Transforming Growth Factor-β1 and Incident Type 2 Diabetes: Results from the MONICA/KORA case-cohort study, 1984–2002

Subclinical inflammation leads to insulin resistance and beta-cell dysfunction. This study aimed to assess whether levels of circulating transforming growth factor-beta1 (TGF-beta1)-a central, mainly immunosuppressive, and anti-inflammatory cytokine-were associated with incident type 2 diabetes. RESEARCH DESIGN AND METHODS: We measured serum levels of TGF-beta1 from 460 individuals with and 1,474 individuals without incident type 2 diabetes in a prospective case-cohort study within the population-based MONICA (MONItoring of Trends and Determinants in CArdiovascular Disease)/KORA (Cooperative Health Research in the Region of Augsburg) cohort. RESULTS: Elevated TGF-beta1 concentrations were associated with higher, not lower, risk for type 2 diabetes (age-, sex-, and survey-adjusted hazard ratios [95% CI] for increasing TGF-beta1 tertiles: 1.0, 1.08 [0.83-1.42], and 1.41 [1.08-1.83]; P(for) (trend) = 0.012). Adjustment for BMI and metabolic and lifestyle factors had virtually no impact on the effect size. CONCLUSIONS: Elevated serum concentrations of the cytokine TGF-beta1 indicate an increased risk for type 2 diabetes. TGF-beta1 may be upregulated to counterbalance metabolic and immunological disturbances preceding type 2 diabetes

Effect of serum 25-hydroxyvitamin D on risk for type 2 diabetes may be partially mediated by subclinical inflammation: results from the MONICA/KORA Augsburg study

OBJECTIVE: To assess the association between serum 25-hydroxyvitamin D (25-OHD) and incident type 2 diabetes and to determine whether the association is mediated by subclinical inflammation. RESEARCH DESIGN AND METHODS: Using a case-cohort design, baseline levels of 25-OHD were measured in 416 case subjects with incident type 2 diabetes and 1,267 noncase subjects selected from a source population of 7,936 middle-aged participants in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) study. RESULTS: A significant inverse association was observed between serum 25-OHD and incident type 2 diabetes after adjustment for diabetes risk factors and season. The hazard ratio (HR) and 95% CI comparing tertile extremes was 0.63 (0.44–0.90) (P(trend) = 0.010). Further adjustment for C-reactive protein, interleukin-6, soluble intercellular adhesion molecule-1, and interferon-γ–inducible protein-10 attenuated this association by 16% (HR 0.73 [0.50–1.05], P = 0.090). CONCLUSIONS: Vitamin D status is inversely related to type 2 diabetes risk and our data suggest that this association may be partially mediated by subclinical inflammation

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women

Immunological and Cardiometabolic Risk Factors in the Prediction of Type 2 Diabetes and Coronary Events: MONICA/KORA Augsburg Case-Cohort Study

BACKGROUND: This study compares inflammation-related biomarkers with established cardiometabolic risk factors in the prediction of incident type 2 diabetes and incident coronary events in a prospective case-cohort study within the population-based MONICA/KORA Augsburg cohort. METHODS AND FINDINGS: Analyses for type 2 diabetes are based on 436 individuals with and 1410 individuals without incident diabetes. Analyses for coronary events are based on 314 individuals with and 1659 individuals without incident coronary events. Mean follow-up times were almost 11 years. Areas under the receiver-operating characteristic curve (AUC), changes in Akaike's information criterion (ΔAIC), integrated discrimination improvement (IDI) and net reclassification index (NRI) were calculated for different models. A basic model consisting of age, sex and survey predicted type 2 diabetes with an AUC of 0.690. Addition of 13 inflammation-related biomarkers (CRP, IL-6, IL-18, MIF, MCP-1/CCL2, IL-8/CXCL8, IP-10/CXCL10, adiponectin, leptin, RANTES/CCL5, TGF-β1, sE-selectin, sICAM-1; all measured in nonfasting serum) increased the AUC to 0.801, whereas addition of cardiometabolic risk factors (BMI, systolic blood pressure, ratio total/HDL-cholesterol, smoking, alcohol, physical activity, parental diabetes) increased the AUC to 0.803 (ΔAUC [95% CI] 0.111 [0.092-0.149] and 0.113 [0.093-0.149], respectively, compared to the basic model). The combination of all inflammation-related biomarkers and cardiometabolic risk factors yielded a further increase in AUC to 0.847 (ΔAUC [95% CI] 0.044 [0.028-0.066] compared to the cardiometabolic risk model). Corresponding AUCs for incident coronary events were 0.807, 0.825 (ΔAUC [95% CI] 0.018 [0.013-0.038] compared to the basic model), 0.845 (ΔAUC [95% CI] 0.038 [0.028-0.059] compared to the basic model) and 0.851 (ΔAUC [95% CI] 0.006 [0.003-0.021] compared to the cardiometabolic risk model), respectively. CONCLUSIONS: Inclusion of multiple inflammation-related biomarkers into a basic model and into a model including cardiometabolic risk factors significantly improved the prediction of type 2 diabetes and coronary events, although the improvement was less pronounced for the latter endpoint

HbA(1c) levels in non-diabetic older adults No J-shaped associations with primary cardiovascular events, cardiovascular and all-cause mortality after adjustment for confounders in a meta-analysis of individual participant data from six cohort studies

Background To determine the shape of the associations of HbA1c with mortality and cardiovascular outcomes in non-diabetic individuals and explore potential explanations. Methods The associations of HbA1c with all-cause mortality, cardiovascular mortality and primary cardiovascular events (myocardial infarction or stroke) were assessed in non-diabetic subjects ≥50 years from six population-based cohort studies from Europe and the USA and meta-analyzed. Very low, low, intermediate and increased HbA1c were defined as <5.0, 5.0 to <5.5, 5.5 to <6.0 and 6.0 to <6.5 % (equals <31, 31 to <37, 37 to <42 and 42 to <48 mmol/mol), respectively, and low HbA1c was used as reference in Cox proportional hazards models. Results Overall, 6,769 of 28,681 study participants died during a mean follow-up of 10.7 years, of whom 2,648 died of cardiovascular disease. Furthermore, 2,493 experienced a primary cardiovascular event. A linear association with primary cardiovascular events was observed. Adjustment for cardiovascular risk factors explained about 50 % of the excess risk and attenuated hazard ratios (95 % confidence interval) for increased HbA1c to 1.14 (1.03–1.27), 1.17 (1.00–1.37) and 1.19 (1.04–1.37) for all-cause mortality, cardiovascular mortality and cardiovascular events, respectively. The six cohorts yielded inconsistent results for the association of very low HbA1c levels with the mortality outcomes and the pooled effect estimates were not statistically significant. In one cohort with a pronounced J-shaped association of HbA1c levels with all-cause and cardiovascular mortality (NHANES), the following confounders of the association of very low HbA1c levels with mortality outcomes were identified: race/ethnicity; alcohol consumption; BMI; as well as biomarkers of iron deficiency anemia and liver function. Associations for very low HbA1c levels lost statistical significance in this cohort after adjusting for these confounders. Conclusions A linear association of HbA1c levels with primary cardiovascular events was observed. For cardiovascular and all-cause mortality, the observed small effect sizes at both the lower and upper end of HbA1c distribution do not support the notion of a J-shaped association of HbA1c levels because a certain degree of residual confounding needs to be considered in the interpretation of the results

HbA1c levels in non-diabetic older adults - No J-shaped associations with primary cardiovascular events, cardiovascular and all-cause mortality after adjustment for confounders in a meta-analysis of individual participant data from six cohort studies

Background:To determine the shape of the associations of HbA1c with mortality and cardiovascular outcomes in non-diabetic individuals and explore potential explanations. Methods: The associations of HbA1c with all-cause mortality, cardiovascular mortality and primary cardiovascular events (myocardial infarction or stroke) were assessed in non-diabetic subjects ≥50 years from six population-based cohort studies from Europe and the USA and meta-analyzed. Very low, low, intermediate and increased HbA1c were defined as <5.0, 5.0 to <5.5, 5.5 to <6.0 and 6.0 to <6.5 % (equals <31, 31 to <37, 37 to <42 and 42 to <48 mmol/mol), respectively, and low HbA1c was used as reference in Cox proportional hazards models. Results:Overall, 6,769 of 28,681 study participants died during a mean follow-up of 10.7 years, of whom 2,648 died of cardiovascular disease. Furthermore, 2,493 experienced a primary cardiovascular event. A linear association with primary cardiovascular events was observed. Adjustment for cardiovascular risk factors explained about 50 % of the excess risk and attenuated hazard ratios (95 % confidence interval) for increased HbA1c to 1.14 (1.03–1.27), 1.17 (1.00–1.37) and 1.19 (1.04–1.37) for all-cause mortality, cardiovascular mortality and cardiovascular events, respectively. The six cohorts yielded inconsistent results for the association of very low HbA1c levels with the mortality outcomes and the pooled effect estimates were not statistically significant. In one cohort with a pronounced J-shaped association of HbA1c levels with all-cause and cardiovascular mortality (NHANES), the following confounders of the association of very low HbA1c levels with mortality outcomes were identified: race/ethnicity; alcohol consumption; BMI; as well as biomarkers of iron deficiency anemia and liver function. Associations for very low HbA1c levels lost statistical significance in this cohort after adjusting for these confounders.Conclusions: A linear association of HbA1c levels with primary cardiovascular events was observed. For cardiovascular and all-cause mortality, the observed small effect sizes at both the lower and upper end of HbA1c distribution do not support the notion of a J-shaped association of HbA1c levels because a certain degree of residual confounding needs to be considered in the interpretation of the results. Keywords: Glycated hemoglobin, Cardiovascular disease, Myocardial infarction, Stroke, Mortality, Cohort study, Meta-analysi

Association between variations in the TLR4 gene and incident type 2 diabetes is modified by the ratio of total cholesterol to HDL-cholesterol

<p>Abstract</p> <p>Background</p> <p>Toll-like receptor 4 (TLR4), the signaling receptor for lipopolysaccharides, is an important member of the innate immunity system. Since several studies have suggested that type 2 diabetes might be associated with changes in the innate immune response, we sought to investigate the association between genetic variants in the <it>TLR4 </it>gene and incident type 2 diabetes.</p> <p>Methods</p> <p>A case-cohort study was conducted in initially healthy, middle-aged subjects from the MONICA/KORA Augsburg studies including 498 individuals with incident type 2 diabetes and 1,569 non-cases. Seven SNPs were systematically selected in the <it>TLR4 </it>gene and haplotypes were reconstructed.</p> <p>Results</p> <p>The effect of <it>TLR4 </it>SNPs on incident type 2 diabetes was modified by the ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C). In men, four out of seven <it>TLR4 </it>variants showed significant interaction with TC/HDL-C after correction for multiple testing (p < 0.01). The influence of the minor alleles of those variants on the incidence of type 2 diabetes was observed particularly for male patients with high values of TC/HDL-C. Consistent with these findings, haplotype-based analyses also revealed that the effect of two haplotypes on incident type 2 diabetes was modified by TC/HDL-C in men (p < 10^-3). However, none of the investigated variants or haplotypes was associated with type 2 diabetes in main effect models without assessment of effect modifications.</p> <p>Conclusion</p> <p>We conclude that minor alleles of several <it>TLR4 </it>variants, although not directly associated with type 2 diabetes might increase the risk for type 2 diabetes in subjects with high TC/HDL-C. Additionally, our results confirm previous studies reporting sex-related dissimilarities in the development of type 2 diabetes.</p

Association of glycated hemoglobin A1c levels with cardiovascular outcomes in the general population: results from the BiomarCaRE (Biomarker for Cardiovascular Risk Assessment in Europe) consortium

Background: Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA1c with cardiovascular outcomes in the general population. Methods: Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684). Results: Kaplan\u2013Meier curves showed higher event rates with increasing HbA1c levels (log-rank-test: p &lt; 0.001). Cox regression analysis revealed significant associations between HbA1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02\u20131.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03\u20131.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02\u20131.17, p = 0.01) for overall mortality was observed per 10&nbsp;mmol/mol increase in HbA1c. The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA1c levels (HR 1.12; 95% CI 1.01\u20131.25, p = 0.04) and HR 1.10; 95% CI 1.01\u20131.20, p = 0.02) respectively. HbA1c cut-off values of 39.9&nbsp;mmol/mol (5.8%), 36.6&nbsp;mmol/mol (5.5%), and 38.8&nbsp;mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk. Conclusions: HbA1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA1c levels and outcomes. Elevated HbA1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA1c levels in the overall population

Functional Characterization of Promoter Variants of the Adiponectin Gene Complemented by Epidemiological Data

# These authors contributed equally to the work. *Corresponding author

BiomarCaRE: rationale and design of the European BiomarCaRE project including 300,000 participants from 13 European countries

Biomarkers are considered as tools to enhance cardiovascular risk estimation. However, the value of biomarkers on risk estimation beyond European risk scores, their comparative impact among different European regions and their role towards personalised medicine remains uncertain. Biomarker for Cardiovascular Risk Assessment in Europe (BiomarCaRE) is an European collaborative research project with the primary objective to assess the value of established and emerging biomarkers for cardiovascular risk prediction. BiomarCaRE integrates clinical and epidemiological biomarker research and commercial enterprises throughout Europe to combine innovation in biomarker discovery for cardiovascular disease prediction with consecutive validation of biomarker effectiveness in large, well-defined primary and secondary prevention cohorts including over 300,000 participants from 13 European countries. Results from this study will contribute to improved cardiovascular risk prediction across different European populations. The present publication describes the rationale and design of the BiomarCaRE project. Electronic supplementary material The online version of this article (doi:10.1007/s10654-014-9952-x) contains supplementary material, which is available to authorized users