Sex hormone-binding globulin may explain sex differences for glucose homeostasis and incidence of type 2 diabetes: the KORA study.

Research has indicated that sex hormone-binding globulin (SHBG) is associated with glucose homeostasis and may play a role in the etiology of type 2 diabetes (T2D). While it is unclear whether SHBG may mediate sex differences in glucose control and subsequently, incidence of T2D. We used observational data from the German population-based KORA F4 study (n = 1937, mean age: 54 years, 41% women) and its follow-up examination KORA FF4 (median follow-up 6.5 years, n = 1387). T2D was initially assessed by self-report and validated by contacting the physicians and/ or reviewing the medical charts. Mediation analyses were performed to assess the role of SHBG in mediating the association between sex (women vs. men) and glucose- and insulin-related traits (cross-sectional analysis) and incidence of T2D (longitudinal analysis). After adjustment for confounders, (model 1: adjusted for age; model 2: model 1 + smoking + alcohol consumption + physical activity), women had lower fasting glucose levels compared to men (ß = -4.94 (mg/dl), 95% CI: -5.77, -4.11). SHBG levels were significantly higher in women than in men (ß = 0.47 (nmol/l), 95% CI:0.42, 0.51). Serum SHBG may mediate the association between sex and fasting glucose levels with a proportion mediated (PM) of 30% (CI: 22-41%). Also, a potential mediatory role of SHBG was observed for sex differences in incidence of T2D (PM = 95% and 63% in models 1 and 2, respectively). Our novel findings suggest that SHBG may partially explain sex-differences in glucose control and T2D incidence.

Bidirectional modulation of TCA cycle metabolites and anaplerosis by metformin and its combination with SGLT2i.

BACKGROUND: Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans. METHODS: Metformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications. RESULTS: Metformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses. CONCLUSION: This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.

Plasma proteome association with coronary heart disease and carotid intima media thickness: results from the KORA F4 study.

BACKGROUND AND AIMS: Atherosclerosis is the main cause of stroke and coronary heart disease (CHD), both leading mortality causes worldwide. Proteomics, as a high-throughput method, could provide helpful insights into the pathological mechanisms underlying atherosclerosis. In this study, we characterized the associations of plasma protein levels with CHD and with carotid intima-media thickness (CIMT), as a surrogate measure of atherosclerosis. METHODS: The discovery phase included 1000 participants from the KORA F4 study, whose plasma protein levels were quantified using the aptamer-based SOMAscan proteomics platform. We evaluated the associations of plasma protein levels with CHD using logistic regression, and with CIMT using linear regression. For both outcomes we applied two models: an age-sex adjusted model, and a model additionally adjusted for body mass index, smoking status, physical activity, diabetes status, hypertension status, low density lipoprotein, high density lipoprotein, and triglyceride levels (fully-adjusted model). The replication phase included a matched case-control sample from the independent KORA F3 study, using ELISA-based measurements of galectin-4. Pathway analysis was performed with nominally associated proteins (p-value < 0.05) from the fully-adjusted model. RESULTS: In the KORA F4 sample, after Bonferroni correction, we found CHD to be associated with five proteins using the age-sex adjusted model: galectin-4 (LGALS4), renin (REN), cathepsin H (CTSH), and coagulation factors X and Xa (F10). The fully-adjusted model yielded only the positive association of galectin-4 (OR = 1.58, 95% CI = 1.30-1.93), which was successfully replicated in the KORA F3 sample (OR = 1.40, 95% CI = 1.09-1.88). For CIMT, we found four proteins to be associated using the age-sex adjusted model namely: cytoplasmic protein NCK1 (NCK1), insulin-like growth factor-binding protein 2 (IGFBP2), growth hormone receptor (GHR), and GDNF family receptor alpha-1 (GFRA1). After assessing the fully-adjusted model, only NCK1 remained significant (ß = 0.017, p-value = 1.39e-06). Upstream regulators of galectin-4 and NCK1 identified from pathway analysis were predicted to be involved in inflammation pathways. CONCLUSIONS: Our proteome-wide association study identified galectin-4 to be associated with CHD and NCK1 to be associated with CIMT. Inflammatory pathways underlying the identified associations highlight the importance of inflammation in the development and progression of CHD.

Omentin associates with serum metabolite profiles indicating lower diabetes risk: KORA F4 Study.

INTRODUCTION: Circulating omentin levels have been positively associated with insulin sensitivity. Although a role for adiponectin in this relationship has been suggested, underlying mechanisms remain elusive. In order to reveal the relationship between omentin and systemic metabolism, this study aimed to investigate associations of serum concentrations of omentin and metabolites. RESEARCH DESIGN AND METHODS: This study is based on 1124 participants aged 61-82 years from the population-based KORA (Cooperative Health Research in the Region of Augsburg) F4 Study, for whom both serum omentin levels and metabolite concentration profiles were available. Associations were assessed with five multivariable regression models, which were stepwise adjusted for multiple potential confounders, including age, sex, body mass index, waist-to-hip ratio, lifestyle markers (physical activity, smoking behavior and alcohol consumption), serum adiponectin levels, high-density lipoprotein cholesterol, use of lipid-lowering or anti-inflammatory medication, history of myocardial infarction and stroke, homeostasis model assessment 2 of insulin resistance, diabetes status, and use of oral glucose-lowering medication and insulin. RESULTS: Omentin levels significantly associated with multiple metabolites including amino acids, acylcarnitines, and lipids (eg, sphingomyelins and phosphatidylcholines (PCs)). Positive associations for several PCs, such as diacyl (PC aa C32:1) and alkyl-alkyl (PC ae C32:2), were significant in models 1-4, whereas those with hydroxytetradecenoylcarnitine (C14:1-OH) were significant in all five models. Omentin concentrations were negatively associated with several metabolite ratios, such as the valine-to-PC ae C32:2 and the serine-to-PC ae C32:2 ratios in most models. CONCLUSIONS: Our results suggest that omentin may influence insulin sensitivity and diabetes risk by changing systemic lipid metabolism, but further mechanistic studies investigating effects of omentin on metabolism of insulin-sensitive tissues are needed.

Deep learning to estimate impaired glucose metabolism from Magnetic Resonance Imaging of the liver: An opportunistic population screening approach.

AIM: Diabetes is a global health challenge, and many individuals are undiagnosed and not aware of their increased risk of morbidity/mortality although dedicated tests are available, which indicates the need for novel population-wide screening approaches. Here, we developed a deep learning pipeline for opportunistic screening of impaired glucose metabolism using routine magnetic resonance imaging (MRI) of the liver and tested its prognostic value in a general population setting. METHODS: In this retrospective study a fully automatic deep learning pipeline was developed to quantify liver shape features on routine MR imaging using data from a prospective population study. Subsequently, the association between liver shape features and impaired glucose metabolism was investigated in individuals with prediabetes, type 2 diabetes and healthy controls without prior cardiovascular diseases. K-medoids clustering (3 clusters) with a dissimilarity matrix based on Euclidean distance and ordinal regression was used to assess the association between liver shape features and glycaemic status. RESULTS: The deep learning pipeline showed a high performance for liver shape analysis with a mean Dice score of 97.0±0.01. Out of 339 included individuals (mean age 56.3±9.1 years; males 58.1%), 79 (23.3%) and 46 (13.6%) were classified as having prediabetes and type 2 diabetes, respectively. Individuals in the high risk cluster using all liver shape features (n = 14) had a 2.4 fold increased risk of impaired glucose metabolism after adjustment for cardiometabolic risk factors (age, sex, BMI, total cholesterol, alcohol consumption, hypertension, smoking and hepatic steatosis; OR 2.44 [95% CI 1.12-5.38]; p = 0.03). Based on individual shape features, the strongest association was found between liver volume and impaired glucose metabolism after adjustment for the same risk factors (OR 1.97 [1.38-2.85]; p<0.001). CONCLUSIONS: Deep learning can estimate impaired glucose metabolism on routine liver MRI independent of cardiometabolic risk factors and hepatic steatosis.

Trajectories of glycaemic traits exhibit sex-specific associations with hepatic iron and fat content: Results from the KORA-MRI study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) represents a major disease burden in the population. While the bidirectional association between NAFLD and diabetes is established, little is known about the association of hepatic iron content and glycaemia. Moreover, analyses of sex-specific effects and of dynamic changes in glycaemia are scarce. METHODS: We investigated 7-year sex-specific trajectories of glycaemia and related traits (HbA1c, fasting glucose, fasting insulin, HOMA-IR, 2-h glucose and cross-sectional 2-h insulin) in a sample from a population-based cohort (N = 365; 41.1% female). Hepatic iron and fat content were assessed by 3T-Magnetic Resonance Imaging (MRI). Two-step multi-level models adjusted for glucose-lowering medication and confounders were applied. RESULTS: In women and men, markers of glucose metabolism correlated with hepatic iron and fat content. Deterioration of glycaemia was associated with increased hepatic iron content in men (normoglycaemia to prediabetes: beta = 2.21 s-1 , 95% CI [0.47, 3.95]). Additionally, deterioration of glycaemia (e.g. prediabetes to diabetes: 1.27 log(%), [0.84, 1.70]) and trajectories of glucose, insulin and HOMA-IR were significantly associated with hepatic fat content in men. Similarly, deterioration of glycaemia as well as trajectories of glucose, insulin and HOMA-IR was significantly associated with increased hepatic fat content in women (e.g. trajectory of fasting insulin: 0.63 log(%), [0.36, 0.90]). CONCLUSIONS: Unfavourable 7-year trajectories of markers of glucose metabolism are associated with increased hepatic fat content, particularly in women, whereas the association with hepatic iron content was less clear. Monitoring changes of glycaemia in the sub-diabetic range might enable early identification of hepatic iron overload and steatosis.

Associations of myosteatosis with disc degeneration: A 3T magnetic resonance imaging study in individuals with impaired glycaemia.

BACKGROUND: Intervertebral disc degeneration (IVDD) may be linked to dysregulations of skeletal muscle glucose metabolism and fatty alterations of muscle composition (Myosteatosis). Our aim was to evaluate the different associations of magnetic resonance imaging (MRI)-based paravertebral myosteatosis with lumbar disc degeneration in individuals with impaired glucose metabolism and normoglycaemic controls. METHODS: In total, 304 individuals (mean age: 56.3 ± 9.1 years, 53.6% male sex, mean body mass index [BMI]: 27.6 ± 4.7 kg/m2 ) from a population-based cohort study who underwent 3-Tesla whole-body chemical-shift-encoded (six echo times) and T2-weighted single-shot-fast-spin-echo MRI were included. Lumbar disc degeneration was assessed at motion segments L1 to L5, categorized according to the Pfirrmann score and defined as Pfirrmann grade > 2 and/or disc bulging/herniation on at least one segment. Fat content of the autochthonous back muscles and the quadratus lumborum muscle was quantified as proton density fat fraction (PDFFmuscle ). Logistic regression models adjusted for age, sex, BMI and regular physical activity were calculated to evaluate the association between PDFFmuscle and outcome IVDD. RESULTS: The overall prevalence of IVDD was 79.6%. There was no significant difference in the prevalence or severity distribution of IVDD between participants with or without impaired glucose metabolism (77.7% vs. 80.7%, P = 0.63 and P = 0.71, respectively). PDFFmuscle was significantly and positively associated with an increased risk for the presence of IVDD in participants with impaired glycaemia when adjusted for age, sex and BMI (PDFFautochthonous back muscles : odds ratio [OR] 2.16, 95% confidence interval [CI] [1.09, 4.3], P = 0.03; PDFFquadratus lumborum : OR 2.01, 95% CI [1.04, 3.85], P = 0.04). After further adjustment for regular physical activity, the results attenuated, albeit approaching statistical significance (PDFFautochthonous back muscles : OR 1.97, 95% CI [0.97, 3.99], P = 0.06; PDFFquadratus lumborum : OR 1.86, 95% CI [0.92, 3.76], P = 0.09). No significant associations were shown in healthy controls (PDFFautochthonous back muscles : OR 0.62, 95% CI [0.34, 1.14], P = 0.13; PDFFquadratus lumborum : OR 1.06, 95% CI [0.6, 1.89], P = 0.83). CONCLUSIONS: Paravertebral myosteatosis is positively associated with intervertebral disc disease in individuals with impaired glucose metabolism, independent of age, sex and BMI. Regular physical activity may confound these associations. Longitudinal studies will help to better understand the pathophysiological role of skeletal muscle in those with concomitant disturbed glucose haemostasis and intervertebral disc disease, as well as possible underlying causal relationships.

Association of Aldosterone with Mortality in the General Population.

INTRODUCTION: Aldosterone excess is linked to cardiovascular events and mortality as well as to low-grade inflammation in the context of metabolic diseases. Whether mildly elevated aldosterone levels in the general population promote cardiovascular risk is still under debate. We analyzed the association of plasma aldosterone concentrations with incident cardiovascular events, cardiovascular and all-cause mortality as well as with biomarkers of subclinical inflammation in the population-based KORA F4 study. METHODS: Plasma aldosterone concentrations were measured with an in-house immunoflurometric assay. The analyses included 2935 participants (n=1076 for selected biomarkers of subclinical inflammation) with a median follow-up of 8.7 (8.2; 9.1) years. The associations were estimated using Cox proportional hazard and linear regression models adjusted for renin, sex, age, body mass index, arterial hypertension, diabetes, estimated glomerular filtration rate, low- and high-density lipoprotein cholesterol, physical activity, smoking, use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, diuretics and calcium channel blockers. RESULTS: Aldosterone was significantly associated with all-cause mortality (hazard ratio per standard deviation increase: 1.20; 95% confidence interval 1.04-1.37), but not with cardiovascular mortality, incident cardiovascular events, or with biomarkers of subclinical inflammation. CONCLUSIONS: Aldosterone was associated with all-cause mortality in the population-based KORA F4 study, but the previously described associations of excess aldosterone with cardiovascular complications and biomarkers of subclinical inflammation could not be shown.

Association between the fatty liver index and chronic kidney disease: the population-based KORA study.

BACKGROUND: We aimed to evaluate the relationship of fatty liver, estimated by the fatty liver index (FLI), with kidney function and chronic kidney disease (CKD) in a German cohort study, given the lack of prospective evidence in Europeans. METHODS: We included 2920 participants (51.6% women, mean age 56.1 years) from the KORA study, of which 1991 were followed up for an average of 6.5 years (± 0.3). Kidney function was assessed using the glomerular filtration rate estimated by creatinine (eGFR-Cr) or cystatin C (eGFR-cC). We used multiple logistic or linear regressions to evaluate the associations between the FLI, kidney function and CKD (eGFR < 60 ml/min/1.73 m2) and mediation analysis to explore the mediation effects of metabolic factors. RESULTS: The prevalence of FLI ≥60 and CKD was 40.4% and 5.6% at baseline, respectively, and 182 participants developed CKD during the follow-up. Cross-sectionally, FLI was significantly inversely associated with eGFR-cC {ß = -1.14 [95% confidence interval (CI) -1.81 to -0.47]} and prevalent CKD based on eGFR-cC [OR 1.28 (95% CI 1.01-1.61)], but not with other markers. After adjusting for lifestyle factors, we found a positive association between FLI and incident CKD defined by eGFR-cC or/eGFR-Cr, which was attenuated after controlling for metabolic risk factors. Mediation analysis showed that the association was completely mediated by inflammation, diabetes and hypertension jointly. CONCLUSION: The positive association between FLI and CKD incidence was fully mediated by the joint effect of metabolic risk factors. Future longitudinal studies need to explore the chronological interplay between fatty liver, cardiometabolic risk factors and kidney function with repeated measurements.

Environmental risk factors of incident distal sensorimotor polyneuropathy: Results from the prospective population-based KORA F4/FF4 study.

Distal sensorimotor polyneuropathy (DSPN) is a common condition in older populations with high prevalence of obesity and type 2 diabetes. We hypothesised that the risk of DSPN is increased by multiple ubiquitous environmental risk factors, particularly in people with obesity. This study was based on 423 individuals aged 62-81 years without DSPN who participated in the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 survey (2006-2008) in Southern Germany. During 6.5 years of follow-up, 188 participants developed clinical DSPN as assessed by the Michigan Neuropathy Screening Instrument. Environmental exposures, including air temperature, surrounding greenness (assessed with the normalized difference vegetation index [NDVI]), long-term road traffic noise and air pollution, were assessed at participants' residences. The cumulative risk index (CRI) evaluated the joint effects of co-occurring exposures on DSPN risk based on effect estimates from multi-exposure Poisson regression models. The models were adjusted for age, sex, height, waist circumference, smoking, alcohol consumption, physical activity, education and neighbourhood socioeconomic status. In the entire cohort, the co-occurrence of an interquartile range (IQR) decrease in temperature of the warm season and NDVI in a 100-m buffer and of an IQR increase in night-time average traffic noise and in annual average particle number concentration (PNC) was positively associated with incident DSPN (CRI [95 % CI] 1.39 [1.02, 1.91]). Effect estimates for exposure combinations were generally higher in individuals with obesity (CRI 1.34-2.01) than in those without obesity (CRI 0.90-1.33). The four-exposure model showed a twofold increased risk of DSPN among obese (CRI [95 % CI] 2.01 [1.10, 3.67]), but not among non-obese individuals (CRI [95 % CI] 1.18 [0.83, 1.67]). Thus, ubiquitous environmental exposures jointly augment the risk of DSPN in the older population. Lower air temperature in the warm season, less greenness, and higher noise levels and ultrafine particle concentrations identified people with obesity as a particularly vulnerable subgroup.

Do Glucagonlike Peptide-1 Receptor Agonist and Sodium-glucose Co-transporter 2 Inhibitor Prescriptions in Germany Reflect Recommendations for Type 2 Diabetes with Cardiovascular Disease of the ADA/EASD Consensus Report?

OBJECTIVES: To analyze whether prescription use of GLP-1RA and SGLT2i in individuals with type 2 diabetes with cardiovascular disease (CVD) has increased after the ADA/EASD consensus guidelines (2018) in a German Real-World setting and which clinical characteristics are associated with prescription use of these drugs. METHODS: The Disease Analyzer database (IQVIA) comprises a representative panel of 1,373 general practitioners, diabetologists, and cardiologists throughout Germany (01/2015-12/2020: 12.6 million patients). Newly diagnosed type 2 diabetes (n=45,531) was identified by ICD-10 codes (E11). Matching (1:1) on practice specialty, sex, age, and year of diabetes diagnosis was performed for CVD. Logistic regression models were fitted to obtain adjusted odds ratios (OR) for characteristics associated with prescription use (median follow-up: 1.9 years). RESULTS: Overall, 35% of patients (n=16,006) were treated with glucose-lowering drugs during the first year after type 2 diabetes diagnosis (HbA1c≥7.0%: 80%). GLP-1RA (2.4%) and SGLT2i (8.5%) were rarely prescribed. After the consensus, use of GLP-1RA and SGLT2i increased, however, almost independently of pre-existing CVD (12/2019-11/2020 vs. 12/2017-11/2018: yes, no): GLP-1RA: from 5.7 to 9.2%, 5.2 to 7.6%; SGLT2i: from 13.9 to 20.4%, 12.1 to 16.6%. Among cardiovascular risk factors, the largest OR for GLP-1RA was for obesity (4.5; 95%CI: 3.2-6.3). CVD was moderately related with SGLT2i (1.45; 1.32-1.60) and GLP-1RA (1.35; 1.08-1.69) prescriptions. A weak association was observed between SGLT2i and heart failure (1.18; 95%CI: 1.05-1.32). CONCLUSION: National prescription use of GLP-1RA and SGLT2i did not come close to the recommendation in subjects with CVD issued by the 2018 ADA/EASD consensus.

Record linkage of claims and cancer registries data-Evaluation of a deterministic linkage approach based on indirect personal identifiers.

PURPOSE: In Germany, record linkage of claims and cancer registry data is cost- and time-consuming, since up until recently no unique personal identifier was available in both data sources. The aim of this study was to evaluate the feasibility and performance of a deterministic linkage procedure based on indirect personal identifiers included in the data sources. METHODS: We identified users of glucose-lowering drugs with residence in four federal states in Northern and Southern Germany (Bavaria, Bremen, Hamburg, Lower Saxony) in the German Pharmacoepidemiological Research Database (GePaRD) and assessed colorectal and thyroid cancer cases. Cancer registries of the federal states selected all colorectal and thyroid cancer cases between 2004 and 2015. A deterministic linkage approach was performed based on indirect personal identifiers such as year of birth, sex, area of residence, type of cancer and an absolute difference between the dates of cancer diagnosis in both data sources of at most 90 days. Results were compared to a probabilistic linkage using "direct" personal identifiers (gold standard). RESULTS: The deterministic linkage procedure yielded a sensitivity of 71.8% for colorectal cancer and 66.6% for thyroid cancer. For thyroid cancer, the sensitivity improved when using only inpatient diagnosis to define cancer in GePaRD (71.4%). Specificity was always above 99%. Using the probabilistic linkage to define cancer cases, the risk for colorectal cancer was estimated 10 percentage points lower than when using the deterministic approach. CONCLUSIONS: Sensitivity of the deterministic linkage approach appears to be too low to be considered as reasonable alternative to the probabilistic linkage procedure.

Association of C-Terminal Pro-Endothelin-1 with Mortality in the Population-Based KORA F4 Study.

Introduction: Endothelin-1 and its prohormone C-terminal pro-endothelin-1 (CT-proET-1) have been linked to metabolic alterations, inflammatory responses and cardiovascular events in selected study populations. We analyzed the association of CT-proET-1 with cardiovascular events and mortality, carotid intima-media-thickness as surrogate for early atherosclerotic lesions, biomarkers of subclinical inflammation and adipokines in a population-based study. Methods: The cross-sectional and prospective analyses used data from the KORA F4 study with a median follow-up time of 9.1 (8.8-9.4) years. Data on CT-proET-1 and mortality were available for 1554 participants, data on the other outcomes in subgroups (n = 596-1554). The associations were estimated using multivariable linear regression and Cox proportional hazard models adjusted for sex, age, body mass index, estimated glomerular filtration rate, arterial hypertension, diabetes, low-density and high-density lipoprotein cholesterol, current and former smoking and physical activity. The Bonferroni method was used to correct for multiple testing. Results: In the fully adjusted model, CT-proET-1 was associated with cardiovascular (hazard ratio (HR) per standard deviation increase: 1.66; 95% confidence interval (CI): 1.10-2.51; p = 0.017) and all-cause mortality (HR: 2.03; 95% CI 1.55-2.67; p < 0.001), but not with cardiovascular events, and was inversely associated with the intima-media thickness (ß: -0.09 ± 0.03; p = 0.001). CT-proET-1 was positively associated with five out of ten biomarkers of subclinical inflammation and with two out of five adipokines after correction for multiple testing. After inclusion of biomarkers of subclinical inflammation in the Cox proportional hazard model, the association of CT-proET-1 with all-cause mortality persisted (p < 0.001). Conclusion: These results emphasize the complexity of endothelin-1 actions and/or indicator functions of CT-proET-1. CT-proET-1 is a risk marker for all-cause mortality, which is likely independent of vascular endothelin-1 actions, cardiovascular disease and inflammation.

DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases.

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.

Association of MRI-based adrenal gland volume and impaired glucose metabolism in a population-based cohort study.

OBJECTIVES: The aim of this study was to assess adrenal gland volume by using magnetic resonance imaging (MRI) and to study its role as an indirect marker of impaired glucose metabolism and hypothalamic-pituitary-adrenal (HPA) axis activation in a population-based cohort. METHODS: Asymptomatic participants were enrolled in a nested case-control study and underwent a 3-T MRI, including T1w-VIBE-Dixon sequences. For the assessment of adrenal gland volume, adrenal glands were manually segmented in a blinded fashion. Impaired glucose metabolism was determined using fasting glucose and oral glucose tolerance test. Cardiometabolic risk factors were also obtained. Inter- and intrareader reliability as well as univariate and multivariate associations were derived. RESULTS: Among 375 subjects included in the analysis (58.5% male, 56.1 ± 9.1 years), 25.3% participants had prediabetes and 13.6% had type 2 diabetes (T2DM). Total adrenal gland volume was 11.2 ± 4.2 ml and differed significantly between impaired glucose metabolism and healthy controls with largest total adrenal gland volume in T2DM (healthy controls: 10.0 ± 3.9 ml, prediabetes: 12.5 ± 3.8 ml, T2DM: 13.9 ± 4.6 ml; p < 0.001). In the multivariate analysis, association of T2DM and increased adrenal gland volume was independent of age, sex, hypertension, triglycerides and body mass index (BMI), but was attenuated in subjects with prediabetes after adjustment for BMI. CONCLUSIONS: T2DM is significantly associated with increased adrenal gland volume by MRI in an asymptomatic cohort, independent of age, sex, dyslipidaemia, hypertension and BMI. Adrenal gland volume may represent an indirect marker of impaired glucose metabolism and HPA axis dysfunction.

Association between hepatic iron overload assessed by magnetic resonance imaging and glucose intolerance states in the general population.

BACKGROUND AND AIM: While there is evidence that iron overload disorders are associated with type 2 diabetes, the relationship between hepatic iron overload and prediabetes remains unclear. We aimed to investigate the association between hepatic iron overload, as assessed by magnetic resonance imaging (MRI), and different glucose intolerance states in the population-based Study. METHODS AND RESULTS: We included data from 1622 individuals with MRI data, who did not have known type 2 diabetes (T2DM). Using an oral glucose tolerance testing, participants were classified as having isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG and IGT (IFG + IGT) or previously unknown T2DM. Hepatic iron and fat contents were assessed through quantitative MRI. We undertook linear and multinomial logistic regression models adjusted for potential confounders and MRI-assessed hepatic fat content to examine the association of hepatic iron overload with different glucose intolerance states or continuous markers of glucose metabolism. MRI-assessed hepatic iron overload was positively associated only with both 2-h plasma glucose (ß = 0.32; 95%CI 0.04-0.60) and the combined IFG + IGT category (relative risk ratio = 1.87; 95%CI 1.15-3.06). No significant associations were found between hepatic iron overload and other glucose intolerance states or biomarkers of glucose metabolism, independently of potential confounders. CONCLUSIONS: MRI-assessed hepatic iron overload was associated with higher 2-h glucose concentrations and the combined IFG + IGT category, but not with other glucose intolerance states. Our findings suggest a weak adverse impact of hepatic iron overload on glucose metabolism, but further studies are needed to confirm these findings.

Population-based cohort imaging: skeletal muscle mass by magnetic resonance imaging in correlation to bioelectrical-impedance analysis.

BACKGROUND: Skeletal muscle mass is subjected to constant changes and is considered a good predictor for outcome in various diseases. Bioelectrical-impedance analysis (BIA) and magnetic resonance imaging (MRI) are approved methodologies for its assessment. However, muscle mass estimations by BIA may be influenced by excess intramuscular lipids and adipose tissue in obesity. The objective of this study was to evaluate the feasibility of quantitative assessment of skeletal muscle mass by MRI as compared with BIA. METHODS: Subjects from a population-based cohort underwent BIA (50 kHz, 0.8 mA) and whole-body MRI including chemical-shift encoded MRI (six echo times). Abdominal muscle mass by MRI was quantified as total and fat-free cross-sectional area by a standardized manual segmentation-algorithm and normalized to subjects' body height2 (abdominal muscle mass indices: AMMIMRI ). RESULTS: Among 335 included subjects (56.3 ± 9.1 years, 56.1% male), 95 (28.4%) were obese (BMI ≥ 30 kg/m2 ). MRI-based and BIA-based measures of muscle mass were strongly correlated, particularly in non-obese subjects [r < 0.74 in non-obese (P < 0.001) vs. r < 0.56 in obese (P < 0.001)]. Median AMMITotal(MRI) was significantly higher in obese as compared with non-obese subjects (3246.7 ± 606.1 mm2 /m2 vs. 2839.0 ± 535.8 mm2 /m2 , P < 0.001, respectively), whereas the ratio AMMIFat-free /AMMITotal (by MRI) was significantly higher in non-obese individuals (59.3 ± 10.1% vs. 53.5 ± 10.6%, P < 0.001, respectively). No significant difference was found regarding AMMIFat-free(MRI) (P = 0.424). In analyses adjusted for age and sex, impaired glucose tolerance and measures of obesity were significantly and positively associated with AMMITotal(MRI) and significantly and inversely with the ratio AMMIFat-free(MRI) /AMMITotal(MRI) (P < 0.001). CONCLUSIONS: MRI-based assessment of muscle mass is feasible in population-based imaging and strongly correlated with BIA. However, the observed weaker correlation in obese subjects may explain the known limitation of BIA in obesity and promote MRI-based assessments. Thus, skeletal muscle mass parameters by MRI may serve as practical imaging biomarkers independent of subjects' body weight.

Incidence rates and predictors of microvascular and macrovascular complications in patients with type 2 diabetes: Results from the longitudinal global discover study.

BACKGROUND: Micro- and macrovascular complications are a major cause of morbidity and mortality in people with type 2 diabetes (T2D). We sought to understand the global incidence rates and predictors of these complications. METHODS: We examined the incidence of vascular complications over 3 years of follow-up in the DISCOVER study-a global, observational study of people with T2D initiating second-line glucose-lowering therapy. Hierarchical Cox proportional hazards regression models examined factors associated with development of micro- and macrovascular complications during follow-up. RESULTS: Among 11,357 people with T2D from 33 countries (mean age 56.9 ± 11.7 years, T2D duration 5.7 ± 5.1 years, HbA1c 8.4 ± 1.7%), 19.0% had a microvascular complication at enrolment (most commonly neuropathy), and 13.2% had a macrovascular complication (most commonly coronary disease). Over 3 years of follow-up, 16.0% developed an incident microvascular complication, and 6.6% had an incident macrovascular complication. At the end of 3 years of follow-up, 31.5% of patients had at least one microvascular complication, and 16.6% had at least one macrovascular complication. Higher HbA1c and smoking were associated with greater risk of both incident micro- and macrovascular complications. Known macrovascular complications at baseline was the strongest predictor for development of new microvascular complications (HR 1.40, 95% CI 1.21 -1.61) and new macrovascular complications (HR 3.39, 95% CI 2.84 -4.06). CONCLUSIONS: In this global study, both the prevalence and 3-year incidence of vascular complications were high in patients with relatively short T2D duration, highlighting the need for early risk-factor modification.

Prediabetes and risk of mortality, diabetes-related complications and comorbidities: umbrella review of meta-analyses of prospective studies.

AIMS/HYPOTHESIS: The term prediabetes is used for individuals who have impaired glucose metabolism whose glucose or HbA1c levels are not yet high enough to be diagnosed as diabetes. Prediabetes may already be associated with an increased risk of chronic 'diabetes-related' complications. This umbrella review aimed to provide a systematic overview of the available evidence from meta-analyses of prospective observational studies on the associations between prediabetes and incident diabetes-related complications in adults and to evaluate their strength and certainty. METHODS: For this umbrella review, systematic reviews with meta-analyses reporting summary risk estimates for the associations between prediabetes (based on fasting or 2 h postload glucose or on HbA1c) and incidence of diabetes-related complications, comorbidities and mortality risk were included. PubMed, Web of Science, the Cochrane Library and Epistemonikos were searched up to 17 June 2021. Summary risk estimates were recalculated using a random effects model. The certainty of evidence was evaluated by applying the GRADE tool. This study is registered with PROSPERO, CRD42020153227. RESULTS: Ninety-five meta-analyses from 16 publications were identified. In the general population, prediabetes was associated with a 6-101% increased risk for all-cause mortality and the incidence of cardiovascular outcomes, CHD, stroke, heart failure, atrial fibrillation and chronic kidney disease, as well as total cancer, total liver cancer, hepatocellular carcinoma, breast cancer and all-cause dementia with moderate certainty of evidence. No associations between prediabetes and incident depressive symptoms and cognitive impairment were observed (with low or very low certainty of evidence). The association with all-cause mortality was stronger for prediabetes defined by impaired glucose tolerance than for prediabetes defined by HbA1c. CONCLUSIONS/INTERPRETATION: Prediabetes was positively associated with risk of all-cause mortality and the incidence of cardiovascular outcomes, CHD, stroke, chronic kidney disease, cancer and dementia. Further high-quality studies, particularly on HbA1c-defined prediabetes and other relevant health outcomes (e. g. neuropathy) are required to support the evidence.

[Linkage of claims data with data from epidemiological cancer registries: possibilities and limitations in the German federal states]. / Verknüpfung von Abrechnungsdaten gesetzlicher Krankenkassen mit Daten epidemiologischer Krebsregister: länderspezifische Möglichkeiten und Limitationen.

BACKGROUND: In recent years, there has been an increasing demand for the reuse of research data in accordance with the so-called FAIR principles. This would allow researchers to conduct projects on a broader data basis and to investigate new research questions by linking different data sources. OBJECTIVES: We explored if nationwide linking of claims data from statutory health insurances (SHI) with data from population-based cancer registries can be used to obtain additional information on cancer that is missing in claims data and to assess the validity of SHI tumour diagnoses. This paper focuses on describing the specific requirements of German federal states for such data linkage. MATERIALS AND METHODS: The Pharmacoepidemiological Research Database GePaRD at the Leibniz Institute for Prevention Research and Epidemiology - BIPS and six cancer registries were used as data sources. The logistically complex direct linkage was compared with a less complex indirect linkage. For this purpose, permission had to be obtained for GePaRD and for each cancer registry from the respective responsible authority. RESULTS: Regarding the linkage of cancer registry data with GePaRD, the cancer registries showed profound differences in the modalities for data provision, ranging from a complete rejection to an uncomplicated implementation of linkage procedures. DISCUSSION: In Germany, a consistent legal framework is needed to adequately enable the reuse and record linkage of personal health data for research purposes according to the FAIR principles. The new law on the consolidation of cancer registry data could provide a remedy regarding the linkage of cancer registry data with other data sources.