Bisphenol A (BPA) is suspected to be associated with several chronic metabolic diseases. The aim of the present study was to review the epidemiological literature on the relation between BPA exposure and the risk of cardiometabolic disorders. PubMed and Embase databases were searched up to August 2014 by two independent investigators using standardized subject terms. We included observational studies (cohort, case–control and cross-sectional studies) carried out in children or adults, measuring urinary BPA (uBPA), including at least 100 participants and published in English. The health outcomes of interest were diabetes, hyperglycemia, measures of anthropometry, cardiovascular disease (CVD) and hypertension. Data were extracted and meta-analyzed when feasible, using a random-effects model. Thirty-three studies with sample size ranging from 239 to 4811 met the inclusion criteria, including five with a prospective design. Twelve studies reported on diabetes or hyperglycemia, 16 on anthropometry, 6 on CVD and 3 on hypertension. Evidence for a positive association between uBPA concentrations and diabetes, overweight, obesity, elevated waist circumference (WC), CVD and hypertension was found in 7/8, 2/7, 6/7, 5/5, 4/5 and 2/3 of the cross-sectional studies, respectively. We were able to conduct outcome-specific meta-analyses including 12 studies. When comparing the highest vs. the lowest uBPA concentrations, the pooled ORs were 1.47 (95 % CI: 1.21–1.80) for diabetes, 1.21 (95 % CI: 0.98–1.50) for overweight, 1.67 (95 % CI: 1.41–1.98) for obesity, 1.48 (95 % CI: 1.25–1.76) for elevated WC, and 1.41 (95 % CI: 1.12–1.79) for hypertension. Moreover, among the five prospective studies, 3 reported significant findings, relating BPA exposure to incident diabetes, incident coronary artery disease, and weight gain. To conclude, there is evidence from the large body of cross-sectional studies that individuals with higher uBPA concentrations are more likely to suffer from diabetes, general/abdominal obesity and hypertension than those with lower uBPA concentrations. Given the potential importance for public health, prospective cohort studies with proper adjustment for dietary characteristics and identification of critical windows of exposure are urgently needed to further improve knowledge about potential causal links between BPA exposure and the development of chronic disease.

OBJECTIVE: To investigate whether the association between insulin resistance and cardiovascular disease (CVD) differs by glucose tolerance status. RESEARCH DESIGN AND METHODS: We analyzed a nationwide sample of 111,576 adults without CVD at baseline, using data from the China Cardiometabolic Disease and Cancer Cohort Study. Insulin resistance was estimated by sex-specific HOMA of insulin resistance (HOMA-IR) quartiles for participants with normal glucose tolerance, prediabetes, or diabetes, separately, and by 1 SD of HOMA-IR for the overall study participants. We used Cox proportional hazards models to examine the association between insulin resistance and incident CVD according to glucose tolerance status and evaluate the CVD risk associated with the combined categories of insulin resistance and obesity in prediabetes and diabetes, as compared with normal glucose tolerance. Models were adjusted for age, sex, education attainment, alcohol drinking, smoking, physical activity, and diet quality. RESULTS: In participants with normal glucose tolerance, prediabetes, and diabetes defined by three glucose parameters, multivariable-adjusted hazard ratios (95% CIs) for incident CVD associated with the highest versus the lowest quartile of HOMA-IR were 1.03 (0.82–1.30), 1.23 (1.07–1.42), and 1.61 (1.30–2.00), respectively; the corresponding values for CVD per 1-SD increase in HOMA-IR were 1.04 (0.92–1.18), 1.12 (1.06–1.18), and 1.15 (1.09–1.21), respectively (P for interaction = 0.011). Compared with participants with normal glucose tolerance, in participants with prediabetes, the combination of the highest HOMA-IR quartile and obesity showed 17% (95% CI 2–34%) higher risk of CVD, while the combination of the lowest two HOMA-IR quartiles and nonobesity showed 15–17% lower risk of CVD. In participants with diabetes, the upper two HOMA-IR quartiles exhibited 44–77% higher risk of CVD, regardless of obesity status. Consistent findings were observed for glucose tolerance status defined by different combinations of glycemic parameters. CONCLUSIONS: Glucose intolerance status exacerbated the association between insulin resistance and CVD risk. Compared with adults with normal glucose tolerance, adults with prediabetes who were both insulin resistant and obese exhibited higher risks of CVD, while in adults with diabetes, the CVD risk related to insulin resistance remained, regardless of obesity.

OBJECTIVE Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We examined the association of serum BA profile and coregulation with the risk of developing type 2 diabetes mellitus (T2DM) among normoglycemic Chinese adults. RESEARCH DESIGN AND METHODS We tested 23 serum BA species in subjects with incident diabetes (n = 1,707) and control subjects (n = 1,707) matched by propensity score (including age, sex, BMI, and fasting glucose) from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was composed of 54,807 normoglycemic Chinese adults with a median follow-up of 3.03 years. Multivariable-adjusted odds ratios (ORs) for associations of BAs with T2DM were estimated using conditional logistic regression. RESULTS In multivariable-adjusted logistic regression analysis, per SD increment of unconjugated primary and secondary BAs were inversely associated with incident diabetes, with an OR (95% CI) of 0.89 (0.83–0.96) for cholic acid, 0.90 (0.84–0.97) for chenodeoxycholic acid, and 0.90 (0.83–0.96) for deoxycholic acid (P < 0.05 and false discovery rate <0.05). On the other hand, conjugated primary BAs (glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, and sulfated glycochenodeoxycholic acid) and secondary BA (tauroursodeoxycholic acid) were positively related with incident diabetes, with ORs ranging from 1.11 to 1.19 (95% CIs ranging between 1.05 and 1.28). In a fully adjusted model additionally adjusted for liver enzymes, HDL cholesterol, diet, 2-h postload glucose, HOMA-insulin resistance, and waist circumference, the risk estimates were similar. Differential correlation network analysis revealed that perturbations in intraclass (i.e., primary and secondary) and interclass (i.e., unconjugated and conjugated) BA coregulation preexisted before diabetes onset. CONCLUSIONS These findings reveal novel changes in BAs exist before incident T2DM and support a potential role of BA metabolism in the pathogenesis of diabetes.

Background: Education, intelligence, and cognition are associated with hypertension, but which one plays the most prominent role in the pathogenesis of hypertension and which modifiable risk factors mediate the causal effects remains unknown. Methods: Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted 2-sample multivariable Mendelian randomization to estimate the independent effects of education, intelligence, or cognition on hypertension (FinnGen study, 70 651 cases/223 663 controls; UK Biobank, 77 723 cases/330 366 controls) and blood pressure (International Consortium of Blood Pressure, 757 601 participants), and used 2-step Mendelian randomization to evaluate 25 potential mediators of the association and calculate the mediated proportions. Results: Meta-analysis of inverse variance weighted Mendelian randomization results from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was associated with 44% (95% CI: 0.40–0.79) decreased hypertension risk and 1.682 mm Hg lower systolic and 0.898 mm Hg lower diastolic blood pressure, independently of intelligence and cognition. While the causal effects of intelligence and cognition on hypertension were not independent of education; 6 out of 25 cardiometabolic risk factors were identified as mediators of the association between education and hypertension, ranked by mediated proportions, including body mass index (mediated proportion: 30.1%), waist-to-hip ratio (22.8%), body fat percentage (14.1%), major depression (7.0%), high-density lipoprotein cholesterol (4.7%), and triglycerides (3.4%). These results were robust to sensitivity analyses. Conclusions: Our findings illustrated the causal, independent impact of education on hypertension and blood pressure and outlined cardiometabolic mediators as priority targets for prevention of hypertension attributable to low education.

The causal influence of sarcopenia on cardiometabolic disease and Alzheimer's disease and whether and to what extent insulin resistance plays a mediating role therein were unclear. We performed two‐step, two‐sample Mendelian randomization applying genetic instruments of sarcopenia‐related traits based on GWASs from the UK Biobank (up to 461,026 European participants) to examine their causal associations with six cardiometabolic diseases and Alzheimer's disease extracted from large‐scale European descent GWASs with adjustment for body fat percentage and physical activity, and to assess proportions of the causal effects mediated by insulin resistance. Genetic instruments of insulin resistance were derived from the GWASs by Meta‐Analyses of Glucose and Insulin‐related traits Consortium and Global Lipids Genetics Consortium. Each 1‐SD lower grip strength, appendicular lean mass (ALM) and whole‐body lean mass (WBLM), as well as lower walking pace, were causally associated with higher risks of diabetes (odds ratio [OR] range: 1.20 [95% confidence interval: 1.10–1.32] for ALM to 2.30 [1.14–4.68] for walking pace), nonalcoholic fatty liver disease ([NAFLD], 1.33 [1.08–1.64] for ALM to 2.30 [1.02–5.18] for grip strength), hypertension (1.12 [1.05–1.20] for ALM to 4.43 [2.68–7.33] for walking pace), coronary heart disease ([CHD], 1.20 [1.13–1.27] for ALM to 2.73 [1.84–4.05] for walking pace), myocardial infarction ([MI], 1.18 [1.11–1.25] for ALM to 2.47 [1.63–3.73] for walking pace), small vessel stroke (1.25 [1.15–1.37] for ALM to 1.29 [1.10–1.52] for WBLM), and Alzheimer's disease (1.10 [1.05–1.15] for ALM to 1.28 [1.19–1.38] for WBLM). These causal associations were largely independent of body fat percentage and physical activity. Insulin resistance mediated 16%–34% of the effect of grip strength and 7%–28% of the effect of ALM on diabetes, NAFLD, hypertension, CHD, and MI. The direct effect of WBLM on diabetes diminished toward null with adjustment for insulin resistance. We found no evidence that insulin resistance was on the causal pathways from walking pace to the studied disease outcomes. Causal findings from the inverse‐variance weighted method were validated by sensitivity analyses. These findings support improving sarcopenia‐related traits as precautions against major cardiometabolic diseases and Alzheimer's disease, with particular emphasis on insulin resistance as a target in the intervention of sarcopenia‐related cardiometabolic risk.