Historical perspectives of the metabolic syndrome.

The metabolic syndrome (MetS) or insulin resistance syndrome is a constellation of obesity-related metabolic derangements predisposing to type 2 diabetes and cardiovascular disease. In 1998, WHO defined the first criteria of MetS. Three years later, the user-friendly National Cholesterol Education Program criteria of MetS were proposed. Different criteria were issued by the International Diabetes Federation in 2005, making abdominal obesity a necessary component. Several international societies, including The International Diabetes Federation, jointly adopted the revised National Cholesterol Education Program criteria as harmonizing criteria of MetS in 2009. WHO warned the next year that MetS has limited practical utility as a management tool. Adipose tissue inflammation has been shown to be a fundamental mechanism of metabolic derangements, associated with ectopic lipid deposit and mitochondrial dysfunction in skeletal muscle and the liver.

LDL cholesterol was more strongly associated with percent body fat than body mass index and waist circumference in a health screening population.

AIMS: To compare correlations between changes in cardiovascular risk factors and those in obesity indices and to compare associations with incident hyper-LDL cholesterolemia among obesity indices. METHODS: Correlation coefficients were calculated between 7-year changes in cardiovascular risk factors and those in body mass index (BMI), waist circumference (WC) and percent body fat (PBF) in 634 men and 396 women who used no antihypertensive, antidiabetic or antihyperlipidemic drugs. Odds ratios of incident hyper-LDL cholesterolemia after 7 years were calculated for BMI, WC and PBF in 738 men and 388 women. RESULTS: There were no significant differences in the correlations with 7-year changes in cardiovascular risk factors between 7-year changes in BMI and WC. The correlation with 7-year change in LDL cholesterol was stronger for that in PBF than that in BMI or WC (p=0.021 or 0.089, respectively in men and 0.022 or 0.020, respectively in women). The correlations with 7-year changes in log triglycerides, HDL cholesterol and log high-sensitivity CRP were stronger for those in BMI and WC than that in PBF in men. Incident hyper-LDL cholesterolemia after 7 years was significantly associated with PBF, but not BMI or WC, in men after adjusted for age and other covariates. However, the association was not significant after further adjusted for LDL cholesterol. CONCLUSIONS: The correlation with 7-year change in LDL cholesterol was stronger for that in PBF than that in BMI or WC. Incident hyper-LDL cholesterolemia was significantly associated with PBF, but not with BMI or WC, in men.

Ketonuria may be associated with low serum amylase independent of body weight and glucose metabolism.

CONTEXT: Ketonuria, which reflects a preferential combustion of lipids relative to carbohydrates, is often observed in lean rather than obese people. Clinical studies have shown that individuals with diabetes and/or obesity predispose to have low serum amylase (LSA). OBJECTIVE: To investigate the association between ketonuria and LSA. METHODS: We examined ketonuria assessed by dipstick urinalysis and clinical parameters including serum amylase in 3638 Japanese people aged 25-79 years who underwent a health-screening checkup. RESULTS: There was an inverse relationship between body mass index (BMI) and serum amylase. The lowest serum amylase was observed in obese subjects (BMI ≥ 25.0 kg/m2) with positive ketonuria. Logistic regression analysis showed that ketonuria was significantly associated with LSA (<50 IU/L), which was not altered by the adjustments for relevant confounders including age, sex, BMI, and HbA1c. CONCLUSIONS: Current results suggest a relative unavailability of carbohydrates for energy production in individuals with LSA.

Low Vital Capacity Was Associated with Incident Diabetes in a Japanese Health Screening Population in Whom Obesity Was Not Prevalent.

OBJECTIVES: There have been few studies regarding the relationship between respiratory function and incident diabetes in East Asian populations in whom obesity is not prevalent. METHODS: This is a 6-year follow-up study in a Japanese health-screening population that included 1874 men and 1093 women. Using Cox regression models, hazard ratios (HRs) of incident diabetes for percent vital capacity (%VC) and forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC) were calculated. Diabetes was defined as simultaneous fasting plasma glucose (FPG) ≥7.0 mmol/L and glycated hemoglobin (A1C) ≥6.5% or use of antidiabetic medications. RESULTS: During the 6-year follow-up period (mean of 4.8 years), 71 men (3.8%) and 18 women (1.7%) developed diabetes. The HRs (95% confidence intervals [CIs]) of incident diabetes for each 1 SD increase in %VC and the lowest tertile of %VC compared with the highest tertile were 0.81 (0.66 to 1.00) (p=0.045) and 1.78 (1.01 to 3.16) (p=0.048), respectively, adjusted for sex, age, body mass index, antihypertensive drug use and A1C levels. After further adjustment for log high-sensitivity C-reactive protein, the HRs (95% CI) of incident diabetes for each 1 SD increase in %VC and the lowest tertile of %VC were 0.82 (0.67 to 1.01) (p=0.063) and 1.69 (0.95 to 3.01) (p=0.073), respectively. The association between FEV1/FVC and incident diabetes was not significant. CONCLUSIONS: %VC, but not FEV1/FVC, was significantly associated with incident diabetes in a Japanese health-screening population in whom obesity was not prevalent.

Cross-Sectional and Longitudinal Associations between Serum Bilirubin and Prediabetes in a Health Screening Population.

OBJECTIVES: Longitudinal associations between total bilirubin (TB) and prediabetes have not been reported. This study investigated cross-sectional and longitudinal associations between TB and prediabetes. METHODS: Cross-sectional associations between TB and prediabetes were investigated in 3681 nondiabetic subjects. Longitudinal associations between TB and prediabetes over 6 years were investigated in 2149 subjects who were normoglycemic at baseline. Prediabetes was defined as fasting plasma glucose (FPG) levels of ≥5.6 mmol/L or glycated hemoglobin levels of ≥5.7% excluding diabetes. RESULTS: The prevalence of prediabetes was 25.4%, and the cumulative incidence of prediabetes during 6 years was 25.5% in a Japanese health screening population. Prevalent prediabetes was significantly associated with the quintiles of TB in nonsmoking men (trend, p<0.001) and women (trend, p=0.012), but not in smoking men (trend, p=0.689). Incident prediabetes was not significantly associated with the quintiles of TB, while it was positively associated with 1 standard deviation increase in TB in nonsmoking men (hazard ratio [95% confidence interval]; 1.21 [1.07 to 1.37], p=0.002). CONCLUSIONS: TB levels were significantly inversely associated with prevalent prediabetes in nonsmokers, but not in smokers, whereas an inverse association between TB levels and incident prediabetes seemed to be unlikely.

Latent association between low urine pH and low body weight in an apparently healthy population.

Low urine pH, a plausible predictor for chronic kidney disease and metabolic disorders, is often observed in obese individuals. However, the association between low urine pH and low body weight is equivocal. We examined clinical parameters including urine pH and body mass index (BMI) in a cross-sectional study of 3629 apparently healthy Japanese adults aged 25-80 years who underwent a health-screening check-up. Urine pH was lower and the prevalence of proteinuria was significantly higher in subjects with BMI of ≥ 27.0 kg/m(2) compared with those with BMI of 21.0-22.9 kg/m(2). By contrast, hematuria was more prevalent in subjects with BMI of ≤ 20.9 kg/m(2). Logistic regression analysis showed that BMI of ≥ 27.0 kg/m(2) was significantly associated with low urine pH (≤ 5.5), which remained significant after adjustment for relevant confounders including age, sex, proteinuria, estimated glomerular filtration rate, urine density, hematuria, smoking status, and daily alcohol drinking. However, the association disappeared after further adjustment for serum uric acid. In contrast, the association between low urine pH and BMI of ≤ 19.0 kg/m(2) was significant after adjustment for age and sex and rather strengthened by the further adjustment for serum uric acid. In conclusion, low urine pH may be independently associated with low BMI. However, the underlying mechanisms of low urine pH in low body weight may differ from those in high body weight.

The association of serum sodium and chloride levels with blood pressure and estimated glomerular filtration rate.

BACKGROUND: High serum sodium (sNa) concentrations may be associated with hypertension, which deteriorates kidney function. However, it is equivocal whether high sNa concentrations are associated with impaired kidney function independently of blood pressure (BP) or serum chloride (sCl). Therefore, we addressed this issue in an apparently healthy population. METHODS: Clinical variables including estimated glomerular filtration rate (eGFR) were examined in 3603 men and women (aged 25-75 years) who underwent health-screening check-ups. sNa concentrations were classified into five categories. RESULTS: Most parameters, including age and BP, increased with increasing sNa, whereas eGFR decreased. Logistic regression analysis showed that, compared with low-normal sNa (≤ 140 mEq/l), high sNa (≥ 144 mEq/l) was significantly associated with elevated BP (≥ 130/85 mmHg) even after adjustment for blood hematocrit, eGFR, serum potassium (sK) concentration and sCl. The highest sNa category was significantly associated with reduced eGFR (< 60 ml/min/1.73 m(2)) independently of elevated BP. Unlike adjustment for sK, adjustment for sCl strengthened the association between high sNa and elevated BP but attenuated the association between high sNa and reduced eGFR. CONCLUSIONS: These results suggest that high sNa concentrations, even within the normal range, are independently associated with elevated BP and impaired kidney function. These associations may be substantially modified by sCl.

Serum Cholinesterase Is Inversely Associated with Body Weight Change in Men Undergoing Routine Health Screening.

OBJECTIVE: The purpose of this study is to investigate the relationships between serum cholinesterase and body weight change, in addition to incident obesity defined as a body mass index (BMI) of 25 kg/m(2) or greater. METHODS: A retrospective 5-year follow-up study was conducted. The crude incidence and hazard ratios (HRs) of obesity adjusted for the BMI and other confounders were calculated for cholinesterase quartiles in 1,412 men and 921 women. Partial correlation coefficients (PCCs) were calculated between cholinesterase and changes in the BMI during the 5-year follow-up period adjusted for age and other confounders and the change in the BMI were compared among cholinesterase quartiles in 1,223 men and 681 women. RESULTS: During the 5-year follow-up period, 149 men (10.6%) and 65 women (7.1%) developed obesity. The adjusted HRs of obesity decreased, although the crude incidence of obesity increased along the quartiles of cholinesterase in men. The adjusted HRs of obesity for the first (lowest), second and third quartiles of cholinesterase were 2.02 (p=0.006), 1.45 (p=0.122), and 1.28 (p=0.265), respectively compared with the highest quartile in men. The PCC between the baseline level of cholinesterase and change in the BMI was -0.16 (p<0.001) in men. The mean changes in BMI for 5 years were 0.31 kg/m(2), 0.17 kg/m(2), 0.01 kg/m(2) and -0.04 kg/m(2), respectively in the first, second, third and fourth quartiles of cholinesterase in men (p=0.005). Neither incident obesity nor weight gain was significantly associated with cholinesterase in women. CONCLUSION: The serum cholinesterase level was inversely associated with body weight change, as well as incident obesity, after adjusted for the BMI in men.

High-sensitivity C-reactive protein, but not white blood cell count, independently predicted incident diabetes in a Japanese health screening population.

AIMS: To compare high-sensitivity C-reactive protein (hs-CRP) and white blood cell count (WBC) as a predictor of incident diabetes in a population where obesity is not prevalent. METHODS: This is a retrospective 6-year follow-up study in a Japanese health screening population including 1874 men and 1094 women. Using Cox regression methods, hazard ratios (HRs) of incident diabetes for hs-CRP and WBC adjusting for fasting plasma glucose (FPG), hemoglobin A1c (HbA1c) and other confounders were calculated, and using areas under receiver operating characteristic curve (AUCs), diabetes-predicting abilities of hs-CRP and WBC were compared. Diabetes was defined as FPG ≥ 126 mg/dL and HbA1c ≥ 6.5 % or use of antidiabetic medication. RESULTS: During the 6-year follow-up period (mean ± SD, 4.8 ± 1.7 years), 71 men (3.8 %) and 19 women (1.7 %) developed incident diabetes. The fully adjusted HRs [95 % confidence intervals (CIs)] of incident diabetes for each 1 SD increase in log hs-CRP and WBC were 1.20 (0.92-1.56) (p = 0.174) and 1.01 (0.78-1.30) (p = 0.946), respectively. The fully adjusted HRs (95 % CIs) of incident diabetes for the highest tertile of hs-CRP and WBC compared with the lowest tertile were 2.57 (1.05-6.27) (p = 0.039) and 1.20 (0.53-2.70) (p = 0.665), respectively. The AUCs (95 % CIs) of hs-CRP and WBC for the discrimination of incident diabetes were 0.73 (0.68-0.77) and 0.67 (0.62-0.72), respectively. CONCLUSIONS: Hs-CRP, but not WBC, was independently associated with incident diabetes in a Japanese health screening population where obesity is not prevalent.

Associations between serum cholinesterase and incident hyper-LDL cholesterolemia, hypertriglyceridemia and hypo-HDL cholesterolemia as well as changes in lipid levels in a health screening population.

OBJECTIVE: To investigate longitudinal associations between serum cholinesterase (ChE) and lipid status. METHODS: Hazard ratios (HRs) of incident hyper-LDL cholesterolemia, hypertriglyceridemia and hypo-HDL cholesterolemia for baseline ChE and correlation coefficients between baseline ChE and changes in LDL cholesterol, log triglycerides and HDL cholesterol during 5 years were calculated in a health screening population. RESULTS: During the 5-year follow-up period, 337 men (22.9%) and 208 women (26.3%), 330 men (24.3%) and 114 women (12.4%) and 137 men (8.3%) and 117 women (12.7%) developed hyper-LDL cholesterolemia, hypertriglyceridemia and hypo-HDL cholesterolemia, respectively. The HRs of incident hyper-LDL cholesterolemia, hypertriglyceridemia and hypo-HDL cholesterolemia for each 1 SD increase in baseline ChE were 1.15 (p = 0.009) in men and 1.17 (p = 0.017) in women, 1.25 (p < 0.001) in men and 1.37 (p < 0.001) in women and 1.15 (p = 0.113) in men and 1.12 (p = 0.248) in women, respectively adjusted for BMI and other confounders, while the HRs were not significant after further adjusted for each baseline lipid level except for the HR of hypertriglyceridemia in women (HR, 1.22 (p = 0.047)). The baseline ChE was inversely correlated with the changes in LDL cholesterol (r = -0.117, p < 0.001) and log triglycerides (r = -0.114, p < 0.001) in men and the change in LDL cholesterol (r = -0.191, p < 0.001) in women. CONCLUSION: ChE was positively associated with incident hyper-LDL cholesterolemia and hypertriglyceridemia adjusted for BMI, while with only incident hypertriglyceridemia in women after further adjusted for the baseline lipid level.

Cross-sectional and longitudinal associations between serum bilirubin and dyslipidemia in a health screening population.

OBJECTIVE: To investigate cross-sectional and longitudinal associations between serum total bilirubin (TB) and dyslipidemia. METHODS: Odds ratios (ORs) of prevalent dyslipidemia for TB were calculated in 2113 men and 1265 women. Correlation coefficients between baseline TB as well as the change in TB over 5 years and baseline log triglycerides, baseline HDL cholesterol and the changes in log triglycerides and HDL cholesterol over 5 years were calculated. Hazard ratios (HRs) of incident hypertriglyceridemia and hypo-HDL cholesterolemia for TB over 5 years were calculated in 1324 men and 915 women and 1583 men and 884 women, respectively. RESULTS: The ORs of prevalent hypertriglyceridemia and hypo-HDL cholesterolemia for each one SD increase in TB were 0.83 (p < 0.001) in men and 0.71 (p = 0.074) in women and 0.64 (p < 0.001) in men and 0.78 (p = 0.089) in women, respectively adjusted for age, smoking, and other confounders. The baseline TB was significantly correlated with baseline log triglycerides and HDL cholesterol both in men and women while the change in TB was significantly correlated with the changes in log triglycerides and HDL cholesterol in men and the change in HDL cholesterol in women. The HRs of incident hypertriglyceridemia and hypo-HDL cholesterolemia for each one SD increase in TB were 0.99 (p = 0.848) in men and 0.74 (p = 0.033) in women and 1.08 (p = 0.345) in men and 0.85 (p = 0.220) in women, respectively adjusted for age, smoking, and other confounders. CONCLUSION: Baseline TB was significantly associated with both prevalent hypertriglyceridemia and hypo-HDL cholesterolemia in men and with incident hypertriglyceridemia in women.

Tachycardia-dependent augmentation of "notched J waves" in a general patient population without ventricular fibrillation or cardiac arrest: not a repolarization but a depolarization abnormality?

BACKGROUND: J waves can be observed in individuals of the general population, but electrocardiographic characteristics are poorly understood. OBJECTIVE: The purpose of this study was to examine the J-wave dynamicity in a general patient population. METHODS: The responses of J waves (>0.1 mV above the isoelectric line in 2 contiguous leads) to varying RR intervals were analyzed. Patients with aborted sudden cardiac death, documented ventricular fibrillation, or a family history of sudden cardiac death were excluded. The J-wave amplitude was measured at baseline, in beats with short RR intervals in conducted atrial premature beats (APBs) or atrial stimulation during the electrophysiology study, and in the beats next to APBs with prolonged RR intervals. RESULTS: Mainly notched J waves were identified in 94 of 701 (24.5%) general patients (13.4%), and APBs were present in 23 of 94 (24.5%) patients. The mean baseline amplitude of J waves was 0.20 ± 0.06 mV at the baseline RR interval of 853 ± 152 ms, 0.25 ± 0.11 mV at the RR interval in the conducted APB of 545 ± 133 ms (P = .0018), and 0.19 ± 0.08 mV at the RR interval of 1146 ± 314 ms (P = .3102). The clinical characteristics were not different between patients with and without tachycardia-dependent augmentation of J waves. Augmentation of J waves was confirmed by the electrophysiology study: 0.28 ± 0.12 mV vs 0.42 ± 0.11 mV at baseline and in the beats of atrial stimulation, respectively (P = .0001). However, no bradycardia-dependent augmentation (>0.05 mV) was observed. Such tachycardia-dependent augmentation can represent depolarization abnormality rather than repolarization abnormality. CONCLUSION: J waves in a general patient population were augmented at shorter RR intervals, but not at prolonged RR intervals. Mechanistically, conduction delay is most likely responsible for this.

Low vital capacity was found to be associated with incident diabetes in health screening population of Japanese women.

OBJECTIVE: There have been no previous studies regarding the relationship between the respiratory function and incident diabetes in East Asian women in whom obesity is not prevalent. METHODS: Using Cox regression models, hazard ratios (HRs) for incident diabetes for each one SD increase in the percent vital capacity (%VC), a parameter of restrictive pulmonary dysfunction, forced expiratory volume in one second over forced vital capacity (FEV1/FVC), a parameter of obstructive pulmonary dysfunction, and log high-sensitivity C-reactive protein (hs-CRP) were calculated in 1,704 men and 1,016 women among a Japanese health screening population. RESULTS: Over the four-year study period (mean of 3.4 years), 54 men (3.2%) and 19 women (1.9%) developed diabetes. The HRs [95% confidence intervals (CIs); p values] for incident diabetes for each one SD increase in %VC and log hs-CRP were 0.81 (0.61-1.06; 0.127) and 1.29 (0.97-1.73; 0.085), respectively in men, and 0.55 (0.35-0.88) 0.012 and 2.50 (1.37-4.57; 0.003), respectively in women adjusted for age, fasting glucose and body mass index. The FEV1/FVC was not found to be significantly associated with incident diabetes in any regression models. The Spearman's correlation coefficients between %VC and hs-CRP was -0.11 (p<0.001) in men and -0.08 (p=0.007) in women. The HRs (95% CIs; p values) for each one SD increase in %VC and hs-CRP were 0.86 (0.65-1.13; 0.278) and 1.26 (0.94-1.70; 0.125), respectively in men, and 0.56 (0.34-0.94; 0.028) and 2.95 (1.49-5.81; 0.002), respectively in women, further adjusted for each other, systolic blood pressure, triglycerides and HDL cholesterol. CONCLUSION: A low %VC was found to be associated with incident diabetes, independent of hs-CRP in women among a Japanese health screening population.

Overweight and high-sensitivity C-reactive protein are weakly associated with kidney stone formation in Japanese men.

OBJECTIVES: To investigate longitudinal relationships between obesity/inflammation and kidney stone formation in a population where obesity is not prevalent. METHODS: Using Cox regression models, associations between kidney stone formation and body mass index, waist circumference, high-sensitivity C-reactive protein and other possible risk factors were retrospectively examined in a health screening Japanese population including 1726 men and 992 women. RESULTS: During 4 years of follow up (mean 3.2 years), kidney stones were formed in 238 men (34.5 per 1000 person-years) and 82 women (20.7 per 1000 person-years). In men, when the possible risk factors were separately examined as continuous parameters, body mass index (P = 0.030) and waist circumference (P = 0.025) were significantly, and log C-reactive protein (P = 0.092) were marginally, associated with kidney stone formation. However, none of these parameters was independently associated with kidney stone formation after fully adjusted. In women, none of the aforementioned three parameters was associated with kidney stone formation. As a categorical parameter, the higher two quintiles of C-reactive protein were significantly associated with kidney stone formation compared with the lower two quintiles in men (P = 0.026). CONCLUSIONS: Overweight and C-reactive protein are weakly associated with kidney stone formation in Japanese men. Inflammation might be an underlying mechanism of the association between obesity and kidney stone formation.