Higher heart rate may predispose to obesity and diabetes mellitus: 20-year prospective study in a general population.

BACKGROUND: Emerging evidence indicates an association between sympathetic activation and metabolic syndrome. However, sympathetic activation in metabolic syndrome may be a cause, consequence, or just epiphenomenon. To elucidate this issue, the predictive power of resting heart rate for the development of abnormal glucose and lipid metabolisms after 20 years was evaluated in a general population. METHODS: A total of 637 participants (>20 years old) underwent a health examination in 1979 including measurements of blood chemistries. Resting heart rate (bpm) was measured by an electrocardiogram. In 1999, all of the study participants again underwent a health examination, including electrocardiogram and blood chemistries. Because four of them had atrial fibrillation, and 19 subjects were taking antihypertensive medication in 1979, they were excluded from analysis. Therefore, a complete dataset of 614 subjects was available. RESULTS: As was reported in our previous article, in 1999 we found a linear and significant (P < 0.05) cross-sectional relationship between resting heart rate and a cluster of cardiometabolic risk factors (blood pressure (BP), free fatty acid (FFA), plasma glucose, and homeostasis model assessment (HOMA) index). Baseline higher heart rate (heart rate >or=80 bpm in 1979) predicted the development of obesity, diabetes mellitus (DM), and insulin resistance in 1999 after adjustments for age, sex, and other confounders. CONCLUSION: This is one of the first prospective reports demonstrating that higher heart rate may predispose to the development of obesity and DM, suggesting that the sympathetic nerve system may play a role in the development of obesity and DM.

Plasma level of asymmetric dimethylarginine (ADMA) as a predictor of carotid intima-media thickness progression: six-year prospective study using carotid ultrasonography.

This study was designed to determine the relationship between plasma asymmetric dimethylarginine (ADMA) and the development of carotid atherosclerosis. Cross-sectional studies have revealed that plasma ADMA concentration is correlated with the intima-media thickness (IMT) of the carotid artery, but no prospective studies have appeared. Therefore we prospectively investigated whether or not plasma ADMA level can predict IMT progression. In a community-based cohort, we enrolled 712 subjects who were over 40 years old and who had no apparent cardiovascular diseases according to high-resolution carotid ultrasonography. Blood chemistries including ADMA were measured at baseline. In 575 subjects, IMT was re-measured 6 years later. The value of baseline ADMA for predicting IMT changes was investigated by multivariable analysis. At baseline, there was a significant (beta=0.321; p<0.001) relationship between IMT and ADMA levels. Multiple linear regression analysis revealed that baseline ADMA (beta=0.241; p<0.01) was the only predictor of IMT progression after adjustments for age, sex, baseline IMT, and four major risk factors (hypertension, hypercholesterolemia, diabetes mellitus, and smoking) plus hyperuricacidemia. Plasma ADMA was a predictor of carotid IMT progression.

Serum dehydroepiandrosterone sulfate levels predict longevity in men: 27-year follow-up study in a community-based cohort (Tanushimaru study).

OBJECTIVES: To determine whether serum dehydroepiandrosterone sulfate (DHEAS) levels could predict longevity in residents. DESIGN: Prospective community-based cohort study. SETTING: Community. PARTICIPANTS: Nine hundred forty subjects (396 men, 544 women; aged 21 to 88) underwent a health examination in 1978. Serum DHEAS levels were measured according to radioimmunoassay at baseline in all subjects, and subjects were followed periodically until 2005. RESULTS: Baseline DHEAS levels were higher in men than in women and decreased with age in both sexes. In a Cox proportional hazards model, age, DHEAS (inversely), blood pressure, and fasting plasma glucose were significantly associated with shorter longevity in men but not in women. Of these variables, high DHEAS levels in men were the strongest predictor of longevity (beta=-2.032, hazard ratio=0.131, 95% confidence interval=0.029-0.584 in the Cox proportional hazards model after adjustment for age). The Kaplan-Meier survival curve, stratified according to tertiles of DHEAS levels, in men after adjustments for age, systolic blood pressure, and fasting plasma glucose showed significantly (log-rank stat =10.6; P<.001) greater longevity in the highest group (200 microg/dL) than in the moderate (130-199 microg/dL) or lowest groups (129 microg/dL). CONCLUSION: This 27-year study in a community-based cohort indicated that DHEAS level may be a predictor of longevity in men, independent of age, blood pressure, and plasma glucose.

Plasma levels of asymmetric dimethylarginine (ADMA) are related to intima-media thickness of the carotid artery: an epidemiological study.

Asymmetric dimethylarginine (ADMA) is a circulating endogenous nitric oxide (NO) synthase inhibitor. It has been reported that plasma levels of ADMA are related to intima-media thickness (IMT) in small numbers. We investigated this issue in a large number of subjects without overt cerebro-cardiovascular diseases. A total of 712 subjects (305 men and 407 women; age, 62.6+/-11.2 years) received a health examination in 1999 in a farming community. We measured blood pressure (BP), blood chemistries, and fasting plasma total ADMA levels. IMT of the common carotid artery was determined with the use of duplex ultrasonography as an index of atherosclerosis. Uni- and multi-variate analyses for determinants of IMT were performed. For the total population, the mean ADMA level was 0.50 micromol/l. By the use of multiple stepwise regression analysis, IMT was significantly associated with ADMA (p<0.01), age (p<0.001), and systolic BP (p<0.001). Furthermore, when IMT was analyzed across the ADMA tertiles after adjustments for age, sex, and other confounders, analysis of co-variance showed a significant (p<0.001) and linear association between IMT and ADMA levels. In conclusion, our study indicates that plasma level of ADMA is a strong and independent determinant of IMT of the carotid artery in the large number of subjects without overt cerebro-cardiovascular diseases.

Habitual coffee but not green tea consumption is inversely associated with metabolic syndrome: an epidemiological study in a general Japanese population.

In Japan, metabolic syndrome used to be rare, and the level of coffee consumption was low. However, the Japanese life style has been changing rapidly, and these changes have been associated with a steady increase in the frequency of metabolic syndrome and with greater consumption of coffee. We examined the relationship between metabolic syndrome and the consumption of coffee or green tea. A total of 1902 Japanese aged over 40 years (785 men and 1117 women) received population-based health check-up in 1999. We measured components of metabolic syndrome (blood pressure, waist circumference, fasting plasma glucose, and lipid profiles). Eating and drinking patterns were evaluated by a food frequency questionnaire. Multivariate analyses were performed to clarify the association between coffee or green tea consumption and the components of metabolic syndrome. All components of metabolic syndrome except for HDL-cholesterol were significantly (p<0.01) and inversely related to coffee but not green tea consumption by multivariate analysis after adjusting for confounding factors. The larger was the number of components of metabolic syndrome, the lower was the level of coffee consumption (p<0.0001). In addition, there was a high frequency of metabolic syndrome in small coffee drinkers. Thus, coffee but not green tea consumption was inversely associated with metabolic syndrome.

Positive association between serum levels of advanced glycation end products and the soluble form of receptor for advanced glycation end products in nondiabetic subjects.

The advanced glycation end products (AGEs)-receptor for AGE (RAGE) axis is implicated in diabetic vascular complications. Administration of soluble form of RAGE (sRAGE) to mice has been shown to block the AGE-elicited tissue damage by acting as a decoy. These observations suggest that endogenous sRAGE may capture and eliminate circulating AGEs and decrease its serum levels. However, because AGEs up-regulate tissue RAGE expression and endogenous sRAGE could be generated from the cleavage of cell surface RAGE, sRAGE may be positively, rather than inversely, associated with circulating AGEs by reflecting tissue RAGE expression. In this study, we investigated the association of sRAGE with serum levels of AGEs in humans. Data for fasting serum sRAGE and AGE levels of 184 nondiabetic subjects were obtained from a general population in Japan. We also measured body mass index (BMI), waist circumference, blood pressure, and blood biochemistries in this population. Uni- and multivariate analyses were applied for the determinants of serum sRAGE levels. The average sRAGE levels were 0.40 +/- 0.17 ng/mL in males and 0.43 +/- 0.14 ng/mL in females, respectively. In the univariate analysis, BMI (P < .05, inversely), waist circumference (P < .05, inversely), AGEs (P < .05), and alcohol intake (P < .05, inversely) were significantly associated with sRAGE levels. After performing multivariate analyses, BMI (P < .05, inversely) and AGEs (P < .05) still remained significant independently. The present study is the first demonstration that serum sRAGE levels were positively associated with circulating AGEs in the nondiabetic general population. Endogenous sRAGE levels are elevated in parallel with serum AGE levels.

Positive association of serum levels of advanced glycation end products with thrombogenic markers in humans.

Advanced glycation end products (AGEs) are elevated in diabetes. We have demonstrated that AGEs trigger thrombogenic responses in cultured cells. We investigated here whether serum AGE levels were positively correlated with thrombogenic markers in humans. Data for fasting serum AGE levels of 186 nondiabetic subjects were obtained from a general population in Japan. We measured body mass index, blood pressure, total cholesterol, low-density lipoprotein and high-density lipoprotein cholesterol, triglycerides, fasting plasma glucose, glycosylated hemoglobin A(1c), insulin, creatinine, uric acid, high-sensitive C-reactive protein, plasminogen activator inhibitor 1 (PAI-1), and fibrinogen. Uni- and multivariate analyses were applied for the determinants of serum AGE levels. The average AGE levels were 4.11 +/- 0.74 U/mL in males and 4.10 +/- 0.93 U/mL in females. In the univariate analysis, PAI-1 (P < .05) and fibrinogen (P < .05) were significantly associated with AGE levels. After performing multivariate analyses, PAI-1 (P < .05) and fibrinogen (P < .05) still remained significant independently. In conclusion, the present study is the first demonstration that PAI-1 and fibrinogen levels were positively associated with serum AGE levels. Advanced glycation end products may be associated with thrombogenesis in humans.

Elevated serum levels of pigment epithelium-derived factor in the metabolic syndrome.

CONTEXT: Pigment epithelium-derived factor (PEDF), a potent inhibitor of angiogenesis with neuronal differentiating activity, inhibits endothelial cell injury in vitro, thus suggesting the involvement of PEDF in atherosclerosis. Therefore, elucidating the relationship between serum levels of PEDF and coronary risk factors could provide a clue to understanding the pathophysiological role of PEDF in vivo. OBJECTIVE: We examined whether serum levels of PEDF were associated with risk factors for coronary artery disease. DESIGN: The study was designed as a cross-sectional study. SETTING: The study was set within the general community. PATIENTS OR OTHER PARTICIPANTS: A total of 196 general Japanese residents (age 65.7 +/- 9.3 yr; 71 males and 125 females) without clinical evidence of coronary or peripheral arterial occlusive diseases were enrolled in this study. RESULTS: PEDF showed a normal distribution, ranging from 8-24 microg/ml, with a mean of 14.6 +/- 3.2 microg/ml. Multivariate analyses revealed that uric acid (P < 0.001), waist circumference (P = 0.009), insulin (P = 0.019), and triglycerides (P = 0.028) were significant independent determinants of serum PEDF levels. Age- and uric acid-adjusted PEDF levels were significantly higher (P = 0.048 for men and P = 0.007 for women) in proportion to the accumulation of the number of the components of the metabolic syndrome. CONCLUSIONS: The present study reveals that serum levels of PEDF are strongly associated with the metabolic syndrome. Our results suggest that serum PEDF levels may be elevated as a counter-system in the metabolic syndrome.

High plasma level of remnant-like particle cholesterol in the metabolic syndrome.

OBJECTIVE: The metabolic syndrome is associated with a high incidence of cardiovascular disease even when the abnormalities present in the syndrome are mild. The underlying mechanism of the metabolic syndrome has not been elucidated. We investigated whether a strong atherogenic lipoprotein, remnant-like particle (RLP) lipoprotein cholesterol, is elevated in the metabolic syndrome. RESEARCH DESIGN AND METHODS: We performed a health examination among the residents of a rural community in Japan. Complete datasets, including fasting RLP cholesterol levels, were obtained in 1,261 subjects (509 men and 752 women) without diabetes and who were not taking lipid-lowering drugs. The subjects' medical history, use of alcohol, and smoking habits were ascertained by a questionnaire. RESULTS: All of the components of the metabolic syndrome were significantly related to RLP cholesterol by univariate analysis. Total cholesterol and smoking habits were also positively associated with RLP cholesterol. The subjects with the metabolic syndrome showed only mild abnormalities of each component. When RLP cholesterol levels were stratified by the number of the components of the metabolic syndrome, there was a strong association between RLP cholesterol levels and the number of components (P < 0.001 and F = 72.7). CONCLUSIONS: RLP cholesterol levels are elevated in the metabolic syndrome, and this elevation may underlie the high incidence of cardiovascular disease in the metabolic syndrome.

Strong association between serum hepatocyte growth factor and metabolic syndrome.

Hepatocyte growth factor (HGF) is one of the adipocytokines. We evaluated whether serum levels of HGF are related to the metabolic syndrome. A total of 1474 subjects of a general population free of liver, kidney, and lung diseases received a health examination. We measured blood pressure, waist circumference, body mass index, fasting plasma glucose, lipid profiles, serum insulin, liver enzymes, and HGF concentrations. Uni- and multivariate analyses for determinant of HGF were performed. In univariate analysis, all of the components (waist circumference, triglycerides, high-density lipoprotein-cholesterol, blood pressure, and fasting plasma glucose) of the metabolic syndrome and liver enzymes were significantly related to HGF levels. By the use of multiple stepwise regression analysis, HGF levels were significantly related to waist circumference (P < 0.001), high-density lipoprotein-cholesterol (P < 0.05, inversely), and liver enzymes (P < 0.001). HGF levels were higher (P < 0.05) in proportion to the accumulation of the number of the component of the metabolic syndrome. A significant association (P < 0.05) was shown between quartiles of HGF levels and the degree of abnormality of the component of the metabolic syndrome. In conclusion, our results indicate that serum HGF levels are strongly associated with the metabolic syndrome, independent of liver function.