2.77; 95% CI, 2.01-3.82) were associated with an increased risk of consecutive proteinuria. Conclusions Metabolically healthy obesity did not increase the risk of consecutive proteinuria in Japanese middle-aged men.

Aims To describe the roles of intra-abdominal fat and its change in the remission of impaired glucose tolerance (IGT) to normal glucose tolerance (NGT). Methods We followed 157 Japanese Americans with IGT at baseline for 10–11 years without external intervention. We measured intra-abdominal and abdominal subcutaneous fat area (IAFA and ASFA) by computed tomography at baseline and at 5–6 years of follow-up. Change in IAFA and ASFA (ΔIAFA and ΔASFA) were calculated by subtracting baseline fat area from 5–6 year follow-up fat area. Glucose and insulin at fasting and during a 75-g oral glucose tolerance test, insulinogenic index (IGI [Δinsulin/Δglucose (30–0 min)]) and homeostasis model assessment for insulin resistance (HOMA-IR) were measured at baseline. Results Fourty-four subjects remitted to NGT. Among those with lower IAFA (≤median 91.31 cm2) and the lowest tertile of ΔIAFA, 45% remitted, while with higher IAFA (>91.31 cm2) and the highest tertile of ΔIAFA, only 12.5% remitted. ΔIAFA was significantly associated with remission to NGT (multiple-adjusted odd ratio [1-SD decrease] 1.93, 95% CI 1.10–3.36) independent of IAFA, ASFA, ΔASFA, IGI, HOMA-IR, age, sex, and family history of diabetes. Conclusions In the natural history of IGT, change in intra-abdominal fat was associated with remission to NGT.

Risk of bile duct cancer among printing workers exposed to 1,2-dichloropropane and/or dichloromethane: Tomotaka SOBUE, et al. Department of Environmental Medicine and Population Sciences, Graduate School of Medicine, Osaka University— Objectives: We conducted a retrospective cohort study to examine the risk of bile duct cancer among current and former workers in the offset color proof printing department at a printing company in Osaka, Japan. Methods: Standardized incidence ratios (SIRs) between January 1, 1985, and December 31, 2012, were estimated for the cumulative years of exposure to two chemicals, dichloromethane (DCM) and 1,2-dichlo- ropropane (1,2-DCP), using the national incidence level as a reference. In addition, we examined risk patterns by the calendar year in which observation started. Results: Among 106 workers with a total of 1,452.4 person-years of exposure, 17 bile duct cancer cases were observed, resulting in an estimated overall SIR of 1,132.5 (95% confidence interval (CI): 659.7−1,813.2). The SIR was 1,319.9 (95% CI: 658.9−2,361.7) for those who were exposed to both DCM and 1,2-DCP, and it was 1,002.8 (95% CI: 368.0−2,182.8) for those exposed to 1,2-DCP only. SIRs tended to increase according to years of exposure to 1,2-DCP but not DCM when a 5- year lag time was assumed. The SIRs were higher for the cohorts in which observation started in 1993−2000, particularly in cohorts in which it started in 1996−1999, compared with those in which it started before or after 1993−2000. Conclusions: We observed an extraor- dinarily high risk of bile duct cancer among the offset color proof printing workers. Elevated risk may be

Background An outbreak of cholangiocarcinoma occurred among workers in the offset color proof-printing department at a printing company in Japan. The aim of this study was to clarify the characteristics of the patients with cholangiocarcinoma. Methods This was a retrospective study conducted in 13 Japanese hospitals between 1996 to 2013. The clinicopathological findings of cholangiocarcinoma developed in 17 of 111 former or current workers in the department were investigated. Most workers were relatively young. Results The cholangiocarcinoma was diagnosed at 25–45 years old. They were exposed to chemicals, including dichloromethane and 1,2-dichloropropane. The serum γ-glutamyl transpeptidase activity was elevated in all patients. Dilated intrahepatic bile ducts without tumor-induced obstruction were observed in five patients. The cholangiocarcinomas arose from the large bile ducts. The precancerous or early cancerous lesions, such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile ducts, as well as non-specific bile duct injuries, such as fibrosis, were observed in various sites of the bile ducts in all eight patients for whom operative specimens were available. Conclusions The present results showed that cholangiocarcinomas occurred at a high incidence in relatively young workers of a printing company, who were exposed to chemicals including chlorinated organic solvents.

Background/Aims: The association between alcohol consumption and the risk of chronic kidney disease (CKD) has been reported. What is not known is whether drinking pattern combined with the weekly frequency of alcohol consumption and the quantity per drinking day is associated with the risk of CKD. Methods: We enrolled 9,112 Japanese nondiabetic men aged 40 to 55 years with absence of proteinuria, an estimated glomerular filtration rate (eGFR) of 60 ml/min/1.73 m2 or higher, and not on antihypertensive medications at baseline. CKD was defined if eGFR was 2. The weekly frequency classification was nondrinkers, 1-3 drinking days/week, or 4-7 drinking days/week. The quantity consumed per drinking day was classified as 0.1-23.0 g ethanol/drinking day, 23.1-46.0 g ethanol/drinking day, 46.1-69.0 g ethanol/drinking day, and ≥69.1 g ethanol/drinking day. Results: During the 79,099 person-years, 1,253 subjects developed CKD. Compared to nondrinkers, those who consumed 23.1-46.0 or 46.1-69.0 g ethanol/drinking day on 4-7 drinking days/week had a decreased risk of CKD (multiple-adjusted hazard ratio (HR) 0.62 (0.52-0.74) and 0.76 (0.59-0.97), respectively). The association between the quantity per drinking day and the incidence of CKD was U-shaped among each category of the weekly frequency. HRs within similar categories of quantity per drinking day were lower in the 4-7 drinking days/week group than in the 1-3 drinking days/week group. Conclusion: Among middle-aged Japanese men, the people who drank middle-range quantity, specifically who drank 4-7 days/week, had lower risk of CKD than nondrinkers.

SummaryObjective Butyrylcholinesterase is synthesized in the liver. The serum butyrylcholinesterase level has been cross-sectionally reported to be higher in patients with diabetes, hyperlipidaemia, obesity and fatty liver than in those without them. It is not known whether serum butyrylcholinesterase is associated with the risk of future type 2 diabetes. Design A prospective cohort study. Participants A total of 8470 Japanese men aged 40–55 years without type 2 diabetes at baseline. Measurements Type 2 diabetes was diagnosed if a fasting plasma glucose (FPG) level was ≥7·0 mmol/l, if a HbA1c level was ≥6·5% or if participants were taking oral hypoglycaemic medication or insulin. Results During the 42 227 person-years of follow-up, 868 cases had developed type 2 diabetes. Serum butyrylcholinesterase was significantly positively correlated with body mass index (BMI), FPG, alanine aminotransferase (ALT), γ-glutamyltransferase (GGT) and triglycerides (TG), whereas negatively with high-density lipoprotein (HDL) cholesterol. In Cox proportional hazards models, after adjusting for age, BMI, FPG, alcohol consumption, smoking habit, walk to work, regular leisure-time physical activity and family history of diabetes, the highest quartile (398–806 IU/l) of serum butyrylcholinesterase increased the risk of type 2 diabetes compared with the lowest quartile (56–311 IU/l) [hazard ratio (HR) 1·41 (95% confidence interval (CI), 1·14–1·74)]. After further adjusting for ALT and GGT, this association remained [HR 1·40 (95% CI, 1·13–1·73)]. Furthermore, this association was significant independent of TG and HDL cholesterol. Conclusions Elevated serum butyrylcholinesterase was independently associated with an increased risk of future type 2 diabetes.

OBJECTIVE To examine whether the patterns of insulin concentration during the oral glucose tolerance test (OGTT) predict type 2 diabetes. RESEARCH DESIGN AND METHODS We followed 400 nondiabetic Japanese Americans for 10–11 years. Insulin concentrations at 30, 60, and 120 min during a 2-h 75-g OGTT at baseline were used to derive the following possible patterns of insulin: pattern 1 (30-min peak, higher insulin level at 60 than at 120 min), pattern 2 (30-min peak, lower or equal level at 60 vs. 120 min), pattern 3 (60-min peak); pattern 4 (120-min peak, lower level at 30 than at 60 min), and pattern 5 (120-min peak, equal or higher level at 30 vs. 60 min). Insulin sensitivity was estimated by homeostasis model assessment of insulin resistance (HOMA-IR) and Matsuda index. Insulin secretion was estimated by the insulinogenic index (IGI) [Δinsulin/Δglucose (30–0 min)] and disposition index (IGI/HOMA-IR). RESULTS There were 86 incident cases of type 2 diabetes. The cumulative incidence was 3.2, 9.8, 15.4, 47.8, and 37.5% for patterns 1, 2, 3, 4, and 5, respectively. Compared with pattern 1, patterns 4 and 5, characterized by a lasting late insulin response, were associated with significantly less insulin sensitivity as measured by the Matsuda index and lower early insulin response by the disposition index. The multiple-adjusted odds ratios of type 2 diabetes were 12.55 (95% CI 4.79–32.89) for pattern 4 and 8.34 (2.38–29.27) for pattern 5 compared with patterns 1 and 2. This association was independent of insulin secretion and sensitivity. CONCLUSIONS The patterns of insulin concentration during an OGTT strongly predict the development of type 2 diabetes.

Background Moderate alcohol consumption has been reported to be associated with a decreased risk of cardiometabolic diseases. Whether drinking pattern is associated with the risk of proteinuria is unknown. Methods Study subjects were 9154 non-diabetic Japanese men aged 40-55 years, with an estimated glomerular filtration rate ≥60 mL/min/1.73 m(2), no proteinuria, and no use of antihypertensive medications at entry. Data on alcohol consumption were obtained by questionnaire. We defined "consecutive proteinuria" as proteinuria detected twice consecutively as 1+ or higher on urine dipstick at annual examinations. Results During the 81 147 person-years follow-up period, 385 subjects developed consecutive proteinuria. For subjects who reported drinking 4-7 days per week, alcohol consumption of 0.1-23.0 g ethanol/drinking day was significantly associated with a decreased risk of consecutive proteinuria (hazard ratio [HR] 0.54; 95% confidence interval [CI], 0.36-0.80) compared with non-drinkers. However, alcohol consumption of ≥69.1 g ethanol/drinking day was significantly associated with an increased risk of consecutive proteinuria (HR 1.78; 95% CI, 1.01-3.14). For subjects who reported drinking 1-3 days per week, alcohol consumption of 0.1-23.0 g ethanol/drinking day was associated with a decreased risk of consecutive proteinuria (HR 0.76; 95% CI, 0.51-1.12), and alcohol consumption of ≥69.1 g ethanol/drinking day was associated with an increased risk of consecutive proteinuria (HR 1.58; 95% CI, 0.72-3.46), but these associations did not reach statistical significance. Conclusions Men with frequent alcohol consumption of 0.1-23.0 g ethanol/drinking day had the lowest risk of consecutive proteinuria, while those with frequent alcohol consumption of ≥69.1 g ethanol/drinking day had an increased risk of consecutive proteinuria.

Aim: The prevalence of underweight women, who have an increased risk for small-for-gestational-age (SGA) birth, is increasing in Japan. We examined the associations of pre-pregnancy body mass index and gestational weight gain (GWG) with SGA birth among Japanese women. Material and Methods: We conducted a prospective cohort study of 1391 women who delivered full-term singleton babies. SGA was defined as below the 10th percentile of birthweight at each gestational age, baby sex, and parity. We calculated the 5th percentile of birthweight in the same way for another threshold for SGA. According to pre-pregnancy body mass index, we divided the participants into three groups: underweight (

Background. Indication of tonsillectomy in IgA nephropathy is controversial. The purpose of this study was to examine the efficacy of tonsillectomy on remission and progression of IgA nephropathy. Methods. We conducted a single-center 7-year historical cohort study in 200 patients with biopsy-proven IgA nephropathy. Study outcomes were clinical remission defined as disappearance of urine abnormalities at two consecutive visits, glomerular filtration rate (GFR) decline defined as 30% GFR decrease from baseline and GFR slope during the follow-up. Results. Seventy of the 200 patients received tonsillectomy. Tonsillectomy was associated with increased incidence of clinical remission (P < 0.01, log-rank test) and decreased incidence of GFR decline (P ¼ 0.01, log-rank test). After adjustment for age and gender, hazard ratios in tonsillectomy were 3.90 (95% confidence interval 2.46–6.18) for clinical remission and 0.14 (0.02–1.03) for GFR decline. After further adjustment for laboratory (baseline mean arterial pressure, GFR, 24-h proteinuria and hematuria score), histological (mesangial score, segmental sclerosis or adhesion, endocapillary proliferation and interstitial fibrosis) or treatment variables (steroid and renin–angiotensin system inhibitors), similar results were obtained in each model. Even after exclusion of 69 steroid-treated patients, results did not change. GFR slopes in tonsillectomy and non-tonsillectomy groups were 0.60 6 3.65 and � 1.64 6 2.59 mL/min/1.73 m 2 /year, respectively. In the multiple regression model, tonsillectomy prevented GFR decline during the follow-up period (regression coefficient 2.00, P ¼ 0.01). Conclusion. Tonsillectomy was associated with a favorable renal outcome of IgA nephropathy in terms of clinical remission and delayed renal deterioration even in non-steroid-treated patients.

Background/Aims: No prospective studies have estimated the association between white blood cell (WBC) count and the risk of proteinuria. We prospectively examined the relationships of WBC count, as a marker of inflammation, with two outcomes: proteinuria and low estimated glomerular filtration rate (eGFR). Methods: We enrolled 10,008 Japanese men aged 40–55 years who had neither proteinuria nor low eGFR and were not taking antihypertensive medications at entry. Proteinuria was defined as 1+ or higher on urine dipstick. Low eGFR was defined if eGFR was 2. Results: During the 49,644 person-years of follow-up, 1,557 cases of proteinuria were confirmed. After adjusting for age, body mass index, fasting plasma glucose, systolic blood pressure, diastolic blood pressure, antidiabetic medications, alcohol consumption, smoking, regular leisure-time physical activity and eGFR, the highest quintile (≧7.51 × 103/µl) of WBC count was independently associated with an increased risk of incidence of proteinuria [HR: 1.45 (95% CI: 1.23–1.73)] compared with the lowest quintile (≤4.80 × 103/µl). On the other hand, during 52,833 person-years, we confirmed 439 cases of low eGFR. In multivariate models, there was no association between WBC count and low eGFR. Conclusion: Elevated WBC count was independently associated with an increased risk of proteinuria, but not low eGFR.

Aims/Introduction: Reduced insulin sensitivity and secretion are important in the pathogenesis of type 2 diabetes. Their relationships to prediabetes, impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have been previously studied with the oral glucose tolerance test (OGTT). We investigated whether or not baseline measures of insulin secretion and sensitivity obtained from fasting blood specimens were related to the development of prediabetes and how these measures compared with those based on the OGTT. Materials and Methods: In 152 Japanese subjects with normal glucose tolerance, we measured baseline plasma glucose and insulin after an overnight fast and during a 75 g OGTT, insulin resistance index (homeostasis model assessment [HOMA‐IR]), and insulin secretion (insulinogenic index [30 min insulin − fasting insulin] ÷ [30 min glucose − fasting glucose] or HOMA‐β). Results: At a 5–6 year (mean 5.7 years) follow‐up examination, we confirmed 36 cases of prediabetes. After adjusting for age, sex, family history of diabetes, body mass index, and 2‐h plasma glucose, the odds ratio comparing the lowest tertile (≤0.82) of insulinogenic index with the highest tertile (≥1.43) was 6.98 (95% confidence interval, 1.96–24.85) and was 10.72 (2.08–55.3) comparing the lowest tertile (≤76.3) of HOMA‐β with the highest tertile (≥122.1), whereas the respective odds ratios of HOMA‐IR were 3.74 (1.03–13.57) and 10.89 (1.93–61.41) comparing the highest tertile (≥1.95) with the lowest tertile (≤1.25). Conclusions: Lower insulin secretion and sensitivity are independent risk factors for prediabetes. Clinically practical identification of those at risk for prediabetes is obtainable from HOMA‐β and HOMA‐IR, both of which are measured in fasting state. (J Diabetes Invest, doi: 10.1111.j.2040‐1124.2010.00041.x, 2010)

OBJECTIVE—It has been reported that moderate alcohol consumption decreased the risk of type 2 diabetes but that elevated liver enzymes increased it. The comparative importance of alcohol consumption and liver enzymes as predictors of type 2 diabetes remains unconfirmed. RESEARCH DESIGN AND METHODS—The participants included 8,576 Japanese men, aged 40–55 years, without type 2 diabetes at entry. Type 2 diabetes was diagnosed if a fasting plasma glucose level was ≥126 mg/dl or if participants were taking oral hypoglycemic medications or insulin. RESULTS—During the 4-year follow-up period, we confirmed 878 cases. In multivariate models, moderate daily alcohol consumption (16.4–42.6 g ethanol/day) decreased the risk of type 2 diabetes, and higher levels of γ-glutamyltransferase (GGT) and alanine aminotransferase (ALT) increased the risk. In joint analyses of alcohol consumption and liver enzymes, moderate drinkers with the lowest tertile of GGT had the lowest risk of type 2 diabetes. Compared with them, nondrinkers with the highest GGT had the highest risk of type 2 diabetes (odds ratio 3.18 [95% CI 1.75–5.76]). At every level of GGT, moderate or heavy alcohol drinkers (≥42.7 g ethanol/day) had a lower risk of type 2 diabetes than nondrinkers. The relationship of ALT and daily alcohol consumption with the risk of type 2 diabetes was almost the same as that of GGT. CONCLUSIONS—GGT, ALT, and daily alcohol consumption were independently associated with the risk of type 2 diabetes. Nondrinkers with the highest GGT or ALT had a high risk of type 2 diabetes.

Objectives This study aimed to evaluate the relationship between cumulative exposure to 1,2-dichloropropane (1,2-DCP) and incidence risk of cholangiocarcinoma among workers in the offset proof-printing section of a small printing company in Osaka, Japan. Methods We identified 95 workers of a printing company (78 men and 17 women) who had been exposed to 1,2-DCP between 1987 and 2006, and calculated the standardised incidence ratio (SIR) of cholangiocarcinoma from 1987 to 2012. We estimated cumulative exposure to 1,2-DCP and calculated SIRs in four exposure categories. We also calculated incidence rate ratios (RRs) adjusted by sex, age, calendar year and dichloromethane (DCM) exposure for three exposure categories using Poisson regression analysis. Results Cumulative exposures to 1,2-DCP ranged from 32 to 3433 ppm-years (mean, 851 ppm-years) and the SIR was 1171 (95% CI 682 to 1875). In the analysis of the four exposure categories, SIRs increased significantly in the three highest exposure categories, but not in the lowest category. Adjusted RRs in the middle and high exposure categories were 14.9 (95% CI 4.1 to 54.3) and 17.1 (95% CI 3.8 to 76.2), respectively, in the analysis without lag time, and were 11.4 (95% CI 3.3 to 39.6) and 32.4 (95% CI 6.4 to 163.9), respectively, in the analysis with a 5-year lag. The trend analysis revealed a significant increase in RR in association with increasing cumulative exposure to 1,2-DCP. DCM exposure was not significantly associated with the development of cholangiocarcinoma. Conclusions The present study demonstrated an exposure–response relationship between exposure to 1,2-DCP and the development of cholangiocarcinoma.

OBJECTIVE Asian Americans manifest type 2 diabetes at low BMI levels but may not undergo diagnostic testing for diabetes if the currently recommended BMI screening cut point of ≥25 kg/m2 is followed. We aimed to ascertain an appropriate lower BMI cut point among Asian-American adults without a prior diabetes diagnosis. RESEARCH DESIGN AND METHODS We consolidated data from 1,663 participants, ages ≥45 years, without a prior diabetes diagnosis, from population- and community-based studies, including the Mediators of Atherosclerosis in South Asians Living in America study, the North Kohala Study, the Seattle Japanese American Community Diabetes Study, and the University of California San Diego Filipino Health Study. Clinical measures included a 2-h 75-g oral glucose tolerance test, BMI, and glycosylated hemoglobin (HbA1c). RESULTS Mean age was 59.7 years, mean BMI was 25.4 kg/m2, 58% were women, and type 2 diabetes prevalence (American Diabetes Association 2010 criteria) was 16.9%. At BMI ≥25 kg/m2, sensitivity (63.7%), specificity (52.8%), and Youden index (0.16) values were low; limiting screening to BMI ≥25 kg/m2 would miss 36% of Asian Americans with type 2 diabetes. For screening purposes, higher sensitivity is desirable to minimize missing cases, especially if the diagnostic test is relatively simple and inexpensive. At BMI ≥23 kg/m2, sensitivity (84.7%) was high in the total sample and by sex and Asian-American subgroup and would miss only ∼15% of Asian Americans with diabetes. CONCLUSIONS The BMI cut point for identifying Asian Americans who should be screened for undiagnosed type 2 diabetes should be

OBJECTIVE—Because skeletal muscle is one of the target tissues for insulin, skeletal muscle mass might be associated with type 2 diabetes. Serum creatinine is a possible surrogate marker of skeletal muscle mass. The purpose of this study was to determine whether serum creatinine level is associated with type 2 diabetes. RESEARCH DESIGN AND METHODS—The study participants were nondiabetic Japanese men (n = 8,570) aged 40–55 years at entry. Type 2 diabetes was diagnosed if fasting plasma glucose was ≥126 mg/dl or if participants were taking oral hypoglycemic medication or insulin. RESULTS—During the 4-year follow-up period, 877 men developed type 2 diabetes. Lower serum creatinine was associated with an increased risk of type 2 diabetes. The multiple-adjusted odds ratio for those who had serum creatinine levels between 0.40 and 0.60 mg/dl was 1.91 (95% CI 1.44–2.54) compared with those who had levels between 0.71 and 0.80 mg/dl. CONCLUSIONS—Lower serum creatinine increased the risk of type 2 diabetes.

OBJECTIVE We prospectively assessed whether the combined measurements of fasting plasma glucose (FPG) and A1C were effective for predicting type 2 diabetes. RESEARCH DESIGN AND METHODS Study participants included 6,736 nondiabetic Japanese men aged 40–55 years. Type 2 diabetes was diagnosed in those who had an FPG ≥126 mg/dl or who were being treated with an oral antidiabetic agent or insulin. The models including FPG, A1C, and both were compared using the area under the receiver operating characteristic (AUROC) curves. RESULTS During the 4-year follow-up period, we confirmed 659 diabetes cases. In multivariate analysis, both FPG and A1C were independently associated with the risk of type 2 diabetes. The model including both FPG and A1C had a greater AUROC curve than that including FPG alone (0.853 vs. 0.818; P < 0.001) or A1C alone (0.853 vs. 0.771; P < 0.001). CONCLUSIONS The combined measurement of FPG and A1C was effective for predicting type 2 diabetes.

Previous epidemiological studies have shown that vigorous physical activity reduces the development of type 2 diabetes (1–3). A recommendation from the Centers for Disease Control and Prevention reported that individuals should engage in ≥30 min of moderate-intensity physical activity, such as brisk walking, on most days of the week for health promotion and disease prevention (4); however, it is unclear whether mild physical activity (i.e., walking to walk) reduces the risk for type 2 diabetes. In the present study, we examined the relationship between walking to work and the development of type 2 diabetes during a 4-year observational period. The Kansai Healthcare Study is an ongoing cohort investigation designed to clarify the risk factors for cardiometabolic diseases. Between April 2000 and March 2001, 12,647 male employees of a company in the area of Kansai, Japan, who were aged 40–55 years at entry and considered to be involved in sedentary jobs were enrolled in this study. All employees aged ≥40 years underwent annual detailed medical check-ups. The protocol for this research was reviewed by the Human Subjects Review Committee at Osaka City University. For current analysis, study participants consisted of 11,073 Japanese men aged 40–55 years at entry with a fasting plasma glucose (FPG)

Although short sleep duration has been reported to be associated with future cardiometabolic diseases, it is not fully understood whether sleep duration is prospectively associated with the risk of each lipid profile abnormality.Subjects were nondiabetic Japanese, 40-55 years of age, who were not taking oral lipid-lowering medications: for the incidence of low high-density lipoprotein cholesterol (HDL-C), 7627 men with an HDL-C level ≥ 40 mg/dL; for high triglycerides, 6973 men with a triglyceride level200 mg/dL; for high low-density lipoprotein cholesterol (LDL-C), 7273 men with an LDL-C level160 mg/dL; for high non-HDL-C, 7415 men with a non-HDL-C level190 mg/dL; and for high total cholesterol (TC), 7196 men with a TC level240 mg/dL. Lipid profile abnormalities were defined according to the Adult Treatment Panel III guidelines of the National Cholesterol Education Program.During the 6-year observation period, there were 1022 cases of low HDL-C. Multiple-adjusted hazard ratios for low HDL-C were 0.79 (95% confidence interval, 0.64-0.97) for sleep durations of 5 to7 h and 0.62 (0.46-0.83) for ≥ 7 h compared with5 h. There were 1473 cases of high triglycerides. Multiple-adjusted hazard ratios for high triglycerides were 0.81 (0.68-0.98) for sleep durations of 5 to7 h and 0.90 (0.72-1.13) for ≥ 7 h compared with5 h. However, no association between sleep duration and the risk of future high LDL-C, non-HDL-C, or TC was observed.Moderate and/or long sleep durations decreased the risk of future low HDL-C and high triglycerides.

Objective Small-for-gestational-age (SGA) infants, who have growth restriction, have higher perinatal morbidity and mortality. Excessive inflammatory reaction such as neutrophil activation has been observed in pregnant women whose offspring had restricted fetal growth, but the association between white blood cell (WBC) counts and SGA birth has not yet been assessed. We therefore examined the association of WBC count and its change with the risk of SGA birth. Study design We enrolled 2356 pregnant women who had full-term singleton delivery at a private maternity hospital in Hirakata, Japan. SGA was defined as under the 10th percentile of birthweight for gestational age, baby sex, and mother's parity according to the Japanese neonatal anthropometric charts renewed in 2010. Blood samples were measured in the first and third trimesters. We performed multiple logistic regression analysis to assess associations between total and differential WBC counts and SGA birth. Results Women with SGA birth tended to have higher total WBC count in the third trimester compared with women who did not have SGA birth. This tendency was not observed for total WBC count in the first trimester. After adjustment for age, height, body mass index at entry, smoking habit, weekly gestational weight gain, and pregnancy-induced hypertension, higher total WBC count in the third trimester was associated with an increased risk of SGA birth. Total WBC count in the first trimester did not show any significant association with SGA birth. The ratio of total WBC count in the third trimester to that in the first trimester was associated with SGA birth; the odds ratio for 1 unit increase was 3.02 (95% CI: 1.54–5.92). Regarding differential WBC counts in the third trimester, neutrophil count but not lymphocyte count was associated positively with SGA birth. Conclusions Higher total WBC and absolute neutrophil counts in the third trimester were associated with SGA birth. In addition, greater ratio of increase in total WBC counts during pregnancy showed a positive association with the incidence of SGA birth. These associations may reflect a vicious cycle of inflammation and placental dysfunction as a cause of fetal growth restriction.

Summary Background and objectives Glomerular hyperfiltration and albuminuria accompanied by early-stage diabetic kidney disease predict future renal failure. Cigarette smoking has reported to be associated with elevated GFR in cross-sectional studies and with renal deterioration in longitudinal studies. The degree of glomerular hyperfiltration and proteinuria associated with smoking, which presumably is a phenomenon of early renal damage, has not been investigated in a satisfying manner so far. Design, setting, participants, & measurements This study included 10,118 Japanese men aged 40 to 55 years without proteinuria or renal dysfunction at entry. Estimated GFR was calculated using the Modification of Diet in Renal Disease equation for Japanese. Glomerular hyperfiltration was defined as estimated GFR ≥117.0 ml/min per 1.73 m 2 , which was the upper 2.5th percentile value of estimated GFR in the total population. Proteinuria was detected using standard dipstick. Results During the 6-year observation period, there were 449 incident cases of glomerular hyperfiltration and 1653 cases of proteinuria. Current smokers had a 1.32-time higher risk for the development of glomerular hyperfiltration and a 1.51-time higher risk for proteinuria than nonsmokers after adjustment for baseline age, body mass index, systolic and diastolic BP, antihypertensive medication, diabetes, alcohol consumption, regular leisure-time physical activity, and estimated GFR. Both daily and cumulative cigarette consumption were associated with an increased risk for glomerular hyperfiltration and proteinuria in a dose-response manner. Conclusions In middle-aged Japanese men, smoking was associated with an increased risk of glomerular hyperfiltration and dipstick proteinuria. Of importance, past smokers did not exhibit any increased risk for these conditions.

It is unclear which blood pressure (BP) components (that is, systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP) and mean arterial pressure (MAP)) are superior predictors of chronic kidney disease (CKD). Furthermore it is unclear whether the combination of SBP+DBP or PP+MAP is superior to any of these four individual BP components in predicting CKD. We enrolled 9928 Japanese men aged 40-55 years who had a normal estimated glomerular filtration rate (eGFR), no proteinuria and no history of cardiovascular disease and were not taking any antihypertensive medications at baseline. CKD was defined as an eGFR of60 ml min(-1) per 1.73 m(2) using the modified diet in renal disease equation. ΔAkaike's information criterion (ΔAIC) was used to compare the BP components-added model to the model without them in a Cox proportional hazards model. During the 52 428 person-years of follow-up, there were 434 cases of CKD. Of all four BP components, the model including DBP- or MAP-alone had the highest values of ΔAIC (10.2 and 9.85, respectively). The PP-alone model had the lowest ΔAIC value (-1.48). The combination models including SBP+DBP (ΔAIC 8.42) or PP+MAP (8.42) were not superior to the models including DBP- or MAP-alone. These findings suggested that, of the four BP components, both DBP and MAP were the most useful predictors for subsequent incidence of CKD, but PP was not an important predictor. The combination model, including SBP+DBP or PP+MAP, was not superior to the models including DBP- or MAP-alone for predicting CKD.

Visceral adiposity is considered to have a key role in cardiometabolic diseases. The purpose of this study is to investigate cross-sectionally the association between intra-abdominal fat area (IAFA) measured by computed tomography (CT) and high blood pressure independent of abdominal subcutaneous fat area (ASFA) and insulin resistance. Study participants included 624 Japanese men not taking oral hypoglycemic medications or insulin. Abdominal, thoracic and thigh fat areas were measured by CT. Total fat area (TFA) was calculated as the sum of abdominal, thoracic and thigh fat area. Total subcutaneous fat area (TSFA) was defined as TFA minus IAFA. Hypertension and high normal blood pressure were defined using the 1999 criteria of the World Health Organization. Multiple-adjusted odds ratios of hypertension for tertiles of IAFA were 2.64 (95% confidence interval, 1.35-5.16) for tertile 2, and 5.08 (2.48-10.39) for tertile 3, compared with tertile 1 after adjusting for age, fasting immunoreactive insulin, diabetes status, ASFA, alcohol consumption, regular physical exercise and smoking habit. IAFA remained significantly associated with hypertension even after adjustment for ASFA, TSFA, TFA, body mass index or waist circumference, and no other measure of regional or total adiposity was associated with the odds of hypertension in models, which included IAFA. Similar results were obtained for the association between IAFA and the prevalence of high normal blood pressure or hypertension. In conclusion, greater visceral adiposity was associated with a higher odds of high blood pressure in Japanese men.

Background Moderate alcohol consumption is associated with a decreased risk of type 2 diabetes. However, the relationship between drinking patterns, such as the weekly frequency of alcohol consumption and the quantity per drinking day, and the incidence of type 2 diabetes has not been sufficiently addressed. Methods Study participants included 10 631 Japanese men aged 40–55 years without type 2 diabetes at entry. Type 2 diabetes was diagnosed if a fasting plasma glucose level was ≥7.0 mmol/l or if participants were taking diabetes medications. Data on alcohol consumption were obtained from questionnaires. Results During the 37 172 person-years of follow-up, we confirmed 878 cases of type 2 diabetes. Frequent alcohol consumption was associated with a low risk of type 2 diabetes. Compared to non-drinkers, the multiple-adjusted HR for those who drank 4–7 days weekly was 0.76 (95% CI, 0.63 to 0.92). To assess the association between drinking pattern and type 2 diabetes, we examined the joint association of the weekly frequency and the quantity per drinking day with type 2 diabetes. Men who consumed 0.1–2.0 or 2.1–4.0 US standard drinks per drinking day on 4–7 days weekly had a lower risk of type 2 diabetes (HR 0.74, 95% CI 0.58 to 0.95; HR 0.74, 95% CI 0.60 to 0.91, respectively) compared to non-drinkers. Conclusions More frequent alcohol consumption lowered the risk of type 2 diabetes. Light to moderate alcohol consumption per drinking day on 4–7 days weekly lowered the risk of type 2 diabetes compared to non-drinkers.