Serum uromodulin is inversely associated with biomarkers of subclinical inflammation in the population-based KORA F4 study.

BACKGROUND: Uromodulin is a kidney-specific glycoprotein synthesized in tubular cells of Henle's loop exerting nephroprotective and immunomodulatory functions in the urinary tract. A small amount of uromodulin is also released into the systemic circulation, where its physiological role is unknown. Serum uromodulin (sUmod) has been associated with metabolic risk factors and with cardiovascular events and mortality, where these associations were partly stronger in men than in women. In this study, we investigated the associations of sUmod with biomarkers of subclinical inflammation in a population-based sample of women and men. METHODS: Associations of sUmod with 10 biomarkers of subclinical inflammation were assessed in 1065 participants of the Cooperative Health Research in the Region of Augsburg (KORA) F4 study aged 62-81 years using linear regression models adjusted for sex, age, body mass index, estimated glomerular filtration rate and diabetes. Analyses were performed in the total study sample and stratified by sex. RESULTS: sUmod was inversely associated with white blood cell count, high-sensitive C-reactive protein, interleukin (IL)-6, tumour necrosis factor-α, myeloperoxidase, superoxide dismutase-3, IL-1 receptor antagonist and IL-22 after multivariable adjustment and correction for multiple testing (P < 0.001 for each observation). There was a trend towards a stronger association of sUmod with pro-inflammatory markers in men than in women, with a significant P for sex interaction (<0.001) regarding the relation of sUmod with IL-6. CONCLUSIONS: sUmod was inversely associated with biomarkers of subclinical inflammation in older participants of the KORA F4 study. The association of sUmod with IL-6 differed between women and men. Future research should focus on whether the immunomodulatory properties of sUmod are one explanation for the association of sUmod with cardiovascular outcomes and mortality.

Metabolic syndrome and the plasma proteome: from association to causation.

BACKGROUND: The metabolic syndrome (MetS), defined by the simultaneous clustering of cardio-metabolic risk factors, is a significant worldwide public health burden with an estimated 25% prevalence worldwide. The pathogenesis of MetS is not entirely clear and the use of molecular level data could help uncover common pathogenic pathways behind the observed clustering. METHODS: Using a highly multiplexed aptamer-based affinity proteomics platform, we examined associations between plasma proteins and prevalent and incident MetS in the KORA cohort (n = 998) and replicated our results for prevalent MetS in the HUNT3 study (n = 923). We applied logistic regression models adjusted for age, sex, smoking status, and physical activity. We used the bootstrap ranking algorithm of least absolute shrinkage and selection operator (LASSO) to select a predictive model from the incident MetS associated proteins and used area under the curve (AUC) to assess its performance. Finally, we investigated the causal effect of the replicated proteins on MetS using two-sample Mendelian randomization. RESULTS: Prevalent MetS was associated with 116 proteins, of which 53 replicated in HUNT. These included previously reported proteins like leptin, and new proteins like NTR domain-containing protein 2 and endoplasmic reticulum protein 29. Incident MetS was associated with 14 proteins in KORA, of which 13 overlap the prevalent MetS associated proteins with soluble advanced glycosylation end product-specific receptor (sRAGE) being unique to incident MetS. The LASSO selected an eight-protein predictive model with an (AUC = 0.75; 95% CI = 0.71-0.79) in KORA. Mendelian randomization suggested causal effects of three proteins on MetS, namely apolipoprotein E2 (APOE2) (Wald-Ratio = - 0.12, Wald-p = 3.63e-13), apolipoprotein B (APOB) (Wald-Ratio = - 0.09, Wald-p = 2.54e-04) and proto-oncogene tyrosine-protein kinase receptor (RET) (Wald-Ratio = 0.10, Wald-p = 5.40e-04). CONCLUSIONS: Our findings offer new insights into the plasma proteome underlying MetS and identify new protein associations. We reveal possible casual effects of APOE2, APOB and RET on MetS. Our results highlight protein candidates that could potentially serve as targets for prevention and therapy.

Deciphering the Plasma Proteome of Type 2 Diabetes.

With an estimated prevalence of 463 million affected, type 2 diabetes represents a major challenge to health care systems worldwide. Analyzing the plasma proteomes of individuals with type 2 diabetes may illuminate hitherto unknown functional mechanisms underlying disease pathology. We assessed the associations between type 2 diabetes and >1,000 plasma proteins in the Cooperative Health Research in the Region of Augsburg (KORA) F4 cohort (n = 993, 110 cases), with subsequent replication in the third wave of the Nord-Trøndelag Health Study (HUNT3) cohort (n = 940, 149 cases). We computed logistic regression models adjusted for age, sex, BMI, smoking status, and hypertension. Additionally, we investigated associations with incident type 2 diabetes and performed two-sample bidirectional Mendelian randomization (MR) analysis to prioritize our results. Association analysis of prevalent type 2 diabetes revealed 24 replicated proteins, of which 8 are novel. Proteins showing association with incident type 2 diabetes were aminoacylase-1, growth hormone receptor, and insulin-like growth factor-binding protein 2. Aminoacylase-1 was associated with both prevalent and incident type 2 diabetes. MR analysis yielded nominally significant causal effects of type 2 diabetes on cathepsin Z and rennin, both known to have roles in the pathophysiological pathways of cardiovascular disease, and of sex hormone-binding globulin on type 2 diabetes. In conclusion, our high-throughput proteomics study replicated previously reported type 2 diabetes-protein associations and identified new candidate proteins possibly involved in the pathogenesis of type 2 diabetes.

Serum uromodulin is inversely associated with the metabolic syndrome in the KORA F4 study.

OBJECTIVE: Metabolic syndrome and obesity are risk factors for chronic kidney disease. However, early kidney alterations may escape diagnosis in these conditions due to glomerular hyperfiltration. Uromodulin, a glycoprotein exclusively synthesized in tubular cells of the thick ascending limb of Henle's loop, is a novel tissue-specific biomarker for kidney function. In contrast to the commonly used markers creatinine and cystatin C, serum uromodulin does not primarily depend on glomerular filtration. We hypothesized that serum uromodulin is a marker for metabolic syndrome and related components. DESIGN: The analyses included 1088 participants of the population-based KORA F4 study aged 62-81 years. Metabolic syndrome was present in 554 participants. After a mean follow-up time of 6.5 years, 621 participants were reevaluated, of which 92 had developed incident metabolic syndrome. METHODS: The association of serum uromodulin with metabolic syndrome and its components were assessed using multivariable logistic regression models. RESULTS: Serum uromodulin was inversely associated with metabolic syndrome after adjustment for sex, age, estimated glomerular filtration rate, physical activity, smoking, alcohol consumption and high-sensitivity C-reactive protein (OR 0.65; 95% CI 0.56-0.76 per standard deviation uromodulin; P < 0.001). Serum uromodulin was inversely associated with all single components of metabolic syndrome. However, serum uromodulin was not associated with new-onset metabolic syndrome after the follow-up period of 6.5 ± 0.3 years (OR 1.18; 95% CI 0.86-1.60). CONCLUSIONS: Serum uromodulin is independently associated with prevalent, but not with incident metabolic syndrome. Low serum uromodulin may indicate a decreased renal reserve in the metabolic syndrome.

Persistent organic pollutants and the incidence of type 2 diabetes in the CARLA and KORA cohort studies.

BACKGROUND: Associations between several persistent organic pollutants (POPs) and type 2 diabetes have been found in humans, but the relationship has rarely been investigated in the general population. The current nested case-control study examined internal exposure to polychlorinated biphenyls (PCB) and pesticides and the incidence of type 2 diabetes among participants of two population-based German cohort studies. METHODS: We retrospectively selected 132 incident cases of type 2 diabetes and 264 age- and sex-matched controls from the CARdiovascular Living and Aging in Halle (CARLA) study (2002-2006, East Germany) and the Cooperative Health Research in the Region of Augsburg (KORA) study (1999-2001, South Germany) based on diabetes status at follow-up examinations in 2007-2010 and 2006-08, respectively (60% male, mean age 63 and 54 years). We assessed the association between baseline POP concentrations and incident diabetes by conditional logistic regression adjusted for cohort, BMI, cholesterol, alcohol, smoking, physical activity, and parental diabetes. Additionally, we examined effect modification by sex, obesity, parental diabetes and cohort. RESULTS: In both cohorts, diabetes cases showed a higher BMI, a higher frequency of parental diabetes, and higher levels of POPs. We observed an increased chance for incident diabetes for PCB-138 and PCB-153 with an odds ratio (OR) of 1.50 (95%CI: 1.07-2.11) and 1.53 (1.15-2.04) per interquartile range increase in the respective POP. In addition, explorative results suggested higher OR for women and non-obese participants. CONCLUSIONS: Our results add to the evidence on diabetogenic effects of POPs in the general population, and warrant both policies to prevent human exposure to POPs and additional research on the adverse effects of more complex chemical mixtures.

A Systemic Inflammatory Signature Reflecting Cross Talk Between Innate and Adaptive Immunity Is Associated With Incident Polyneuropathy: KORA F4/FF4 Study.

Prospective analyses of biomarkers of inflammation and distal sensorimotor polyneuropathy (DSPN) are scarce and limited to innate immunity. We therefore aimed to assess associations between biomarkers reflecting multiple aspects of immune activation and DSPN. The study was based on 127 case subjects with incident DSPN and 386 noncase subjects from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (follow-up 6.5 years). Proximity extension assay technology was used to measure serum levels of biomarkers of inflammation. Of 71 biomarkers assessed, 26 were associated with incident DSPN. After adjustment for multiple testing, higher levels of six biomarkers remained related to incident DSPN. Three of these proteins (MCP-3/CCL7, MIG/CXCL9, IP-10/CXCL10) were chemokines, and the other three (DNER, CD40, TNFRSF9) were soluble forms of transmembrane receptors. The chemokines had neurotoxic effects on neuroblastoma cells in vitro. Addition of all six biomarkers improved the C statistic of a clinical risk model from 0.748 to 0.783 (P = 0.011). Pathway analyses indicated that multiple cell types from innate and adaptive immunity are involved in the development of DSPN. We thus identified novel associations between biomarkers of inflammation and incident DSPN pointing to a complex cross talk between innate and adaptive immunity in the pathogenesis of the disease.

The Association between Serum 25-Hydroxyvitamin D and Cancer Risk: Results from the Prospective KORA F4 Study.

BACKGROUND: Many studies have examined the relationship between vitamin D and specific types of cancer with inconsistent results. Furthermore, to date, no observational studies have demonstrated a clear relationship between vitamin D and total cancer risk. METHODS: We analyzed data from a population-based prospective cohort study including 2,003 initially cancer-free participants from the KORA F4 study with baseline serum 25-hydroxyvitamin D (25(OH)D) measurements (surveyed between 2006 and 2008). We used Cox proportional hazard models to assess the association between 25(OH)D levels and incident cancer risk. RESULTS: Within a follow-up period of 7 years, 69 of the participants developed cancer. Overall, we observed no significant relationship between serum 25(OH)D levels and cancer risk. The hazard ratio (HR) per 1 ng/ml increase in 25 (OH)D for this relationship was 1.00 (95% confidence interval (CI) 0.97-1.04) adjusting for age, sex, body mass index, and season of blood draw. This was also true in subgroup analysis for prostate cancer (HR 0.95, 95% CI 0.88-1.03), breast cancer (HR 1.03, 95% CI 0.97-1.09), and colorectal cancer (HR 0.97, 95% CI 0.88-1.07). CONCLUSION: Our study found no protective effect of 25(OH)D against developing cancer. However, studies with more participants and additional measurements of 25(OH)D are still needed to accurately clarify the relationship between 25(OH)D and total cancer risk.

Ultra-sensitive troponin I is an independent predictor of incident coronary heart disease in the general population.

Troponins are sensitive markers of myocardial injury and predictive of cardiovascular events, but conventional assays fail to detect slightly elevated troponins in a considerable proportion of the general population. Using a novel ultrasensitive assay, we explored the relationship of troponin levels with the incidence of coronary heart disease (CHD) in a case-cohort sample (mean age 52.5 ± 0.2 years, 51.5% women) comprising 803 CHD cases and 1942 non-cases. Ultrasensitive troponin I was detectable in 99.9% of available case-cohort samples. In an age- and sex-adjusted model, individuals in the highest quartile of the troponin distribution had a more than threefold increased risk for CHD events compared to those in the bottom quartile [hazard ratio, HR, 3.11; 95% confidence interval (CI) 2.15-4.49]. In a model adjusting for cardiovascular risk factors including C-reactive protein, cystatin C and N-terminal pro brain natriuretic peptide, individuals in the highest troponin I quartile still showed a hazard ratio of 2.58 (95% CI 1.66-4.00) for incident CHD as compared to those in the lowest quartile. Ultrasensitive troponin I was detectable in almost all individuals of a study sample reflecting middle-aged to elderly European general population. Ultrasensitive troponin concentrations exhibit an independent, graded, positive relation with incident CHD.

Serum levels of interleukin-22, cardiometabolic risk factors and incident type 2 diabetes: KORA F4/FF4 study.

AIMS: Interleukin-22 (IL-22) has beneficial effects on body weight, insulin resistance and inflammation in different mouse models, but its relevance for the development of type 2 diabetes in humans is unknown. We aimed to identify correlates of serum IL-22 levels and to test the hypothesis that higher IL-22 levels are associated with lower diabetes incidence. METHODS: Cross-sectional associations between serum IL-22, cardiometabolic risk factors and glucose tolerance status were investigated in 1107 persons of the population-based KORA F4 study. The prospective association between serum IL-22 and incident type 2 diabetes was assessed in 504 initially non-diabetic study participants in both the KORA F4 study and its 7-year follow-up examination KORA FF4, 76 of whom developed diabetes. RESULTS: Male sex, current smoking, lower HDL cholesterol, lower estimated glomerular filtration rate and higher serum interleukin-1 receptor antagonist were associated with higher IL-22 levels after adjustment for confounders (all P < 0.05). Serum IL-22 showed no associations with glucose tolerance status, prediabetes or type 2 diabetes. Baseline serum IL-22 levels (median, 25th/75th percentiles) for incident type 2 diabetes cases and non-cases were 6.28 (1.95; 12.35) and 6.45 (1.95; 11.80) pg/ml, respectively (age and sex-adjusted P = 0.744). The age and sex-adjusted OR (95% CI) per doubling of IL-22 for incident type 2 diabetes of 1.02 (0.85; 1.23) was almost unchanged after consideration of further confounders. CONCLUSIONS: High serum levels of IL-22 were positively rather than inversely associated with several cardiometabolic risk factors. However, these associations did not translate into an increased risk for type 2 diabetes. Thus, our data argue against the utility of IL-22 as biomarker for prevalent or incident type 2 diabetes in humans, but identify potential determinants of IL-22 levels which merits further research in the context of cardiovascular diseases.

Proinflammatory Cytokines Predict the Incidence and Progression of Distal Sensorimotor Polyneuropathy: KORA F4/FF4 Study.

OBJECTIVE: Experimental and epidemiological studies have implicated inflammatory processes in the pathogenesis of distal sensorimotor polyneuropathy (DSPN), but prospective studies are lacking. We hypothesized that biomarkers of inflammation predict the development and progression of DSPN in a population-based cohort. RESEARCH DESIGN AND METHODS: This study was based on participants aged 62-81 years from the Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort, with a mean follow-up of 6.5 years. The predictive value of systemic levels of eight biomarkers of inflammation was assessed for incident DSPN in 133 incident case subjects and 397 individuals without incident DSPN, and for DSPN progression in 57 patients with prevalent DSPN at both time points. RESULTS: Higher hs-CRP, interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1 receptor antagonist (IL-1RA), and soluble intercellular adhesion molecule (sICAM-1) and lower adiponectin levels were associated with incident DSPN in age- and sex-adjusted analysis; IL-18 and omentin were not. IL-6 (odds ratio 1.31 [95% CI 1.00-1.71]) and TNF-α (odds ratio 1.31 [95% CI 1.03-1.67]) remained associated with incident DSPN after adjusting for known DSPN risk factors. The addition of both cytokines to a clinical risk model improved model fit and reclassification. sICAM-1 and IL-1RA were positively associated with progression of DSPN. CONCLUSIONS: Systemic subclinical and vascular inflammation predicted both the onset and progression of DSPN over 6.5 years in an older general population. Thus modulation of inflammatory processes may be relevant to prevent and/or treat diabetic neuropathy.

What is the impact of different spirometric criteria on the prevalence of spirometrically defined COPD and its comorbidities? Results from the population-based KORA study.

BACKGROUND: There is an ongoing debate about the appropriate spirometric criterion for airway obstruction to detect COPD. Furthermore, the association of different criteria with comorbidity prevalence and inflammatory biomarkers in advanced age is unclear. MATERIALS AND METHODS: Spirometry was performed in a population-based study (n=2,256) covering an age range of 41-90 years. COPD was spirometrically determined either by a fixed ratio (FR) of <0.7 for forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) or by FEV1/FVC below the lower limit of normal (LLN). Comorbidity prevalences and circulating biomarker levels (C-reactive protein [CRP], interleukin [IL]-6) were compared between subjects with or without COPD by the two criteria using logistic and multiple regression models, adjusting for sex and age. RESULTS: The prevalence of spirometrically defined COPD by FR increased with age from 10% in subjects aged <65 years to 26% in subjects aged ≥75 years. For LLN-defined COPD, it remained below 10% for all age groups. Overall, COPD diagnosis was not associated with specific comorbidities, except for a lower prevalence of obesity in both FR- and LLN-defined cases. Both CRP and IL-6 tended to be higher in cases by both criteria. CONCLUSION: In a population-based cohort of adults up to the age of 90 years, the prevalence of spirometrically defined COPD was higher for the FR criterion than for the LLN criterion. This difference increased with age. Neither prevalences of common comorbidities nor levels of the biomarkers, CRP or IL-6, were conclusively associated with the selection of the COPD criterion. Results have to be considered in light of the predominantly mild cases of airway obstruction in the examined study population.

MASP1, THBS1, GPLD1 and ApoA-IV are novel biomarkers associated with prediabetes: the KORA F4 study.

AIMS/HYPOTHESIS: Individuals at a high risk of type 2 diabetes demonstrate moderate impairments in glucose metabolism years before the clinical manifestation of type 2 diabetes, a state called 'prediabetes'. In order to elucidate the pathophysiological processes leading to type 2 diabetes, we aimed to identify protein biomarkers associated with prediabetes. METHODS: In a proteomics study, we used targeted selected reaction monitoring (SRM)-MS to quantify 23 candidate proteins in the plasma of 439 randomly selected men and women aged 47-76 years from the population-based German KORA F4 study. Cross-sectional associations of protein levels with prediabetes (impaired fasting glucose and/or impaired glucose tolerance), type 2 diabetes, glucose levels in both the fasting state and 2 h after an OGTT, fasting insulin and insulin resistance were investigated using regression models adjusted for technical covariables, age, sex, BMI, smoking, alcohol intake, physical inactivity, actual hypertension, triacylglycerol levels, total cholesterol/HDL-cholesterol ratio, and high-sensitivity C-reactive protein levels. RESULTS: Mannan-binding lectin serine peptidase 1 (MASP1; OR per SD 1.77 [95% CI 1.26, 2.47]), thrombospondin 1 (THBS1; OR per SD 1.55 [95% CI 1.16, 2.07]) and glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1; OR per SD 1.40 [95% CI 1.01, 1.94]) were positively associated with prediabetes, and apolipoprotein A-IV (ApoA-IV; OR per SD 0.75 [95% CI 0.56, 1.00]) was inversely associated with prediabetes. MASP1 was positively associated with fasting and 2 h glucose levels. ApoA-IV was inversely and THBS1 was positively associated with 2 h glucose levels. MASP1 associations with prediabetes and fasting glucose resisted Bonferroni correction. Type 2 diabetes associations were partly influenced by glucose-lowering medication. CONCLUSIONS/INTERPRETATION: We discovered novel and independent associations of prediabetes and related traits with MASP1, and some evidence for associations with THBS1, GPLD1 and ApoA-IV, suggesting a role for these proteins in the pathophysiology of type 2 diabetes.

Intake of Vitamin and Mineral Supplements and Longitudinal Association with HbA1c Levels in the General Non-Diabetic Population--Results from the MONICA/KORA S3/F3 Study.

BACKGROUND: Lower levels of hemoglobin A1c (HbA1c) are associated with a decreased risk of cardiovascular complications in diabetic and non-diabetic individuals. The aim of the study was to longitudinally investigate the association between the use of 11 vitamins and minerals (vitamins E, C, D, B1, folic acid, carotenoids, calcium, magnesium, zinc, iron, and selenium) and change in HbA1c levels over 10 years in non-diabetic individuals drawn from the general population. METHODS: Baseline data were available from 4447 subjects included in the population-based "Monitoring of Trends and Determinants in Cardiovascular Diseases" (MONICA) Augsburg S3 survey (1994/95). Follow-up data were derived from 2774 participants in the follow-up survey named "Cooperative Health Research in the Region of Augsburg" (KORA) F3 (2004/05). Vitamin/mineral intake from supplements and medications was assessed in a personal interview, where participants were asked to bring product packages of preparations that had been ingested during the last 7 days prior to the examination. Associations between regular vitamin/mineral intake amounts and HbA1c levels measured at baseline and follow-up were investigated using generalized estimating equation models. For carotenoids, analyses were stratified by smoking status. RESULTS: None of the investigated nutrients except for carotenoids was significantly associated with changes in HbA1c levels after 10 years. Regular intake of carotenoids from supplements and medications in amounts > 6.8 mg/d (upper tertile) was associated with an absolute -0.26% (95% CI: -0.43 to -0.08) lower increase in HbA1c levels compared with no intake of carotenoids. An inverse association was observed in those who never smoked but not in (former) smokers. CONCLUSION: Larger prospective and intervention studies in non-diabetic/non-smoking individuals are needed to confirm the results and to assess whether the observed associations between carotenoid intake and change in HbA1c levels are causal. If our results are confirmed, high carotenoid intake could be one strategy for the prevention of cardiovascular complications in non-diabetic people.

Biomarkers of iron metabolism are independently associated with impaired glucose metabolism and type 2 diabetes: the KORA F4 study.

OBJECTIVE: Iron has been suggested to play a role in the etiology of type 2 diabetes mellitus (T2DM). Except for ferritin, evidence is sparse for other markers of iron metabolism that are regulated differently and might act through independent pathways. We therefore investigated the associations of serum ferritin, transferrin, soluble transferrin receptor (sTfR), transferrin saturation (TSAT), sTfR-to-log10ferritin (sTfR-F) index, and iron with impaired glucose metabolism (IGM/'prediabetes'), T2DM, and four continuous glucose and insulin traits. DESIGN AND METHODS: Data from 2893 participants of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (Germany) was investigated through regression analysis. The results were adjusted for socio-demographic, life-style, and obesity measures as well as metabolic, inflammatory, and other iron biomarkers following a step-wise approach. Non-linearity was tested by adding a non-linear spline component to the model. RESULTS: Ferritin and transferrin were positively associated with IGM (fourth vs first sex-specific quartile: ferritin odds ratio (OR)=2.08 (95% CI 1.43-3.04) and transferrin OR=1.89 (95% CI 1.32-2.70)), T2DM (ferritin OR=1.98 (95% CI 1.22-3.22) and transferrin OR=2.42 (95% CI 1.54-3.81)), and fasting as well as 2-h glucose. TSAT (OR=0.55 (95% CI 0.34-0.88)) and iron (OR=0.61 (95% CI 0.38-0.97)) were inversely associated with T2DM, sTfR-F-index was inversely associated with IGM (OR=0.67 (95% CI 0.48-0.95)). There was no strong evidence for non-linear relationships. CONCLUSIONS: The observed associations of several markers of iron metabolism with hyperglycemia and insulin resistance suggest that iron stores as well as iron-related metabolic pathways contribute to the pathogenesis of IGM and T2DM. Moreover, TSAT levels are decreased in T2DM patients.

Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study.

AIMS/HYPOTHESIS: The role of biomarkers of subclinical inflammation in the early deterioration of glycaemia before type 2 diabetes is largely unknown. We hypothesised that increased levels of circulating proinflammatory biomarkers and decreased circulating adiponectin would be associated with 7 year increases of HbA(1c) in non-diabetic individuals. METHODS: This study was based on individuals who participated in the prospective Cooperative Health Research in the Region of Augsburg (KORA) S4 survey (1999-2001) and the 7 year follow-up KORA F4 (2006-2008) survey. Individuals with type 2 diabetes at baseline or with a diagnosis of diabetes in the period between both surveys were excluded, which left a sample of 850 men and women. Multivariable linear regression analyses were performed to assess associations among baseline values of leucocyte count and levels of acute-phase proteins (high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA] and fibrinogen), IL-6 and adiponectin with changes in HbA1c between baseline and follow-up. RESULTS: A high leucocyte count and high hsCRP, SAA and IL-6 levels were positively associated with changes in HbA(1c) after adjusting for age, sex, lifestyle factors and baseline HbA(1c). In contrast, the adiponectin level was inversely associated with changes in HbA(1c) (p value between <0.0001 and 0.020). The associations of leucocyte count and levels of hsCRP and SAA with HbA(1c) changes remained significant after additional adjustment for waist circumference and circulating lipids at baseline and for the 7 year change in waist circumference (p value between 0.004 and 0.045). CONCLUSIONS/INTERPRETATION: An elevated leucocyte count and elevated hsCRP and SAA were associated with early deterioration of glycaemia before the diagnosis of type 2 diabetes. These associations were largely independent of baseline abdominal adiposity and increases in waist circumference.

Association of iron indices and type 2 diabetes: a meta-analysis of observational studies.

The literature on the role of body iron status in the development of type 2 diabetes (T2D) in humans is inconsistent. We aimed to assess the association between iron indices and T2D by a meta-analysis of previously published studies. A systematic literature search was conducted in PubMed and EMBASE. Observational studies on the association of ferritin (when controlled for age and sex), transferrin saturation, soluble transferrin receptor and transferrin with T2D were included. Pooled association estimates were calculated using a random effects model. Forty-six eligible studies were identified. The pooled multivariable adjusted relative risks of T2D in the highest versus lowest quartile of ferritin levels were significantly elevated in both cross-sectional as well as prospective studies and after restriction to inflammation-adjusted studies [overall: 1.67 (95% CI 1.41-1.99)]. The mean difference indicated 43.54 ng/mL (95% CI 28.14-58.94) higher ferritin levels in type 2 diabetic individuals. The relative risk for a transferrin saturation ≥ 50% was 1.59 (95% CI 1.28-1.97), the mean difference was -1.92% [95% CI -2.99-(-0.85)]. Study-specific results of soluble transferrin receptor and transferrin levels were extremely heterogeneous. Ferritin and clinically elevated transferrin saturation were strongly associated with an increased risk of T2D, overall and in prospective studies. Ferritin was also significantly associated after multivariable adjustment including inflammation. Thus, the current evidence hints at a causal effect; however, publication bias and unmeasured confounding cannot be excluded.

Novel biomarkers for pre-diabetes identified by metabolomics.

Type 2 diabetes (T2D) can be prevented in pre-diabetic individuals with impaired glucose tolerance (IGT). Here, we have used a metabolomics approach to identify candidate biomarkers of pre-diabetes. We quantified 140 metabolites for 4297 fasting serum samples in the population-based Cooperative Health Research in the Region of Augsburg (KORA) cohort. Our study revealed significant metabolic variation in pre-diabetic individuals that are distinct from known diabetes risk indicators, such as glycosylated hemoglobin levels, fasting glucose and insulin. We identified three metabolites (glycine, lysophosphatidylcholine (LPC) (18:2) and acetylcarnitine) that had significantly altered levels in IGT individuals as compared to those with normal glucose tolerance, with P-values ranging from 2.4×10(-4) to 2.1×10(-13). Lower levels of glycine and LPC were found to be predictors not only for IGT but also for T2D, and were independently confirmed in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort. Using metabolite-protein network analysis, we identified seven T2D-related genes that are associated with these three IGT-specific metabolites by multiple interactions with four enzymes. The expression levels of these enzymes correlate with changes in the metabolite concentrations linked to diabetes. Our results may help developing novel strategies to prevent T2D.

Categories of glucose tolerance and continuous glycemic measures and mortality.

We investigated the association of undiagnosed diabetes, previously known diabetes and prediabetes (WHO 1999 classification) with all-cause and cause-specific mortality in an older German population. Previous study results for mortality in patients with very low levels of HbA1c, fasting plasma glucose (FPG), and 2-h plasma glucose (2hPG) are still inconclusive. Thus we have extended the analyses to continuous measures of glycemia. A total of 1,466 subjects aged 55-74 years from the population-based KORA survey S4 (conducted from 1999 to 2001) were included in our observational mortality study (152 subjects with previously known diabetes, and 1,314 further subjects who underwent oral glucose tolerance tests). Mortality was followed up for a maximum of 10.0 years (median follow-up 8.8 years). A total of 180 (12.3%) of the 1,466 subjects have died during the follow-up period. The age- and sex-adjusted hazard ratios for all-cause mortality were 2.6 (95%CI, 1.7-3.8) for known diabetes, 2.8 (95%CI, 1.7-4.4) for undiagnosed diabetes, and 1.1 (95%CI, 0.8-1.7) for prediabetes [reference: normal glucose tolerance (NGT)]. After multivariable adjustment, undiagnosed diabetes was associated with 3.0-fold increased cancer mortality, 1.1-fold increased cardiovascular mortality, and 4.7-fold increased non-cancer, non-cardiovascular mortality compared with NGT. For HbA1c, FPG, and 2hPG, J-shaped associations with all-cause mortality were observed. Undiagnosed diabetes is associated with increased all-cause, cancer, and non-cancer non-cardiovascular mortality, but not with cardiovascular mortality in this older population. All-cause mortality in undiagnosed diabetes is similar to that in previously known diabetes but much higher than mortality in prediabetes and NGT.

Joint analysis of individual participants' data from 17 studies on the association of the IL6 variant -174G>C with circulating glucose levels, interleukin-6 levels, and body mass index.

BACKGROUND: Several studies have investigated associations between the -174G>C single nucleotide polymorphism (rs1800795) of the IL6 gene and phenotypes related to type 2 diabetes mellitus (T2DM) but presented inconsistent results. AIMS: This joint analysis aimed to clarify whether IL6 -174G>C was associated with glucose and circulating interleukin-6 concentrations as well as body mass index (BMI). METHODS: Individual-level data from all studies of the IL6-T2DM consortium on Caucasian subjects with available BMI were collected. As study-specific estimates did not show heterogeneity (P>0.1), they were combined by using the inverse-variance fixed-effect model. RESULTS: The main analysis included 9440, 7398, 24,117, or 5659 non-diabetic and manifest T2DM subjects for fasting glucose, 2-hour glucose, BMI, or circulating interleukin-6 levels, respectively. IL6 -174 C-allele carriers had significantly lower fasting glucose (-0.091 mmol/L, P=0.014). There was no evidence for association between IL6 -174G>C and BMI or interleukin-6 levels, except in some subgroups. CONCLUSIONS: Our data suggest that C-allele carriers of the IL6 -174G>C polymorphism have lower fasting glucose levels on average, which substantiates previous findings of decreased T2DM risk of these subjects.

Gene variants of monocyte chemoattractant protein 1 and components of metabolic syndrome in KORA S4, Augsburg.

OBJECTIVE: Monocyte chemoattractant protein 1 (MCP-1) has been suggested to be involved in the development of several components of metabolic syndrome (MetS). The present study investigated the association of nine MCP-1 single nucleotide polymorphisms (SNPs) with MetS, type 2 diabetes mellitus and metabolic risk factors. SUBJECTS AND METHODS: The population-based study sample comprised 1630 subjects aged 55-74 years from KORA S4 (Cooperative Health Research in the Region of Augsburg Survey 4). Genotyping was carried out by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) analysis of allele-dependent primer extension products. RESULTS: The MCP-1 SNP c.-3813C>T exhibited trends for differences between the genotype groups in triglycerides, 2-h glucose and uric acid (P = 0.0084, 0.014, 0.027). Other trends were observed for c.-928G>C associated with height and fasting glucose (P = 0.0024, 0.033), for c.105T>C with height and leukocytes (P = 0.0095, 0.047), for c.*65C>T and c.*3879C>T with MCP-1 levels (both P = 0.012) and for c.-2138A>T with interleukin-6 levels. After correction for multiple testing, none of the analysed SNPs, except c.-928G>C in men showed a significant association with MetS, T2DM or other analysed parameters. Haplotype MCP-1*1 and c.-928G>C in men (P = 0.0002, 0.0004) were significantly associated with an increase in height. CONCLUSIONS: This is the first study to investigate the associations of MCP-1 SNPs with MetS. We found trends for several components of MetS. These parameters were hyperlipidaemia, fasting and 2-h glucose, and uric acid. A new finding is that MCP-1*1 haplotype is associated with height. Further investigation in larger populations is needed to clarify the involvement of MCP-1 in MetS.