Frankfurt am Main, Germany
Frankfurt am Main, Germany

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Silbernagel G.,University of Tübingen | Renner W.,Medical University of Graz | Grammer T.B.,University of Heidelberg | Hugl S.R.,University of Ulm | And 7 more authors.
Diabetes/Metabolism Research and Reviews | Year: 2011

Background: Variants in TCF7L2 have been associated with the age at onset of type 2 diabetes in Mexican Americans. However, there is a lack of data on this relationship in Caucasians. Furthermore, risk alleles in TCF7L2 have been suggested to account for decreased conversion of proinsulin to insulin and decreased expression of GLP-1. We investigated the effect of the allelic variants rs1225537 and rs7903146 in TCF7L2 on the age at onset of type 2 diabetes, the plasma concentrations of proinsulin and GLP-1, and the ratio of proinsulin to insulin in a German cohort. Methods: We studied 3185 participants of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. Among these, 1021 subjects had type 2 diabetes. Data on age at onset of diabetes were available in 925 subjects. OGTTs were performed in a subgroup not previously known to have diabetes. Results: Carriers of the risk alleles in rs1225537 and rs7901346 had increased risk of type 2 diabetes and elevated HbA1c (all p < 0.001). The risk alleles were also associated with early onset of type 2 diabetes, decreased insulin secretion and markedly increased proinsulin and proinsulin to insulin ratio (all p < 0.03). GLP-1 was not significantly related to the TCF7L2 genotype. Conclusions: Our data demonstrate that TCF7L2 variants are associated with an early age of onset of type 2 diabetes in Caucasians and affects the conversion of proinsulin to insulin. However, TCF7L2 is not consistently associated with fasting GLP-1. © 2011 John Wiley & Sons, Ltd.


Silbernagel G.,University of Tübingen | Fauler G.,Medical University of Graz | Hoffmann M.M.,Albert Ludwigs University of Freiburg | Lutjohann D.,University of Bonn | And 4 more authors.
Journal of Lipid Research | Year: 2010

Moderately elevated levels of plasma plant sterols have been suspected to be causally involved in atherosclerosis. The aim of this study was to investigate whether plant sterols and other markers of sterol metabolism predicted all-cause and cardiovascular mortality in participants of the Ludwigshafen Risk and Cardiovascular health (LURIC) study. A total of 1,257 individuals who did not use statins and at baseline had a mean (± SD) age of 62.8 (± 11.0) years were included in the present analysis. Lathosterol, cholestanol, campesterol, and sitosterol were measured to estimate cholesterol synthesis and absorption. The mean (± SD) time of the follow-up for all-cause and cardiovascular mortality was 7.32 (± 2.3) years. All-cause (P = 0.001) and cardiovascular (P = 0.006) mortality were decreased in the highest versus the lowest lathosterol to cholesterol tertile. In contrast, subjects in the third cholestanol to cholesterol tertile had increased all-cause (P < 0.001) and cardiovascular mortality (P = 0.010) compared with individuals in the first tertile. The third campesterol to cholesterol tertile was associated with increased all-cause mortality (P = 0.025). Sitosterol to cholesterol tertiles were not significantly related to all-cause or cardiovascular mortality.jlr The data suggest that high absorption and low synthesis of cholesterol predict increased all-cause and cardiovascular mortality in LURIC participants. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.


Silbernagel G.,Ludwigshafen Risk and Cardiovascular Study Non profit LLC | Silbernagel G.,University of Tübingen | Grammer T.B.,University of Heidelberg | Winkelmann B.R.,Cardiology Group Frankfurt Sachsenhausen | And 3 more authors.
Diabetes Care | Year: 2011

OBJECTIVE-Glycated hemoglobin has been suggested to be superior to fasting glucose for the prediction of vascular disease and death from any cause. The aim of the present work was to analyze and compare the predictive value of glycated hemoglobin and fasting glucose on all-cause and cause-specific mortality in subjects who underwent coronary angiography. RESEARCH DESIGN ANDMETHODS-We studied 2,686 participants of the Ludwigshafen Risk and Cardiovascular health study without a history of diabetes. The majority of this cohort had coronary artery disease. Glycated hemoglobin was measured at the baseline examination. The mean (± SD) duration of the follow-up for all-cause, cardiovascular, and cancer mortality was 7.54 ± 2.1 years. RESULTS-A total of 508 deaths occurred during the follow-up. Of those, 299 were accounted for by cardiovascular diseases and 79 by cancer. Baseline glycated hemoglobin was predictive of all-cause, cardiovascular, and cancer mortality. The multivariable-adjusted hazard ratios (HR) (95% CI) for glycated hemoglobin values of <5.0, 5.0-5.4, 5.5-5.9, 6.0-6.4, 6.5-7.4, and ≥7.5% for all-cause mortality were 1.36 (0.85-2.18), 1.00 (0.76-1.32), 1.00 (reference), 1.11 (0.88-1.41), 1.39 (1.07-1.82), and 2.15 (1.32-3.53), respectively. Similar J-shaped relationships were found between glycated hemoglobin and cardiovascular and cancer mortality. The associations of glycated hemoglobin with all-cause and cardiovascular mortality remained significant after inclusion of fasting glucose as a covariate. However, fasting glucose was not significantly related to mortality when adjusting for glycated hemoglobin. CONCLUSIONS-Glycated hemoglobin significantly and independently of fasting glucose predicts all-cause and cardiovascular mortality in whites at intermediate to high cardiovascular risk. © 2011 by the American Diabetes Association.


Silbernagel G.,LURIC Study Nonprofit LLC | Silbernagel G.,University of Tübingen | Rosinger S.,University of Ulm | Grammer T.B.,University of Heidelberg | And 6 more authors.
Atherosclerosis | Year: 2012

Objective: Type 2 diabetes represents a major cardiovascular risk factor. However, few studies have addressed the impact of the disease duration on mortality. Thus, we aimed to investigate the predictive value of diabetes duration for all-cause and cardiovascular mortality in subjects undergoing coronary angiography. Methods: We studied 2455 participants of the LUdwigshafen RIsk and Cardiovascular health study (1768 males/687 females). They had a mean±standard deviation (SD) age of 63.1±9.0 years (range: 40.0-79.9) and a mean±SD body mass index of 27.7±4.0kg/m 2. 704 subjects were newly diagnosed with type 2 diabetes according to the 2010 criteria of the American Diabetes Association and 446 subjects had a known history of type 2 diabetes. The mean±SD duration of the follow-up for all-cause and cardiovascular mortality was 7.4±2.3 years. Results: A total of 543 deaths occurred during the follow-up. Among these, 343 were accounted for by cardiovascular diseases. The duration of type 2 diabetes was strongly and positively correlated with all-cause and cardiovascular mortality (both P<. 0.001). The multivariate adjusted hazard ratios (95% confidence intervals) for cardiovascular mortality compared to subjects without diabetes were 1.76 (1.34-2.32), 2.86 (2.00-4.08), 2.96 (1.85-4.74), and 4.55 (3.24-6.39) for subjects with new onset type 2 diabetes and subjects with known type 2 diabetes (duration ≤5, >5 and ≤10, >10 years), respectively. Conclusions: The data emphasise the need to consider the diabetes duration for the prediction of mortality in subjects at intermediate to high cardiovascular risk. © 2012 Elsevier Ireland Ltd.


Marx N.,RWTH Aachen | Silbernagel G.,University of Tübingen | Brandenburg V.,RWTH Aachen | Burgmaier M.,RWTH Aachen | And 8 more authors.
Diabetes Care | Year: 2013

OBJECTIVEdC-peptide is a proinsulin cleavage product released from the pancreas in amounts equimolar to insulin, and elevated levels of C-peptide have been found in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest that C-peptide could play a causal role in the pathophysiology of vascular disease, but nothing is known about the prognostic value of C-peptide concentrations in the circulation. RESEARCH DESIGNANDMETHODSdWe examined whether C-peptide is associated with cardiovascular and total mortality in 2,306 patients from the Ludwigshafen Risk and Cardiovascular Health Study who underwent coronary angiography at baseline (1997-2000). RESULTSdDuring amean follow-up of 7.6 years, 440 deaths (19.1%) occurred, 252 (10.9%) of which were due to cardiovascular causes. Age-and sex-adjusted hazard ratios (HRs) in the third compared with the first tertile of C-peptide were 1.46 (95%CI 1.15-1.85; P = 0.002) for all cause and 1.58 (1.15-2.18; P = 0.005) for cardiovascular mortality. After further adjustment for common risk factors as well as markers of glucosemetabolism, these HRs remained significant at 1.46 (1.10-1.93; P = 0.008) and 1.55 (1.07-2.24; P = 0.022), respectively. Moreover, patients in higher tertiles of C-peptide exhibited higher levels of markers of endothelial dysfunction and atherosclerosis as well as a more severe extent of coronary lesions. CONCLUSIONSdIn patients undergoing coronary angiography, C-peptide levels are independently associated with all cause and cardiovascular mortality as well as presence and severity of coronary artery disease. Further studies are needed to examine a potential causal role of Cpeptide in atherogenesis in humans. Copyright © 2013 by the American Diabetes Association.


Kozian D.H.,Sanofi S.A. | Barthel A.,University Tsklinikum Carl Gustav Carus | Cousin E.,Sanofi S.A. | Brunnhofer R.,Sanofi S.A. | And 9 more authors.
Hormone and Metabolic Research | Year: 2010

Two strongly correlated polymorphisms located within the gene of the glucokinase regulator protein (GKRP), rs780094 and rs1260326, are associated with increased plasma triglyceride levels and provide a genetic model for the long-term activation of hepatic glucokinase. Because pharmacological glucokinase activators are evaluated for the treatment of diabetes, the aim of the study was to assess if these polymorphisms could provide evidence for an increased cardiovascular risk of long-term glucokinase activation. Therefore, these polymorphisms were tested in 3500 patients of the Ludwigshafen Risk and Cardiovascular Health study, which was designed to assess cardiovascular risk factors. The two variants were associated with a significant increase of both plasma triglycerides (p<0.0001) and VLDL triglyceride levels (p<0.0001). Plasma free fatty acid concentrations were also significantly elevated (p<0.0078). LDL and HDL cholesterol levels were unchanged. No association was found with respect to coronary stenosis, myocardial infarction, left ventricular wall hypertrophy, and hypertension. In conclusion, long-term genetic glucokinase activation by the GKRP polymorphisms was not associated with an increased cardiovascular risk in the study population. © 2010 Georg Thieme Verlag KG Stuttgart.


Silbernagel G.,Ludwigshafen Risk and Cardiovascular Health Study Nonprofit LLC | Silbernagel G.,University of Tübingen | Kleber M.E.,Ludwigshafen Risk and Cardiovascular Health Study Nonprofit LLC | Kleber M.E.,Synlab Center | And 6 more authors.
Diabetes Care | Year: 2011

OBJECTIVE - To study the prognosis of people with newly diagnosed type 2 diabetes as per the American Diabetes Association (ADA) 2010 definition but without diabetes as per the ADA 2009 definition. RESEARCHDESIGNANDMETHODS - A total of 2,002 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study without a history of diabetes were studied. RESULTS - During the follow-up of a mean duration ± SD of 7.7 ± 2.0 years, 346 people died (202 cardiovascular deaths). Subjects with type 2 diabetes as per the ADA 2009 definition (n = 468) had significantly increased all-cause and cardiovascular mortality compared with people without diabetes as per the ADA 2010 definition (both P≤ 0.003). Subjects with type 2 diabetes as per the ADA 2010 definition but without diabetes as per the ADA 2009 definition (n = 150) were at significantly increased risk to die of cardiovascular diseases (P = 0.029). CONCLUSIONS - Use of the ADA 2010 diabetes definition may be instrumental in improving cardiovascular risk stratification in people undergoing coronary angiography. © 2011 by the American Diabetes Association.


Silbernagel G.,LURIC Study Nonprofit LLC | Silbernagel G.,University of Tübingen | Sourij H.,Medical University of Graz | Grammer T.B.,University of Heidelberg | And 8 more authors.
Atherosclerosis | Year: 2012

Objective: The American Diabetes Association (ADA) has revised the criteria for the diagnosis of diabetes in 2010. Glycated haemoglobin at a cut-point of ≥6.5% has been included in the diagnostic algorithm. We aimed to investigate whether there is still the need to perform oral glucose tolerance tests (OGTT). Methods: We studied 2002 people referred for angiography who did not have a history of diabetes. OGTT were performed in all 1772 subjects with fasting glucose <126 mg/dl. Participants were prospectively followed for all-cause and cardiovascular mortality over a mean duration (±standard deviation) of 7.7 ± 2.0 years. Results: Using the ADA 2010 criteria 618 individuals were categorised as having new-onset type 2 diabetes. Among these, 167 had isolated post-challenge hyperglycaemia. A total of 346 participants died during follow-up. Cardiovascular death occurred in 202 cases. Those with elevated fasting glucose ≥126 mg/dl and/or glycated haemoglobin ≥6.5% had increased all-cause (hazard ratio [HR]: 1.63, 95% confidence interval [95%CI]: 1.28-2.08, p < 0.001) and cardiovascular mortality (HR: 1.66, 95%CI: 1.21-2.29, p = 0.002) compared to subjects without diabetes according to the ADA 2010 definition. Isolated elevation of post-challenge glucose independently predicted increased cardiovascular mortality (HR: 1.57, 95%CI: 1.02-2.43, p = 0.041). All-cause and cardiovascular mortality were not significantly different between subjects with increased fasting glucose and/or glycated haemoglobin and those with isolated elevation of post-challenge glucose. Conclusions: Performing OGTT will identify a high risk group for cardiovascular mortality undetected by fasting glucose or glycated haemoglobin. © 2012.


Winkelmann B.R.,ClinPhenomics GmbH | Winkelmann B.R.,Cardiology Group Frankfurt Sachsenhausen | Von Holt K.,Toxicology Consultant | Unverdorben M.,Clinical Research Institute
Biomarkers in Medicine | Year: 2010

Genes influence smoking behavior, affect the metabolism of nicotine and specific chemicals produced during combustion, and enhance (or diminish) pathomechanistic pathways associated with the atherogenic potential of smoking, including oxidative stress, its inflammatory burden or procoagulant potential. Genome-wide association studies have revolutionized the search for new functional genetic markers with ever increasing marker density and the precision in identifying new genetic loci without the need for prior knowledge of functional pathways. Nevertheless, the satistical challenge remains to identify the few true positives, the need for replication of findings and the tedious work of identifying functional genetic variants and their mode of action. Genetic variation within a gene or in areas of the genetic code that control the expression of such a gene is far from being understood. Major advances include the detection of large-scale copy-number variants in the human genome and the demonstration of the decisive role of 'miRNA in controlling gene expression. The role of the genomic methylation pattern in controlling the transcription of the underlying genetic sequence and its role in interacting with environmental influences have yet to be explored in depth. Although candidate genes and their genetic variants have been associated with atherosclerosis and cigarette smoking, a major breakthrough has still to be made. © 2010 Future Medicine Ltd.


Stojakovic T.,Medical University of Graz | Scharnagl H.,Medical University of Graz | Trauner M.,Medical University of Graz | Pieske B.,Medical University of Graz | And 7 more authors.
Atherosclerosis | Year: 2010

Objective: Serum gamma-glutamyl transferase (GGT) seems to be a predictor for coronary artery disease (CAD). The objective of this study was to elucidate the relationship between GGT and total as well as cardiovascular mortality. Methods: Serum levels of GGT were determined in 2556 subjects with and 699 subjects without angiographic evidence of CAD in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Results: Serum GGT was positively associated with male gender, alcohol consumption and markers of the metabolic syndrome (triglycerides, blood pressure, waist circumference and insulin resistance). It was positively related to aspartate aminotransferase, alanine aminotransferase, C-reactive protein, interleukin-6, and negatively related to glutathione and increased age. During a mean follow-up period of 7.75 years, 754 subjects died. Compared with subjects in the lowest quartile of GGT, the unadjusted hazard ratios (95% CI) for all-cause death were 1.2 (0.9-1.5), 1.4 (1.1-1.8) and 1.9 (1.5-2.3), respectively, in other GGT quartiles. Hazard ratios (CI) for death from cardiovascular causes were 1.4 (1.0-2.0), 1.8 (1.4-2.5) and 2.2 (1.6-2.9). After adjustment for age, gender and cardiovascular risk factors GGT remained a significant predictor for total and cardiovascular mortality. In angiographic CAD the predictive value of GGT was also significant and similar to that in the entire cohort. Conclusion: Serum GGT is predictive of all-cause and cardiovascular mortality in individuals with CAD independently of other cardiovascular risk factors. © 2009 Elsevier Ireland Ltd. All rights reserved.

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