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Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA 1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA 1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA 1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA 1c per serine, p=6·0 × 10 −5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10 −8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA 1c reduction per methionine, p=5·2 × 10 −6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA 1c than the 9% of the population with the worse response. Interpretation: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists.

Introduction Cardiovascular biomarkers may reflect different aspects of cardiovascular disease, including myocardial tissue damage (high-sensitive cardiac troponin [hs-cTn]), hemodynamic stress (N-terminal prohormone of brain natriuretic peptide [NT-proBNP)), or inflammation (high-sensitivity C-reactive protein [hs-CRP]). Purpose To determine the risk for fatal and non-fatal cardiovascular events in patients with diabetes mellitus (DM), a high-risk group for cardiovascular complications, after accounting for these biomarkers and to determine the risk associated with these biomarkers. Methods Harmonized data of population-based studies from the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomaCaRE) and MOnica Risk, Genetics, Archiving and Monograph (MORGAM) consortia were used to calculate hazard ratios (HRs, 95% confidence intervals [CI] per standard deviation) for these biomarkers adjusted for diabetes, patient characteristics and biomarkers for their association with the primary endpoint of fatal and non-fatal cardiovascular events during a median follow-up of 9.6 years (maximum 28 years). Additionally, a years-of-life-lost analysis was conducted stratified by prevalent diabetes and specific biomarker cut-offs known to be associated with increased risk for events (hs-cTnI >5 ng/L, NTproBNP >125 ng/L, hs-CRP >5mg/L). Results We included 95,302 individuals, of whom 6,501 had DM (6.8%). Cox-regression analysis revealed DM to be independently associated with the primary endpoint (2.1 [95% CI 1.9, 2.3], p Conclusion Our findings confirm that diabetes confers a residual cardiovascular risk beyond adjustment for clinical characteristics and cardiovascular biomarker. Furthermore, biomarkers may aid in the identification of patients at highest risk, which should be considered in future models of risk prediction. Funding Acknowledgement Type of funding sources: None.

Background Accurate risk prediction for future cardiovascular disease (CVD) is crucial for timely initiation of preventive measures in high-risk individuals. Most risk scores, such as the recently updated SCORE2 risk-prediction model supported by the European Society of Cardiology, consider only traditional cardiovascular risk factors. Whether the addition of circulating biomarkers to the existing SCORE2 model may improve risk prediction is unclear. Purpose We aimed to evaluate the incremental utility of four widely available circulating biomarkers to improve the prediction of 10-year CVD-risk beyond SCORE2. Methods Data from ten prospective population-based cohorts from seven countries across Europe were collected if information on SCORE2-variables and at least one of the following four investigational biomarkers was available: high-sensitivity cardiac troponin I (hs-cTnI), NT-pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP) and creatinine-based estimated glomerular filtration rate (eGFR). Primary outcome was incidence of CVD at 10 years, defined as the composite of cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke. We used Fine and Gray models adjusted for competing-risk and SCORE2-variables as well as penalized cubic splines to assess and visualize the association of individual biomarkers with incident CVD. In a multimarker approach, we performed backward selection to identify biomarkers providing independent predictive value beyond SCORE2-components. C-indices and category-free net reclassification index (cfNRI) were used to compare the performance of the original SCORE2 model to the biomarker-extended model. Results In 78'507 individuals, median age was 50 years and 50.3% were females. NT-proBNP, hs-CRP and hs-cTnI but not eGFR showed strong associations with 10-year CVD-risk when adjusted for SCORE2 and provided incremental predictive value when individually added to SCORE2 (Figure 1). In a multimarker approach, all three biomarkers remained independently associated with CVD beyond SCORE2 with strongest association of NT-proBNP, followed by hs-CRP and hs-cTnI (Table 1). The simultaneous addition of these three biomarkers to the SCORE2 model significantly increased discrimination (C-index; 0.782 [95% CI, 0.757, 0.806] versus 0.793 [95% CI, 0.768, 0.817], Delta 0.011 [95% CI, 0.005, 0.016]) and risk reclassification, driven by an improvement in non-events (cfNRIoverall 0.17 [95% CI, 0.12, 0.22], cfNRIevents 0.06 [95% CI, 0.02, 0.11], cfNRInon-events 0.11 [95% CI, 0.10, 0.11]). Conclusion NT-proBNP, hs-CRP and hs-cTnI but not eGFR provide incremental predictive value when added to the SCORE2 risk-prediction model and may help to further improve personalized CVD-risk prediction. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Community's Seventh Framework Programme (FP7/2007-2013)

Aim: To test the association of alcohol consumption with total and cause-specific mortality risk. Design: Prospective observational multi-centre population-based study. Setting: Sixteen cohorts (15 from Europe) in the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project. Participants: A total of 142 960 individuals (mean age 50±13 years, 53.9% men). Measurements: Average alcohol intake by food frequency questionnaire, total and cause-specific mortality. Findings: In comparison with life-time abstainers, consumption of alcohol less than 10 g/day was associated with an average 11% [95% confidence interval (CI)=7–14%] reduction in the risk of total mortality, while intake >20 g/day was associated with a 13% (95% CI=7–20%) increase in the risk of total mortality. Comparable findings were observed for cardiovascular (CV) deaths. With regard to cancer, drinking up to 10 g/day was not associated with either mortality risk reduction or increase, while alcohol intake >20 g/day was associated with a 22% (95% CI=10–35%) increased risk of mortality. The association of alcohol with fatal outcomes was similar in men and women, differed somewhat between countries and was more apparent in individuals preferring wine, suggesting that benefits may not be due to ethanol but other ingredients. Mediation analysis showed that high-density lipoprotein cholesterol explained 2.9 and 18.7% of the association between low alcohol intake and total as well as CV mortality, respectively. Conclusions: In comparison with life-time abstainers, consuming less than one drink per day (nadir at 5 g/day) was associated with a reduced risk of total, cardiovascular and other causes mortality, except cancer. Intake of more than two drinks per day was associated with an increased risk of total, cardiovascular and especially cancer mortality.

BackgroundPrevious studies have shown that differential exposure to lifestyle factors may mediate the association between education and coronary heart diseases (CHD). However, few studies have examined the potential roles of allostatic load (AL) or differential susceptibility.Methods25 310 men and 26 018 women aged 35–74 and CHD free at baseline were identified from 21 European cohorts and followed for a median of 10 years, to investigate the mediating role of AL, as well as of smoking, alcohol use and body mass index (BMI), on educational differences in CHD incidence, applying marginal structural models and three-way decomposition.ResultsAL is a mediator of the association between educational status and CHD incidence, with the highest proportion mediated observed among women and largely attributable to differential exposure, (28% (95% CI 19% to 44%)), with 8% (95% CI 0% to 16%) attributable to differential susceptibility. The mediating effects of smoking, alcohol and BMI, compared with AL, were relatively small for both men and women.ConclusionOverall, the educational inequalities in CHD incidence were partially mediated through differential exposure to AL. By contrast, the mediation of the educational gradient in CHD by investigated lifestyle risk factors was limited. As differential susceptibility in men was found to have a predominant role in the accumulation of AL in low educational classes, the investigation of AL-related risk factors is warranted.

BackgroundWe investigate whether socially disadvantaged individuals are more susceptible to the detrimental effects of smoking and alcohol intake on allostatic load (AL), a marker of physiological ‘wear and tear’, resulting from adaptation to chronic stress.MethodsIn a cross-sectional analysis, 27 019 men and 26 738 women aged 35–74 years were identified from 21 European cohorts in the BiomarCaRE consortium. We defined three educational classes (EDs) according to years of schooling and an AL score as the sum of z-scores of eight selected biomarkers from the cardiovascular, metabolic and inflammatory systems. We used the Oaxaca-Blinder decomposition to disentangle the ED gradient in AL score into the differential exposure (DE, attributable to different distribution of smoking and alcohol intake across EDs) and the differential susceptibility (DS, attributable to a different effect of risk factors on AL across EDs) components.ResultsLess-educated men (mean AL difference: 0.68, 95% CI 0.57 to 0.79) and women (1.52, 95% CI 1.40 to 1.64) had higher AL scores. DE accounted for 7% and 6% of the gradient in men and women, respectively. In men, combining smoking and alcohol intake, DS accounted for 42% of the gradient (smoking DS coefficient=0.177, 26% of the gradient; alcohol DS coefficient=0.109; 16%, not statistically significant). DS contribution increased to 69% in metabolic markers. DS estimates were consistent across age groups, irrespective of comorbidities and robust to unmeasured confounding. No DS was observed in women.ConclusionsIn men, a DS mechanism substantially contributes to the educational class gradient in allostatic load.

Background Functional iron deficiency (FID) has been established as a risk factor in patients with cardiovascular diseases (CVD). As opposed to absolute iron deficiency, it reflects stored iron as well as utilized iron and allows for a more accurate evaluation of individual iron status. However, evidence is scant on the relevance of FID to the incidence of CVD in the general population. Aim This study aimed to evaluate the association of FID with incident cardiovascular diseases and mortality endpoints in a large population-based cohort. Methods FID was defined as either ferritin below 100 μg/L or ferritin between 100 and 299 μg/L and transferrin saturation below 20%. Only individuals free of CVD at baseline from three population-based European cohorts were included. Multivariable-adjusted sex- and cohort-stratified Cox regression analyses were performed to evaluate the association of functional iron deficiency with incident cardiovascular diseases (coronary heart disease, cerebral infarction, heart failure and atrial fibrillation) as well as with all-cause and cardiovascular mortality. Adjustments were performed for sex (as strata), age (as time scale), smoking, total cholesterol, systolic blood pressure, diabetes, body mass index and high-sensitive C-reactive protein. Results In total, N=12146 individuals were included in the analysis with a median age of 59.0 years (25thpercentile 45.0, 75thpercentile 68.0), and 45.2% men. Incidence of FID was 64.3%. Median follow-up times were 12.3 to 21.8 years, with an all-cause mortality rate of 18.2% and a cardiovascular mortality rate of 6.2%. Incident coronary heart disease, cerebral infarction, heart failure and atrial fibrillation were observed in 8.7%, 6.5%, 5.9% and 11.7%, respectively. FID was significantly associated with all-cause mortality (hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.01–1.24, p=0.034), cardiovascular death (HR 1.26, 95% CI 1.03–1.54, p=0.027) and incident coronary heart disease (HR 1.23, 95% CI 1.06–1.43, p Conclusion In our analysis of population-based cohorts, FID showed a significant positive association with all-cause as well as cardiovascular mortality and incident coronary heart disease. Further research is needed to validate the role of FID as a cardiovascular risk factor in the general population and to evaluate the impact of iron supplementation on gender and outcome.

AIMS: Our aims were to evaluate the distribution of troponin I concentrations in population cohorts across Europe, to characterize the association with cardiovascular outcomes, to determine the predictive value beyond the variables used in the ESC SCORE, to test a potentially clinically relevant cut-off value, and to evaluate the improved eligibility for statin therapy based on elevated troponin I concentrations retrospectively.METHODS AND RESULTS: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, we analysed individual level data from 10 prospective population-based studies including 74 738 participants. We investigated the value of adding troponin I levels to conventional risk factors for prediction of cardiovascular disease by calculating measures of discrimination (C-index) and net reclassification improvement (NRI). We further tested the clinical implication of statin therapy based on troponin concentration in 12 956 individuals free of cardiovascular disease in the JUPITER study. Troponin I remained an independent predictor with a hazard ratio of 1.37 for cardiovascular mortality, 1.23 for cardiovascular disease, and 1.24 for total mortality. The addition of troponin I information to a prognostic model for cardiovascular death constructed of ESC SCORE variables increased the C-index discrimination measure by 0.007 and yielded an NRI of 0.048, whereas the addition to prognostic models for cardiovascular disease and total mortality led to lesser C-index discrimination and NRI increment. In individuals above 6 ng/L of troponin I, a concentration near the upper quintile in BiomarCaRE (5.9 ng/L) and JUPITER (5.8 ng/L), rosuvastatin therapy resulted in higher absolute risk reduction compared with individuals CONCLUSION: In individuals free of cardiovascular disease, the addition of troponin I to variables of established risk score improves prediction of cardiovascular death and cardiovascular disease.

Background and Aims We investigated the associations of serum fasting (FG) and 2-h postload (2HG) glucose from an oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c), fasting insulin and the homeostasis model assessment-insulin resistance index (HOMA-IR) with urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). Methods and Results We performed cross-sectional analyses of 2713 subjects (1429 women; 52.7%) without known type 2 diabetes, aged 31–82 years, from the KORA (Cooperative Health Research in the Augsburg Region) F4-Study. FG, 2HG, HbA1c, fasting insulin, HOMA-IR and glucose tolerance categories were analyzed for association with ACR and eGFR in multivariable adjusted linear and median regression models, and with isolated microalbuminuria (i-MA), isolated reduced kidney function (i-RKF) and chronic kidney disease (CKD, defined as MA and/or RKF) in multivariable adjusted logistic regression models. Among the 2713 study participants, 28% revealed prediabetes (isolated impaired fasting glucose [i-IFG], isolated glucose tolerance [i-IGT] or both by American Diabetes Association definition), 4.2% had unknown type 2 diabetes, 6.5% had i-MA, 3.1% i-RKF and 10.9% CKD. In multivariable adjusted analysis, all continuous variables (FG, 2HG, HbA1c, fasting insulin and HOMA-IR) were associated with i-MA, i-RKF and CKD. The odds ratios (ORs) for i-MA and CKD were 1.54 (95% confidence interval: 1.02–2.33) and 1.58 (1.10–2.25) for individuals with i-IFG. Moreover, the OR for i-RKF was 2.57 (1.31–5.06) for individuals with IFG + IGT. Conclusion Our findings suggest that prediabetes might have harmful effects on the kidney.

Background— Oxidized low-density lipoprotein may be a key factor in the development of atherosclerosis. We performed a genome-wide association study on oxidized low-density lipoprotein and tested the impact of associated single-nucleotide polymorphisms (SNPs) on the risk factors of atherosclerosis and cardiovascular events. Methods and Results— A discovery genome-wide association study was performed on a population of young healthy white individuals (N=2080), and the SNPs associated with a P –8 were replicated in 2 independent samples (A: N=2912; B: N=1326). Associations with cardiovascular endpoints were also assessed with 2 additional clinical cohorts (C: N=1118; and D: N=808). We found 328 SNPs associated with oxidized low-density lipoprotein. The genetic variant rs676210 (Pro2739Leu) in apolipoprotein B was the proxy SNP behind all associations ( P =4.3×10 –136 , effect size=13.2 U/L per allele). This association was replicated in the 2 independent samples (A and B, P =2.5×10 –47 and 1.1×10 –11 , effect sizes=10.3 U/L and 7.8 U/L, respectively). In the meta-analyses of cohorts A, C, and D (excluding cohort B without angiographic data), the top SNP did not associate significantly with the age of onset of angiographically verified coronary artery disease (hazard ratio=1.00 [0.94–1.06] per allele), 3-vessel coronary artery disease (hazard ratio=1.03 [0.94–1.13]), or myocardial infarction (hazard ratio=1.04 [0.96–1.12]). Conclusions— This novel genetic marker is an important factor regulating oxidized low-density lipoprotein levels but not a major genetic factor for the studied cardiovascular endpoints.

We estimated the prevalence of sarcopenia and its impact on disability in older people. Sarcopenia was found to contribute to higher disability scores. However, our study was not able to show any influence of sarcopenia on the rate of functional decline. This directs attention to an accurate diagnosis of sarcopenia as the onset may be influenced, but its rate may not. The objectives of this study using data from a population-based cohort were to estimate the prevalence of sarcopenia in older people in Germany and to test the hypothesis that sarcopenia is associated with disability in older adults. Cross-sectional (n = 927) and longitudinal analyses (n = 859) of participants aged ≥65 years at baseline from southern Germany enrolled in the Cooperative Health Research in the Region Augsburg (KORA)-Age study (2009–2012). Sarcopenia was defined based on the European Working Group on Sarcopenia in Older People (EWGSOP) algorithm which includes the presence of both low muscle mass and low muscle function (strength or performance). Disability status was measured by the Health Assessment Questionnaire–Disability Index (HAQ-DI). The presence of disability was defined as HAQ-DI >0. Directed acyclic graphs (DAGs) were constructed to identify potential confounders. The effect of sarcopenia on disability was analyzed using linear mixed effect models with disability values as a continuous outcome. The overall prevalence of sarcopenia was 5.7% (men 4.0%, women 7.5%) and increased with age. The 3-year incidence of disability was 32.7%. After adjustment for potential confounders, presence of sarcopenia was significantly associated with higher disability scores (0.142 [confidence interval 0.029–0.254]). The prevalence of sarcopenia is consistent with estimates from other European studies using this algorithm. Our results suggest that sarcopenia can contribute to higher disability scores in older adults. However, our study was not able to show any influence of sarcopenia on the rate of functional decline using the EWGSOP diagnostic algorithm for sarcopenia. This directs attention to an accurate diagnosis of sarcopenia as the onset may be influenced, but its rate may not.

Cohort descriptions, Table S1–S9 and Figure S1. (DOC 450 kb)

During pregnancy the demands for energy and nutrients are increased. Despite increasing awareness about nutrition in the population of a western country like Germany, there is a discrepancy between actual food intake and recommended quantities of certain nutrients, particularly during pregnancy. There are correlations between deficiencies in micro-nutrients such as iodine, iron and folic acid and the course and outcome of pregnancy. The consequences of an insufficient supply of these micronutrients during pregnancy are described and high-risk-groups for an inadequate supply are defined. Recommendations for nutrition counselling during this period of life are given.

An official iron supplementation programme for pregnant women in Jeneponto, South Sulawesi, Indonesia was assessed for efficiency. Data were collected in a cross-sectional study of 107 women in the second or third trimester of pregnancy from 18 villages. 47.7% of the women were anaemic, although 63.6% stated they had received prenatal care. Of the 68 women who had received prenatal care. 49 had obtained iron tablets. However, 32.7% of the 49 women who received iron admitted that they had not taken all of the tablets. Mean Hb levels of women in the second trimester who had received tablets was 9 g/l higher (P=0.049) than that of women who had not received tablets. To improve the efficiency of the iron supplementation programme there must be an improvement in the coverage of pre-natal care, in the completeness of iron tablet distribution, and in efforts to assure that the pregnant women actually take the tablets given to them.

BackgroundMore accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design.MethodsUsing data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5-18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived.ResultsBoth scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50-59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events.ConclusionsGenetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men.

The objective of the KORA-Age research consortium is to assess the determinants and consequences of multimorbidity in the elderly and to look into reasons for successful aging in the general public.In the KORA-Age cohort study 9,197 persons were included who where born in the year 1943 or before and participants of previous KORA cohort studies conducted between 1984 and 2001 (KORA: Cooperative Health Research in the Region of Augsburg). The randomized intervention study KORINNA (Coronary infarct follow-up treatment in the elderly) tested a nurse-based case management program with 338 patients with myocardial infarct and included an evaluation in health economics.A total of 2,734 deaths were registered, 4,565 participants submitted a postal health status questionnaire and 4,127 participants were interviewed by telephone (response 76.2% and 68.9% respectively). A gender and age-stratified random sample of the cohort consisting of 1,079 persons took part in a physical examination (response 53.8%).The KORA-Age consortium was able to collect data in a large population-based sample and is contributing to the understanding of multimorbidity and successful aging.

To estimate population values of health-related quality of life (HRQL) in subjects with and without Type 2 diabetes mellitus across several large population-based survey studies in Germany. Systematic differences in relation to age and sex were of particular interest.Individual data from four population-based studies from different regions throughout Germany and the nationwide German National Health Interview and Examination Survey (GNHIES98) were included in a pooled analysis of primary data (N = 9579). HRQL was assessed using the generic index instrument SF-36 (36-item Short Form Health Survey) or its shorter version, the SF-12 (12 items). Regression analysis was carried out to examine the association between Type 2 diabetes and the two component scores derived from the SF-36/SF-12, the physical component summary score (PCS-12) and the mental component summary score (MCS-12), as well as interaction effects with age and sex.The PCS-12 differed significantly by -4.1 points in subjects with Type 2 diabetes in comparison with subjects without Type 2 diabetes. Type 2 diabetes was associated with significantly lower MCS-12 in women only. Higher age was associated with lower PCS-12, but with an increase in MCS-12, for subjects with and without Type 2 diabetes.Pooled analysis of population-based primary data offers HRQL values for subjects with Type 2 diabetes in Germany, stratified by age and sex. Type 2 diabetes has negative consequences for HRQL, particularly for women. This underlines the burden of disease and the importance of diabetes prevention. Factors that disadvantage women with Type 2 diabetes need to be researched more thoroughly.

The aim was to derive Type 2 diabetes prediction models for the older population and to check to what degree addition of 2-h glucose measurements (oral glucose tolerance test) and biomarkers improves the predictive power of risk scores which are based on non-biochemical as well as conventional clinical parameters.Oral glucose tolerance tests were carried out in a population-based sample of 1353 subjects, aged 55-74 years (62% response) in Augsburg (Southern Germany) from 1999 to 2001. The cohort was reinvestigated in 2006-2008. Of those individuals without diabetes at baseline, 887 (74%) participated in the follow-up. Ninety-three (10.5%) validated diabetes cases occurred during the follow-up. In logistic regression analyses for model 1, variables were selected from personal characteristics and additional variables were selected from routinely measurable blood parameters (model 2) and from 2-h glucose, adiponectin, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) (model 3).Age, sex, BMI, parental diabetes, smoking and hypertension were selected for model 1. Model 2 additionally included fasting glucose, HbA(1c) and uric acid. The same variables plus 2-h glucose were selected for model 3. The area under the receiver operating characteristic curve significantly increased from 0.763 (model 1) to 0.844 (model 2) and 0.886 (model 3) (P0.01). Biomarkers such as adiponectin and insulin did not improve the predictive abilities of models 2 and 3. Cross-validation and bootstrap-corrected model performance indicated high internal validity.This longitudinal study in an older population provides models to predict the future risk of Type 2 diabetes. The OGTT, but not biomarkers, improved discrimination of incident diabetes.

Adipocyte-derived hormones seem to be involved in the development of Type 2 diabetes. Therefore, we assessed the association between the proinflammatory adipokine leptin and incident Type 2 diabetes, taking into account interactions between leptin and the anti-inflammatory adipokine adiponectin.Using a case-cohort design, serum levels of adipokines were measured in 460 cases with incident Type 2 diabetes and 1474 non-cases selected from a source population of 7936 middle-aged subjects participating in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) Augsburg cohort study between 1984 and 1995 and followed up until 2002 (mean follow-up 10.9+/-4.7 years).High leptin and low adiponectin levels were associated with an increased Type 2 diabetes risk. The multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) comparing tertile extremes were 1.71 (1.12-2.63) for leptin (top vs. bottom tertile) and 2.65 (1.88-3.76) for adiponectin (bottom vs. top tertile), respectively. There was a significant interaction between leptin and adiponectin, with highest diabetes risk being observed in individuals with high leptin and low adiponectin levels (P = 0.029 for interaction).While the addition of adiponectin to a basic risk factor model improved model prediction (Delta area under the curve 0.011), the change in model prediction was only marginal after the addition of leptin (Delta area under the curve 0.002).Our findings indicate that the two adipokines leptin and adiponectin interact in modulating Type 2 diabetes risk, but adiponectin is more strongly associated with Type 2 diabetes risk than leptin.

To determine the incidence of Type 2 diabetes in an elderly population in Germany and its association with clinical and lifestyle factors.Oral glucose tolerance tests (OGTT, World Health Organization criteria) were carried out in a random sample of 1353 subjects (age group 55-74 years; 62% response) in Augsburg (Southern Germany) (1999-2001). The cohort was re-investigated in 2006-2008. Of those individuals without diabetes (baseline), 887 (74%) participated in the follow-up.Ninety-three (10.5%) developed diabetes during the 7-year follow-up period {standardized incidence rates [95% confidence interval (CI)] per 1000 person-years: total 15.5; 12.6, 19.1; men 20.2; 15.6, 26.1; women 11.3; 7.9, 16.1}. In both sexes, those who developed diabetes were slightly older, were more obese, had a more adverse metabolic profile (higher glucose values, HbA(1c), fasting insulin, uric acid, and triglycerides) and were more likely to have hypertension at baseline than were participants remaining free of diabetes (P0.05). On stepwise logistic regression, age, parental diabetes, body mass index, uric acid, current smoking, HbA(1c) and fasting and 2-h glucose (OGTT) were strong predictors of diabetes incidence. The risk of diabetes was higher in subjects with isolated impaired glucose tolerance (odds ratio 8.8; 95% CI 5.0, 15.6) than in isolated impaired fasting glucose (4.7; 2.2, 10.0), although the difference did not reach statistical significance.For the first time, we have estimated the incidence of Type 2 diabetes in an elderly German cohort and demonstrated that it is among the highest in Europe. The OGTT appears to be useful in identifying individuals with high Type 2 diabetes risk. Our results support a role of smoking in the progression to diabetes.

Fragestellung: Es wird vermutet, dass das Cytokin Interleukin-6 eine kausale Rolle in der Entstehung von Diabetes mellitus Typ 2 (T2DM) spielt. In zahlreichen kleineren Studien wurden die zwei im Promoterbereich liegenden Einzelnukleotidpolymorphismen (SNPs) -174G>C (rs1800795) und -573G>C (rs1800796) des fur Interleukin-6 kodierenden IL6-Gens auf ihren Zusammenhang mit T2DM untersucht. Die vorliegenden Ergebnisse waren jedoch nicht eindeutig. Um den Zusammenhang zwischen den beiden IL6-Varianten und T2DM zu klaren, wurde eine auf Individualdaten beruhende Meta-Analyse publizierter und unpublizierter Studien initiiert. Methodik: Nach einer systematischen Literaturrecherche sowie Rekrutierung aller verfugbaren publizierten und unpublizierten Studien, wurden die Individualdaten im Studienzentrum (Institut fur Epidemiologie des Helmholtz Zentrum Munchen, Neuherberg) gesammelt und auf Plausibilitat gepruft. Studienspezifische Assoziationsschatzer zum Zusammenhang zwischen den IL6-Varianten und dem Phanotyp T2DM – und wo verfugbar dem Phanotyp Nuchternglucose – wurden mittels multivariablen Regressionsmodellen mithilfe der Statistiksoftware SAS Version 9.1 berechnet. Die Heterogenitat zwischen den studienspezifischen Schatzern wurde untersucht und die Schatzer mit der „inverse-variance fixed-effect“ Methode zusammengefasst, da die Heterogenitat sehr gering war. Ergebnisse: Der Analysedatensatz umfasste fur den dichotomen Phanotyp T2DM Individualdaten von uber 20.000 Teilnehmern aus 21 publizierten und unpublizierten Studien, fur den quantitativen Phanotyp Nuchternglucose Individualdaten von uber 10.000 Teilnehmern aus acht publizierten und unpublizierten Studien. Die GC- und CC-Genotypen des IL6–174G>C Polymorphismus waren mit einem erniedrigten T2DM-Risiko (OR=0.91; P=0.04) und erniedrigter Nuchternglucose assoziiert (beta=-0.09mmol/l; P=0.01). Es gab keinen Hinweis auf eine Assoziation zwischen IL6–573G>C and T2DM. Schlussfolgerungen: Die Assoziationen zwischen dem IL6–174 C-Allel und reduziertem T2DM-Risiko sowie erniedrigten Nuchternglucosespiegeln, die in dieser bisher grosten auf Individualdaten basierenden Assoziationsanalyse fur T2DM entdeckt wurden, liefern weitere Hinweise dafur, dass Immunmediatoren in kausalem Zusammenhang mit T2DM stehen.

The performance of health delivery for chronic diseases in Germany has been considered deficient for a long time and in need of improvement. The launch of Disease Management Programmes (DMP) for type 2 diabetes in the summer of 2002 can be seen as an attempt to optimise health care for the chronically ill. The aim of our study was to find out at an early stage of DMP development which factors, personal or otherwise, would have an influence on whether diabetic patients know of, and are willing to participate in, such a programme. The data of 679 diabetic patients, collected between late 2002 and the end of 2003, presented here have been extracted from a written follow-up study to the three baseline surveys S1 (1984/85), S2 (1989/90) und S3 (1994/95) in Augsburg as part of the WHO-MONICA project with more than 13,000 participants. The study population is characterised by a rather high age (mean: 67.4 years), a long duration of the disease (mean: 9.8 years) as well as a high intensity of contacts with physicians. Only 28 % of the diabetic patients had heard of the DMP, but a majority of the participants (54 %) stated their readiness to participate in DMP once offered. Higher age, low education as well as no participation in diabetes education have been identified in logistic regression models as impeding factors both for the knowing of and the participation in DMP. As a consequence, promotion of the DMP should be directed to those sections of the diabetic population outside the effective reach of the traditional diabetes care organisations.

During pregnancy the demands for energy and far more for micronutrients are increased. Discrepancies between the intake of certain micronutrients such as iodine, iron and folic acid and the recommended quantities during pregnancy are to be expected. Consequences of an unsufficient supply of these micronutrients might be goitre, anemia and with special reference to folic acid the occurrence of neural tube defects. Deficiency can be prevented by careful choice of food. Supplementation with special micronutrients is necessary before respective during pregnancy however for example to prevent neural tube defects by periconceptional supplementation with folic acid.

In the present study maternal and fetal serum and red cell folate and vitamin B12 concentrations were determined in NTD affected and in control pregnancies. Fetal serum folate (p0.001) and red cell folate (p0.001) concentrations were significantly higher than maternal levels in the cases as well as in the controls. Maternal and fetal vitamin B12 concentrations did not differ significantly in both groups. There were also no significant differences in maternal and fetal vitamin concentrations in the peripheral blood between cases and controls. However, when a subgroup analysis was performed according to the type of NTD we found significant differences in fetal vitamin B12 status between anencephaly and spina bifida cases as well as between anencephaly cases and the controls.