Long-term weight-change slope, weight fluctuation and risk of type 2 diabetes mellitus in middle-aged Japanese men and women: findings of Aichi Workers' Cohort Study.

OBJECTIVE: This study aims to investigate the association of long-term weight-change slopes, weight fluctuation and the risk of type 2 diabetes mellitus (T2DM) in middle-aged Japanese men and women. METHODS: A total of 4234 participants of Aichi Workers' Cohort Study who were aged 35-66 years and free of diabetes in 2002 were followed through 2014. Past body weights at the ages of 20, 25, 30, 40 years, and 5 years before baseline as well as measured body weight at baseline were regressed on the ages. Slope and root-mean-square-error of the regression line were obtained and used to represent the weight changes and the weight fluctuation, respectively. The associations of the weight-change slopes and the weight fluctuation with incident T2DM were estimated by Cox proportional hazards models. RESULTS: During the median follow-up of 12.2 years, 400 incident cases of T2DM were documented. After adjustment for baseline overweight and other lifestyle covariates, the weight-change slopes were significantly associated with higher incidence of T2DM (hazard ratio (HR): 1.80, 95% confident interval (CI): 1.17-2.77 for men; and HR: 2.78, 95% CI: 1.07-7.23 for women), while the weight fluctuation was not (HR: 1.08, 95% CI: 1.00-1.18 for men and HR: 1.02, 95% CI: 0.84-1.25 for women). CONCLUSIONS: Regardless of the presence of overweight, the long-term weight-change slopes were significantly associated with the increased risk of T2DM; however, the weight fluctuation was not associated with the risk of T2DM in middle-aged Japanese men and women.

Association of coffee consumption with serum adiponectin, leptin, inflammation and metabolic markers in Japanese workers: a cross-sectional study.

BACKGROUND: Mechanisms underlying coffee's beneficial actions against cardiovascular disease and glucose metabolism are not well understood. Little information is available regarding association between coffee consumption and adipocytokines. OBJECTIVE: We investigated potential associations between coffee consumption and adiponectin, leptin, markers for subclinical inflammation, glucose metabolism, lipids and liver enzymes. We then investigated whether adipocytokines played a role in the association between coffee consumption and these markers. DESIGN AND SUBJECTS: This is a cross-sectional study comprising 2554 male and 763 female Japanese workers. Potential relations between coffee consumption and adipocytokines or other markers were evaluated using a multiple linear regression model adjusted for confounding factors. We evaluated whether adiponectin and leptin partly explain the associations between coffee consumption and each marker by multiple mediation analysis. RESULTS: Coffee consumption showed significant positive associations with adiponectin and total and low-density lipoprotein cholesterol, and inverse associations with leptin, high sensitivity C-reactive protein (hs-CRP), triglycerides and liver enzymes (all P<0.05). An adjustment for adiponectin and leptin significantly attenuated the associations between coffee consumption and hs-CRP or triglycerides, but not for liver enzymes. No associations were observed between coffee consumption and glucose metabolism-related markers. CONCLUSION: Coffee consumption was associated with high adiponectin and low leptin levels. We speculated that adipocytokines mainly explain the associations of coffee consumption with lipids and hs-CRP. Factors other than adipocytokines may explain the association between coffee consumption and liver function.

Smoking status, sports participation and mortality from coronary heart disease.

BACKGROUND: Since smoking and exercise have opposite effects on coronary risk factors, the hypothesis was proposed that smoking might weaken the protective effect of exercise on prevention of coronary heart disease. OBJECTIVE: To determine the effect of smoking on the relationship between sports participation and mortality from coronary heart disease. DESIGN: Population-based prospective cohort study in Japan. PARTICIPANTS: A total of 76 832 Japanese men and women, aged 40-79 years with no history of stroke, coronary heart disease, or cancer, completed a self-administered questionnaire between 1988 and 1990. MAIN OUTCOME MEASURES: Systematic mortality surveillance was carried out through 2003, and 638 deaths from coronary heart disease (496 myocardial infarction) were identified. RESULTS: People who reported the longest time in sports participation (>or=5 hours/week) had an approximately 50-80% lower age-adjusted risk of mortality from coronary heart disease compared with those in the second lowest category (1-2 hours/week) among never and ex-smokers, but no association was found among current smokers. Adjustment for known risk factors and exclusion of subjects who died within 2 years of the baseline inquiry did not substantially alter these associations. The multivariable hazard ratios (95% confidence interval) of coronary heart disease for the >or=5 hours/week versus 1-2 hours/week of sports participation were 0.44 (0.23 to 0.86) among never smokers, 0.18 (0.05 to 0.60) among ex-smokers, and 0.82 (0.47 to 1.40) among current smokers. Similar associations were found for men and women. CONCLUSIONS: Smoking may reduce the beneficial effect of sports participation for reduction of fatal coronary heart disease.

Parental longevity and mortality amongst Japanese men and women: the JACC Study.

OBJECTIVES: To examine whether the risk of mortality varies according to parents' age at death. DESIGN AND SUBJECTS: A large prospective study in Japanese men and women from 45 communities across Japan. A total of 51 485 men and women aged 40-79 years completed self-administered questionnaires at baseline and followed up for 9.6 years. RESULTS: The risk of mortality from stroke, cardiovascular disease, and all causes was 20-30% lower in men and women with fathers who died at age > or = 80 years, compared with those with fathers whose age at death was <60 years. A similar reduction was found when the age at death of mothers was > or = 85 years compared with <65 years. Furthermore, the risk reduction was more evident amongst persons with both parents being long-lived parents compared with those with being short-lived parents, especially for death from cardiovascular disease. CONCLUSIONS: Our findings indicate that parental longevity could be a predictor for reduced risk of mortality from stroke, cardiovascular disease, and all causes for both Japanese men and women.

Validity of self-reported height and weight in a Japanese workplace population.

OBJECTIVE: To assess the validity of self-reported height and weight in a Japanese workplace population, and to examine factors associated with the validity of self-reported weight. DESIGN: Comparison of self-reported height and weight with independent measurement. SUBJECTS: In total, 4253 men and 1148 women aged 35-64 y (mean measured body mass index (BMI): 23.3 kg/m(2) in men, 21.9 kg/m(2) in women) were included in the study. MEASUREMENTS: Self-reported height and weight were obtained by a self-administered questionnaire. Measured height and weight were based on annual health checkups. Sex, age, measured BMI, and the presence of hypertension, diabetes, and hyperlipidemia were examined as potential factors associated with the accuracy of self-reported weight. RESULTS: Self-reported height and weight were highly correlated with measured height and weight for men and women (Pearson's r for men and women: 0.979 and 0.988 in height, 0.961 and 0.959 in weight, 0.943 and 0.950 in BMI, respectively). For men, mean differences+/-2 s.d. of height and weight were 0.078+/-2.324 cm and -0.034+/-5.012 kg, respectively, and for women 0.029+/-1.652 cm and 0.024+/-4.192 kg, respectively. The prevalence of obesity with BMI > or =25 kg/m(2) based on self-reported data (23.6 and 11.5% for men and women, respectively) was slightly smaller than that based on measured data (24.9 and 12.4%, respectively). Specificity and sensitivity, however, were quite high for both men and women (sensitivity was 85.8 and 85.2%, and specificity was 97.0 and 98.9%, respectively). The subjects with higher measured BMI significantly underestimated their weight compared with those with smaller BMI after adjustments for age in men and women. Furthermore, the presence of diabetes in men and age in women affected self-reported weight. Neither the presence of hypertension nor hyperlipidemia was associated with reporting bias. CONCLUSION: The self-reported height and weight were generally reliable in the middle-aged employed Japanese men and women. However, it should be remembered that self-reported weight was biased by actual BMI and affected by age and the presence of diabetes.

Familial aggregation and coaggregation of history of hypertension and stroke.

We attempted to evaluate familial aggregation and coaggregation of history of hypertension and stroke. Past and family history of hypertension and stroke for 83 089 probands and their relatives were obtained from a data set for the Japan Collaborative Cohort Study for Evaluation of Cancer Risk sponsored by the Ministry of Education (JACC Study), which was initiated from 1988 to 1990. First, evaluation was performed for familial aggregation of each of two disorders using ordinal logistic regression of the generalized estimation equations (GEE) to account for dependence of observations within families. Secondly, in order to evaluate the familial congregation of the history of hypertension and stroke, a GEE-based multivariate probed predictive model was applied. After adjusting for the proband's age, level of obesity, smoking status, drinking status, habitation area, and the gender and type of the relatives, the estimated odds ratios for the intraindividual clustering and familial aggregation of the disease history showed statistically significant relationships. In addition, the history of the two disorders showed a significant relationship in terms of familial coaggregation independently of the aggregation of each disorder itself. Our results confirmed that hypertension and stroke coaggregate strongly within families through possible effects of genetic factors, which, alone or in conjunction with environmental factors, influence susceptibility to both hypertension and stroke.

Individual and joint impact of family history and Helicobacter pylori infection on the risk of stomach cancer: a nested case-control study.

We used 202 cases of stomach cancer and 394 controls nested within the Japan Collaborative Cohort Study For Evaluation of Cancer Risk (JACC study) to investigate whether family history has an independent effect on the risk of stomach cancer after controlling for the Helicobacter pylori infection. A positive history of stomach cancer in one or more first-degree relatives was associated with an increased risk of the disease in women, but not in men after controlling for H. pylori infection and other confounding variables. Women with both a family history and H. pylori infection were associated with more than five-fold increased risk of the disease (OR 5.10, 95% CI 1.58-16.5) compared to those without these factors. These results suggest the existence of inherited susceptibility to the disease in women, and that measurements of H. pylori infection together with the family history allow meaningful evaluation of risk beyond that provided by either factor alone.

Bowel movement frequency and risk of colorectal cancer in a large cohort study of Japanese men and women.

The relationship between bowel movement (BM) frequency and the risk of colorectal cancer was examined in a large cohort of 25 731 men and 37 198 women living in 24 communities in Japan. At enrolment, each participant completed a self-administrated questionnaire on BM frequency and laxative use. Incidence rate ratios (IRR) with 95% confidence intervals (CI) were estimated using Cox's proportional-hazard model. During the follow-up period (average length 7.6 years), 649 cases of colorectal cancer, including 429 cases of colon cancer, were identified. Among women, subjects who reported a BM every 2-3 days had the lowest risk of developing colorectal (IRR=0.71, 95% CI=0.52-0.97) and colon cancer (IRR=0.70, 95% CI=0.49-1.00), whereas those reporting a BM every 6 days or less had an increased risk of developing colorectal (IRR=2.47, 95% CI=1.01-6.01) and colon cancer (IRR=2.52, 95% CI=0.93-6.82) compared with those reporting >or=1 BM per day. A similar, but nonsignificant, association between the frequency of BM and cancer risk was observed in men. There was no association between colorectal or colon cancer risk and laxative use. Regulating BM frequency might therefore have a role in the prevention of colorectal cancer.

A prospective study of body size and colon cancer mortality in Japan: The JACC Study.

OBJECTIVE: To determine whether body size measurements are risk factors for colon cancer death among the Japanese. DESIGN AND SUBJECTS: A nationwide prospective study, the Japan Collaborative Cohort (JACC) Study from 1988 to 1999. The present analysis included 43 171 men and 58 775 women aged 40-79 y who respond to a questionnaire on current weight and height, weight around 20 y of age, and other lifestyle factors. Body mass index (BMI) at baseline and 20 y of age (B-BMI and 20-BMI, respectively) were calculated. RESULTS: We identified 127 deaths from colon cancer during the follow-up of 424 698 person-years among men and 122 deaths during the follow-up of 591 787 person-years among women. After adjustments for the lifestyle factors known to modify the risk of colon cancer, weight at baseline showed a significant positive association in women, while no such association was seen in men. There was also a significant trend of increasing risk with the increase in B-BMI among women. Women with B-BMI >/=28 kg/m(2) had a relative risk (RR) of 3.41 (95% confidence interval (CI): 1.44-8.06) compared with those with BMI of 20-<22 kg/m(2). 20-BMI also presented the same trend of increasing risk as B-BMI. Women with 20-BMI of <22 and B-BMI of >26 kg/m(2), that is, excessive BMI gain, had a high RR of 3.41 (95% CI 1.29-9.02) compared with those with 20-BMI of <22 and B-BMI of <22 kg/m(2). There were no corresponding trends of colon cancer risk for B-BMI, 20-BMI, or BMI change among men. CONCLUSIONS: These study data suggest that obesity and excessive weight gain are associated with the risk of colon cancer death in Japanese women but no such relationship was found in Japanese men.

A nested case-control study of stomach cancer in relation to green tea consumption in Japan.

To evaluate whether green tea consumption provides protection against stomach cancer, the relative risks (RRs) were calculated in the Japan Collaborative Study for Evaluation of Cancer Risk, sponsored by the Ministry of Health and Welfare (JACC Study). The study was based on 157 incident cases and 285 controls aged 40-79 years. Cox proportional hazards regression analysis was used to estimate the RRs for stomach cancer. It was found that green tea consumption had no protective effect against stomach cancer. After adjustment for age, smoking status, H. pylori infection, history of peptic ulcer, and family history of stomach cancer along with certain dietary elements, the risks associated with drinking one or two, three or four, five to nine, and 10 or more cups of green tea per day, relative to those of drinking less than one cup per day, were 1.3 (95% confidence interval (CI): 0.6-2.8), 1.0 (95% CI: 0.5-1.9), 0.8 (95% CI: 0.4-1.6), and 1.2 (95% CI: 0.6-2.5), respectively (P for trend=0.899). We found no inverse association between green tea consumption and the risk of stomach cancer.

Long-term body weight variability is associated with elevated C-reactive protein independent of current body mass index among Japanese men.

OBJECTIVE: To elucidate the effect of long-term weight variability on C-reactive protein (CRP) levels. DESIGN: Cross-sectional study of the circulating CRP. SUBJECTS: A total of 637 Japanese men aged 40-49 y in1997. MEASUREMENTS: Serum CRP levels, body mass index in 1997 (current BMI), the slope of weight on age (weight-slope) representing an individual's weight trend of direction and magnitude, and the root mean square error around the slope of weight on age (weight-RMSE) representing the weight fluctuation magnitude, as calculated by a simple linear regression model in which each value of the subject's five actual weights (aged 20, 25, 30 y, five years ago, and current) was a dependent variable and the subject's ages independent variables. RESULTS: After adjustment for age and confounders, including smoking and health status, the odds ratios of elevated CRP (> or =0.06 mg/dl) were 1.83 (95% CI: 1.25-2.69), 2.63 (1.69-4.11), and 10.31 (2.17-48.98) for upper normal-weight (BMI: 22-<25 kg/m(2)), overweight (25-<30), and obese (> or =30) persons, respectively, compared with lower normal-weight persons (18.5-<22). Adjusting for age, confounders, and current BMI, weight-slope was positively associated with CRP level especially among subjects with BMI> or =25 kg/m(2) (trend P<0.01), and weight-RMSE was positively associated with CRP level particularly among subjects with BMI <25 kg/m(2) (trend P<0.05). CONCLUSION: Our results suggest a state of low-grade systemic inflammation not only in overweight and obese persons, but also in normal-weight persons with large weight fluctuation, possibly explaining in part the positive association between weight fluctuation and CVD.

The metabolic syndrome is associated with elevated circulating C-reactive protein in healthy reference range, a systemic low-grade inflammatory state.

OBJECTIVE: To elucidate the underlying mechanisms between C-reactive protein (CRP) and cardiovascular disease, we examined the association of circulating CRP in healthy reference range (< or =1.0 mg/dl) measured by high-sensitive CRP assay with the metabolic syndrome (MS). DESIGN: Cross-sectional study of circulating CRP in adult men. SUBJECTS: A total of 3692 Japanese men aged 34-69 y. MEASUREMENTS: Serum CRP, total cholesterol, triglycerides, LDL-cholesterol, fasting glucose, fasting insulin, uric acid, systolic blood pressure, diastolic blood pressure, and body mass index (BMI). RESULTS: There was a statistically significant positive correlation between CRP and BMI (r=0.25), total cholesterol (r=0.096), triglycerides (r=0.22), LDL-cholesterol (r=0.12), fasting glucose (r=0.088), fasting insulin (r=0.17), uric acid (r=0.13), systolic blood pressure (r=0.12), and diastolic blood pressure (r=0.11), and a significant negative correlation of CRP with HDL-cholesterol (r=0.24). After adjusting for age, smoking, and all other components of MS, obesity, hypertriglyceridemia, hyper-LDL-cholesterolemia, diabetes, hyperinsulinemia, and hyperuricemia were significantly associated with both mildly (> or =0.06 mg/dl) and moderately (> or =0.11 mg/dl) elevated CRP. Compared with men who had no such components of the MS, those who had one, two, three, four, and five or more components were, respectively, 1.48, 1.84, 1.92, 3.42, and 4.17 times more likely to have mildly elevated CRP levels (trend P<0.001). As for moderately elevated CRP, the same association was observed. CONCLUSIONS: These results indicate that a variety of components of the MS are associated with elevated CRP levels in a systemic low-grade inflammatory state.

Association between weight fluctuation and fasting insulin concentration in Japanese men.

OBJECTIVE: To investigate whether long-term weight fluctuation is associated with the fasting serum insulin concentration. DESIGN AND SUBJECTS: Weight histories of 1932 male Japanese workers aged 40-59 y were analyzed in relation to their current fasting serum insulin concentration. MEASUREMENTS: Individual weight fluctuation was calculated by root mean square error (RMSE) along the linear regression line of weight measured at five to six different ages. RESULTS: The mean RMSE and fasting insulin concentration were 1.22 kg and 4.5 microU/ml, respectively. The multivariate adjusted insulin level became higher with the increase in weight fluctuation. Subanalysis stratified by current body mass index (BMI) showed that the multivariate adjusted insulin level in individuals in the top quartile of fluctuation was 4.3 microU/ml, against 3.9 microU/ml in those in the bottom quartile (P=0.018, analysis of covariance (ANCOVA)) in the normal weight subgroup with current BMI below 25 kg/m(2). In the overweight subgroup with BMI 25 kg/m(2) or above, the level was 6.9 microU/ml in individuals in the top quartile and 6.2 microU/ml in those in the bottom quartile (P=0.054, ANCOVA). CONCLUSION: The results suggest that weight fluctuation increases the risk of developing hyperinsulinemia. Prospective observations together with measurement of changes in adiposity are needed for confirmation.

The accuracy of long-term recall of past body weight in Japanese adult men.

OBJECTIVE: To examine the influences of recall period, current body weight, weight gain and loss, and weight variability on the accuracy of long-term recall of past weight. DESIGN AND SUBJECTS: Comparison of recalled weights around 25 y old with weights measured at age 25y in health checkup records among 2453 Japanese men (age: 34-61 y). MEASUREMENTS: Deviations between reported and measured weights were examined as to the three indexes: actual error (reported-measured), percent error (actual error/measured x 100), and absolute value of the percent error. Weight variability was defined as (1) the coefficient of variation of weight (CV) and (2) the root mean square error around the slope of weight on age (RMSE). RESULTS: Recalled weight strongly correlated with measured weight (r=0.849). Correlation coefficients decreased as age or the elapsed time since age 25y increased. Recalled weight (mean=58.3 kg) was slightly greater than measured weight at age 25y (mean=57.0 kg, mean actual error=1.28 kg). Subjects with a current body mass index (BMI) of less than 28.6 kg/m(2) overestimated their past weights, whereas those with BM1 of 28.6 kg/m(2) or over underestimated it. Subjects with weight loss since age 25y underestimated their past weights, whereas those with stable weight or gain overestimated it. There were monotonic increases in the three indexes of deviation across the CV quartile categories. Concerning the effect RMSE, a similar trend was observed. CONCLUSION: These results indicate that past body weights over a long period seem to be recalled with good accuracy. However, it should be kept in mind when using recalled weight in an epidemiologic study that accuracy of recall is influenced by age or elapsed time, current BMI, weight gain and loss, and weight variability.

A prospective study of stomach cancer death in relation to green tea consumption in Japan.

To evaluate whether green tea consumption provides protection against stomach cancer death, relative risks were calculated using Cox proportional hazards regression analysis in the Japan Collaborative Study for Evaluation of Cancer Risk, sponsored by the Ministry of Health and Welfare (JACC Study). The study was based on 30 370 men and 42 481 women aged 40-79. After adjustment for age, smoking status, history of peptic ulcer, family history of stomach cancer along with certain dietary items, the risks associated with drinking one or two, three or four, five to nine, and 10 or more cups of green tea per day, relative to those of drinking less than one cup per day, were 1.6 (95% CI: 0.9-2.9), 1.1 (95% CI: 0.6-1.9), 1.0 (95% CI: 0.5-2.0), and 1.0 (95% CI: 0.5-2.0), respectively, in men (P for trend=0.669), and 1.1 (95% CI: 0.5-2.5), 1.0 (95% CI: 0.5-2.5), 0.8 (95% CI: 0.4-1.6), and 0.8 (95% CI: 0.3-2.1), respectively, in women (P for trend=0.488). We found no inverse association between green tea consumption and the risk of stomach cancer death.

Elevated levels of vascular endothelial growth factor in the sera of patients with rheumatoid arthritis correlation with disease activity.

To evaluate vascular endothelial growth factor (VEGF) levels in relation to disease activity in rheumatoid arthritis (RA), VEGF in the serum of 155 patients with RA and 75 healthy control subjects was quantified by our highly sensitive enzyme-linked immunosorbent assay. VEGF levels were found to correlate with the articular index (AI) and Lansbury's activity index (LI). Patients with RA had a mean serum VEGF concentration of 153.5+/-111.8 pg/ml, which was significantly higher than control subjects (104.8+/-65.7 pg/ml; P<0.01). VEGF concentration was elevated significantly according to disease progression as expressed by stages I to IV and correlated with AI (r=0.530, P<0.0001) and LI (r=0.688, P<0.0001) in stages I and II as well as with the conventional erythrocyte sedimentation rate or serum C-reactive protein concentration. Serum VEGF levels may therefore be valuable as a marker of disease activity in patients with early RA, and this cytokine may play a significant role in the pathophysiology of RA.

Trends in the mortality (1950-1997) and incidence (1975-1993) of malignant ovarian neoplasm among Japanese women: analyses by age, time, and birth cohort.

OBJECTIVE: The purpose of this study was to explore epidemiological features of malignant ovarian neoplasm in Japan. METHODS: The number of deaths from malignant ovarian neoplasm was obtained from the national vital statistics. Estimated incidence rates, based on several cancer registries, were also used for analyses. We divided the subjects into two age groups (0-29 and 30+ years) and examined secular trends in mortality (1950-1997) and incidence (1975-1993) by age, time, and birth cohort. RESULTS: The age-adjusted mortality rate has increased approximately 4-fold (from 0.9 to 3.6 per 100,000 women) from 1950 to 1997. Age-specific mortality rates showed a rising pattern in the elderly, whereas mortality in the younger people tended to increase in the 1950s and 1960s, but then decreased in the 1970s and afterward. In analyses using a mathematical model, the time effect in the population aged 0-29 years increased with advancing period up to 1970, and then decreased. The cohort effects had positive values, which indicate higher than additive influence from age/time effect, for birth cohorts from 1900 to 1935. The age-adjusted incidence rate increased approximately 1.5-fold (from 3.6 to 5.7) from 1975 to 1993. The rate increased in the early 1980s, but has remained stable since the late 1980s. Age-specific incidence rates in older age groups increased steadily up to 1985, and have remained stable since, while the rates in younger women have remained almost unchanged. CONCLUSION: The major effects on malignant ovarian neoplasm in Japan are supposed to be due to declining parity and therapeutic improvements.

Sterol regulatory element-binding proteins induce an entire pathway of cholesterol synthesis.

To evaluate the effects of sterol regulatory element-binding proteins (SREBPs) on the expression of the individual enzymes in the cholesterol synthetic pathway, we examined expression of these genes in the livers from wild-type and transgenic mice overexpressing nuclear SREBP-1a or -2. As estimated by a Northern blot analysis, overexpression of nuclear SREBP-1a or -2 caused marked increases in mRNA levels of the whole battery of cholesterogenic genes. This SREBP activation covers not only rate-limiting enzymes such as HMG CoA synthase and reductase that have been well established as SREBP targets, but also all the enzyme genes in the cholesterol synthetic pathway tested here. The activated genes include mevalonate kinase, mevalonate pyrophosphate decarboxylase, isopentenyl phosphate isomerase, geranylgeranyl pyrophosphate synthase, farnesyl pyrophosphate synthase, squalene synthase, squalene epoxidase, lanosterol synthase, lanosterol demethylase, and 7-dehydro-cholesterol reductase. These results demonstrate that SREBPs activate every step of cholesterol synthetic pathway, contributing to an efficient cholesterol synthesis.

Insulin up-regulates tumor necrosis factor-alpha production in macrophages through an extracellular-regulated kinase-dependent pathway.

Hyperinsulinemia has recently been reported as a risk factor for atherosclerotic diseases such as coronary heart disease; however, the effect of insulin on the development of atherosclerosis is not well understood. Here we have investigated the direct effect of insulin on macrophages, which are known to be important in the atherosclerotic process. We treated THP-1 macrophages with insulin (10(-7) m) and examined the gene expression using nucleic acid array systems. The results of array analysis showed that insulin stimulated gene expression of tumor necrosis factor-alpha (TNF-alpha) the most among all genes in the analysis. In addition, insulin administration to macrophages enhanced both mRNA expression and protein secretion of TNF-alpha in a dose-dependent manner. To determine the signaling pathway involved in this TNF-alpha response to insulin, we pretreated the cells with three distinct protein kinase inhibitors: wortmannin, PD98059, and SB203580. Only PD98059, which inhibits extracellular signal-regulated kinases, suppressed insulin-induced production of TNF-alpha mRNA and protein in THP-1 macrophages. These observations indicate that insulin stimulates TNF-alpha production in macrophages by regulating the expression of TNF-alpha mRNA and that the extracellular signal-regulated kinase signaling pathway may have a critical role in stimulating the production of TNF-alpha in response to insulin in macrophages.

Leg edema, ST-T abnormalities, and high BNP values are important signs of heart failure in the elderly.

This study was aimed at the mechanism of the circulatory failure characteristic of the elderly through elucidating the cause of leg edema frequently found in patients under treatment in health care facilities for physical or mental handicaps. ECG and measurement of atrial (ANP) and brain (BNP) natriuretic peptides were carried out on 156 patients (mostly females aged 84 years on average) and echocardiographic assessment was done on 44 patients. Non-specific ST-T abnormalities were frequently found in patients with moderate or severe leg edema (61 vs. 37% in those with slight or no edema). BNP levels were markedly increased in patients with either leg edema or ECG abnormalities (Group B) and with both (Group C) compared with those without either (Group A), with averages of 35.5+/-23.9, 91.3+/-80.1, and 184.3+/-139.0 pg/ml, respectively, for Group A, B, and C. UCG examination revealed marked regurgitation of cardiac valves, more frequently in patients with BNP over 50 pg/ml than in those with less (14/24 vs. 2/20), with a difference in extent of 5.7 versus 1.6 on an arbitrary scale. In addition to left ventricular hypertrophy, dilatation of the left atrium and inferior vena cava was frequently observed in patients with higher BNP levels. It is concluded that both cardiac valve regurgitation and myocardial damage represented by ST-T abnormalities on ECG result in heart failure characteristic of the elderly, and that an increase in BNP is an important sign of such heart failure.