Shoichiro Nagasaka

Morning and Evening Home Blood Pressure and Risks of Incident Stroke and Coronary Artery Disease in the Japanese General Practice Population The Japan Morning Surge-Home Blood Pressure Study

Our aim is to determine the optimal time schedule for home blood pressure (BP) monitoring that best predicts stroke and coronary artery disease in general practice. The Japan Morning Surge-Home Blood Pressure (J-HOP) study is a nationwide practice-based study that included 4310 Japanese with a history of or risk factors for cardiovascular disease, or both (mean age, 65 years; 79% used antihypertensive medication). Home BP measures were taken twice daily (morning and evening) over 14 days at baseline. During a mean follow-up of 4 years (16 929 person-years), 74 stroke and 77 coronary artery disease events occurred. Morning systolic BP (SBP) improved the discrimination of incident stroke (C statistics, 0.802; 95% confidence interval, 0.692–0.911) beyond traditional risk factors including office SBP (0.756; 0.646–0.866), whereas the changes were smaller with evening SBP (0.764; 0.653–0.874). The addition of evening SBP to the model (including traditional risk factors plus morning SBP) significantly reduced the discrimination of incident stroke (C statistics difference, −0.008; 95% confidence interval: −0.015 to −0.008; P=0.03). The category-free net reclassification improvement (0.3606; 95% confidence interval, 0.1317–0.5896), absolute integrated discrimination improvement (0.015; SE, 0.005), and relative integrated discrimination improvement (58.3%; all P<0.01) with the addition of morning SBP to the model (including traditional risk factors) were greater than those with evening SBP and with combined morning and evening SBP. Neither morning nor evening SBP improved coronary artery disease risk prediction. Morning home SBP itself should be evaluated to ensure best stroke prediction in clinical practice, at least in Japan. This should be confirmed in the different ethnic groups. Clinical Trial Registration—URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN000000894.

Association of Morning and Evening Blood Pressure at Home With Asymptomatic Organ Damage in the J-HOP Study

BACKGROUND Several guidelines recommend that home blood pressure (HBP) be measured both in the morning and in the evening. However, there have been fewer reports about the clinical significance of morning HBP than about the clinical significance of evening HBP. METHODS Our study included 4,310 patients recruited for the Japan Morning Surge Home Blood Pressure Study who had one or more cardiovascular risk factors. We measured morning and evening HBP, urinary albumin-creatinine ratio (UACR), left ventricular mass index (LVMI), brachial-ankle pulse wave velocity (baPWV), maximum carotid intima media thickness (IMT), N-terminal pro-brain-type natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin T (Hs-cTnT). RESULTS The correlation coefficients for the associations between morning systolic BP (SBP) and log-transformed baPWV, NT-proBNP, or Hs-cTnT were significantly greater than the corresponding relationships for evening SBP (all P < 0.01). The goodness-of-fit of the associations between morning home SBP and UACR (P < 0.05) or baPWV (P < 0.01) was improved by adding evening home SBP to the SBP measurement. In contrast, the goodness-of-fit values of the associations between evening SBP and UACR (P < 0.001), LVMI (P < 0.05), baPWV (P < 0.001), NT-proBNP (P < 0.001), and Hs-cTnT (P < 0.001) were improved by adding morning home SBP to the SBP measurement. CONCLUSIONS Morning BP and evening BP provide equally useful information for subclinical target organ damage, yet multivariate modeling highlighted the stand-alone predictive ability of morning BP.

Metformin, but not pioglitazone, decreases postchallenge plasma ghrelin levels in type 2 diabetic patients: a possible role in weight stability?

Aim:  Effects of metformin and pioglitazone on body weight are clearly different. Recently, the role of ghrelin, an orexigenic peptide derived from stomach, has been appreciated. Plasma ghrelin levels display a preprandial peak and postprandial suppression, suggesting its physiological role. We hypothesized that metformin or pioglitazone may modulate circulating ghrelin levels and this modulation may be related to differential effects on body weight with these agents.

Sleep Blood Pressure Self-Measured at Home as a Novel Determinant of Organ Damage: Japan Morning Surge Home Blood Pressure (J-HOP) Study

To study whether sleep blood pressure (BP) self‐measured at home is associated with organ damage, the authors analyzed the data of 2562 participants in the J‐HOP study who self‐measured sleep BP using a home BP monitoring (HBPM) device, three times during sleep (2 am, 3 am, 4 am), as well as the home morning and evening BPs. The mean sleep home systolic BPs (SBPs) were all correlated with urinary albumin/creatinine ratio (UACR), left ventricular mass index (LVMI), brachial‐ankle pulse wave velocity (baPWV), maximum carotid intima‐media thickness, and plasma N‐terminal pro‐hormone pro–brain‐type natriuretic peptide (NTproBNP) (all P<.001). After controlling for clinic SBP and home morning and evening SBPs, associations of home sleep SBP with UACR, LVMI, and baPWV remained significant (all P<.008). Even in patients with home morning BP <135/85 mm Hg, 27% exhibited masked nocturnal hypertension with home sleep SBP ≥120 mm Hg and had higher UACR and NTproBNP. Masked nocturnal hypertension, which is associated with advanced organ damage, remains unrecognized by conventional HBPM.

Acute effect of late evening meal on diurnal variation of blood glucose and energy metabolism

SUMMARY OBJECTIVE The notion that late evening meal promotes weight gain is popular, and it may also elicit postprandial hyperglycemia, since glucose tolerance decreases during midnight. Diabetic patients with night-eating symptoms, compared with patients without night-eating behaviors, are more likely to be obese and to have elevated A1c. However, epidemiological analysis adjusted for difference in total energy intake did not identify nighttime eating as the risk of obesity. The present study evaluated the effect of a single loading of late evening meal on diurnal variation of blood glucose and 24-h energy expenditure. METHODS Ten young adults stayed twice in a room-size respiratory chamber for 24 h, in a randomized repeated-measures design. After the entrance to the chamber at 1700 h, the subjects took normal (1900 h) or late (2230 h) evening meal, breakfast and lunch, and remained in the chamber until 1700 h. Time course of blood glucose was measured by continuous glucose monitoring system. RESULTS Late evening meal enhanced postprandial blood glucose response to the evening meal and the subsequent breakfast. Overall 24 h average blood glucose level was also elevated by late evening meal. Late evening meal shifted postprandial increase in energy expenditure toward late at night, but overall 24 h energy expenditure remained almost identical in the two dietary conditions. CONCLUSIONS The present study under controlled sedentary condition supports the notion that a single loading of late evening meal enhances average blood glucose over 24 h, but does not support that late evening meal reduces 24 h energy expenditure.

Ectopic Fat Accumulation and Distant Organ-Specific Insulin Resistance in Japanese People with Nonalcoholic Fatty Liver Disease

Objective The aim of this study was to examine the association between ectopic fat and organ-specific insulin resistance (IR) in insulin-target organs in patients with nonalcoholic fatty liver disease (NAFLD). Methods Organ-specific IR in the liver (hepatic glucose production (HGP)×fasting plasma insulin (FPI) and suppression of HGP by insulin [%HGP]), skeletal muscle (insulin-stimulated glucose disposal [Rd]), and adipose tissue (suppression of FFA by insulin [%FFA]) was measured in 69 patients with NAFLD using a euglycemic hyperinsulinemic clamp with tracer infusion ([6,6-2H2]glucose). Liver fat, intramyocellular lipid (IMCL), and body composition were measured by liver biopsy, proton magnetic resonance spectroscopy, and bioelectrical impedance analysis, respectively. Results HGP×FPI was significantly correlated with Rd (r = −0.57, P<0.001), %HGP with %FFA (r = 0.38, P<0.01), and Rd with %FFA (r = 0.27, P<0.05). Liver steatosis score was negatively associated with Rd (r = −0.47, P<0.001) as well as with HGP×FPI (r = 0.43, P<0.001). Similarly, intrahepatic lipid was negatively associated with Rd (r = −0.32, P<0.05). IMCL was not associated with Rd (r = −0.16, P = 0.26). Fat mass and its percentage were associated with HGP×FPI (r = 0.50, P<0.001; r = 0.48, P<0.001, respectively) and Rd (r = −0.59, P<0.001; r = −0.52, P<0.001, respectively), but not with %FFA (r = −0.21, P = 0.10; r = −0.001, P = 0.99, respectively). Conclusion Unexpectedly, fat accumulation in the skeletal muscle and adipose tissue was not associated with organ-specific IR. Instead, liver fat was associated not only with hepatic IR but also with skeletal muscle IR, suggesting a central role of fatty liver in systemic IR and that a network exists between liver and skeletal muscle.

Effect of breakfast skipping on diurnal variation of energy metabolism and blood glucose

Epidemiological studies suggest an association between breakfast skipping and body weight gain, insulin resistance or type 2 diabetes. Time when meal is consumed affects postprandial increase in energy expenditure and blood glucose, and breakfast skipping may reduce 24 h energy expenditure and elevate blood glucose level. The present study evaluated the effect of breakfast skipping on diurnal variation of energy metabolism and blood glucose. The skipped breakfast was compensated by following big meals at lunch and supper. In a randomized repeated-measure design with or without breakfast, eight males stayed twice in a room-size respiratory chamber. Blood glucose was recorded with a continuous glucose monitoring system. Breakfast skipping did not affect 24 h energy expenditure, fat oxidation and thermic effect of food, but increased overall 24 h average of blood glucose (83 ± 3 vs 89 ± 2 mg/dl, P < 0.05). Unlike 24 h glucose level, 24 h energy expenditure was robust when challenged by breakfast skipping. These observations suggest that changes in glucose homeostasis precede that of energy balance, in the potential sequence caused by breakfast skipping, if this dietary habit has any effect on energy balance.:

The lack of long-range negative correlations in glucose dynamics is associated with worse glucose control in patients with diabetes mellitus.

Glucose dynamics measured in ambulatory settings are fluid in nature and exhibit substantial complexity. We recently showed that a long-range negative correlation of glucose dynamics, which is considered to reflect blood glucose controllability over a substantial period, is absent in patients with diabetes mellitus. This was demonstrated using detrended fluctuation analysis (DFA), a modified random-walk analysis method for the detection of long-range correlations. In the present study, we further assessed the relationships between the established clinical indices of glycemic or insulinogenic control of hemoglobin A(1c) (HbA(1c)), glycated albumin (GA), 1,5-anhydroglucitol, and urine C-peptide immunoreactivity and the recently proposed DFA-based indices obtained from continuous glucose monitoring in 104 Japanese diabetic patients. Significant correlations between the following parameters were observed: (1) HbA(1c) and the long-range scaling exponent α(2) (r = 0.236, P < .05), (2) GA and α(2) (r = 0.254, P < .05), (3) GA and the short-range scaling exponent α(1) (r = 0.233, P < .05), and (4) urine C-peptide immunoreactivity and the mean glucose fluctuations (r = -0.294, P < .01). Therefore, we concluded that increases in the long-range DFA scaling exponent, which are indicative of the lack of a long-range negative correlation in glucose dynamics, reflected abnormalities in average glycemic control as clinically determined using HbA(1c) and GA parameters.

Smoking and adipose tissue inflammation suppress leptin expression in Japanese obese males: potential mechanism of resistance to weight loss among Japanese obese smokers

BackgroundThe effect of smoking on leptin regulation is controversial. Smoking may induce low-grade inflammation. Recent series of studies indicated the critical role of macrophage migration in the establishment of adipose tissue inflammation. In this study, we aimed to see the effects of smoking and inflammation on leptin regulation both at cellular and epidemiological levels.MethodsWe compared the concentration of inflammatory markers and serum leptin levels among Japanese male subjects. Additionally, leptin and intercellular adhesion molecule (ICAM) -1 gene expression was assessed in adipocytes co-cultured with or without macrophages in the presence or absence of nicotine and/or lipopolysaccharide (LPS).ResultsIn subjects with BMI below 25 kg/m2, both WBC counts and soluble-ICAM-1 levels are significantly higher in smokers than in non-smokers. However, leptin concentration did not differ according to smoking status. However, in subjects with BMI over 25 kg/m2, smokers exhibited significantly lower serum leptin level as well as higher WBC counts and s-ICAM-1 concentration as compared with non-smokers. Leptin gene expression was markedly suppressed in adipocytes co-cultured with macrophages than in adipocyte culture alone. Furthermore, nicotine further suppressed leptin gene expression. ICAM-1 gene expression was markedly up-regulated in adipocytes co-cultured with macrophages when stimulated with LPS.ConclusionsAdipose tissue inflammation appears to down-regulate leptin expression in adipose tissues. Nicotine further suppresses leptin expression. Thus, both smoking and inflammation may diminish leptin effect in obese subjects. Therefore, obese, but not normal weight, smokers might be more resistant to weight loss than non-smokers.

Circulating TNF receptor 2 is associated with the development of chronic kidney disease in non-obese Japanese patients with type 2 diabetes

AIMS Chronic low-grade inflammation and/or obesity are suggested to induce chronic kidney disease (CKD) in patients with type 2 diabetes. This cross-sectional study was performed to investigate the relationship between inflammatory biomarkers and CKD in non-obese patients with type 2 diabetes. METHODS 106 non-obese Japanese patients with type 2 diabetes were recruited for the measurement of GFR, TNF, HMW adiponectin, leptin, hsCRP and some variables including urinary albumin. BMI, serum creatinine, and urinary albumin levels were 22.2 ± 0.2 kg/m(2) (17.1-24.9 kg/m(2)), 0.76 ± 0.02 mg/dl (0.39-1.38 mg/dl), 40.4 ± 4.3mg/gCr (1.6-195.0mg/gCr), respectively. They were stratified into two groups based on the value of eGFR: low eGFR (eGFR<60 ml/min/1.73 m(2)) and normal eGFR (eGFR>60 ml/min/1.73 m(2)). Logistic regression analysis was used for statistical analysis. RESULTS Whereas univariate logistic regression analysis showed that gender, diabetes duration, triglyceride, HDL cholesterol, uric acid, urinary albumin, and soluble TNF receptors (sTNF-R1, sTNF-R2) are associated with the development of stage 3 CKD, multivariate logistic regression analysis revealed that sTNF-R2 (Odds ratio 1.003, 95% confidence interval 1.000 to 1.005, P=0.030) showed significant associations with the development of stage 3 CKD. CONCLUSIONS Circulating TNF receptor 2 is an independent risk factor for CKD in non-obese Japanese patients with type 2 diabetes.