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Abstract Intelectin-1 (ITLN1; also Omentin-1, OMNT1) is secreted by adipose tissue (AT) and plays an important role in glucose metabolism regulation, with links to obesity-associated diseases. ITLN1 activity so far has rarely been investigated using RNA-sequencing and in larger cohorts. We evaluated ITLN1 expression among three clinical cohorts of the Leipzig Obesity BioBank—a cross-sectional cohort comprising of 1480 people, a cohort of people with metabolically healthy or unhealthy obesity (31 insulin-sensitive, 42 insulin-resistant individuals with obesity), and a longitudinal two-step bariatric surgery cohort (n = 65). We hypothesized that AT ITLN1 expression is associated with serum omentin-1, clinical parameters associated with obesity, and with weight loss after bariatric surgery. We also investigated the correlation of AT ITLN1 expression with genes related to inflammatory response, lipid metabolism, obesity, and regulation of energy balance. Likewise, we inspected gene group expression and metabolic pathways associated with ITLN1 expression using gene set enrichment and gene correlation analysis. We show that ITLN1 expression differs in VAT and SAT, and should therefore be analyzed separately. Furthermore, ITLN1 expression increases with VAT tissue mass, but is negatively affected by AT tissue dysfunction among individuals with unhealthy obesity, corroborated by interplay with genes related to tissue inflammation. Gene set enrichment and gene correlation analysis of ITLN1 expression suggest that AT ITLN1 expression is related to local inflammatory processes in AT, but also in processes such as regulation of appetite, energy balance, and maintenance of body weight.

Abstract Background Protein biomarkers may contribute to the identification of vulnerable subgroups for premature mortality. This study aimed to investigate the association of plasma proteins with all-cause and cause-specific mortality among individuals with and without baseline type 2 diabetes (T2D) and evaluate their impact on the prediction of all-cause mortality in two prospective Cooperative Health Research in the Region of Augsburg (KORA) studies. Methods The discovery cohort comprised 1545 participants (median follow-up 15.6 years; 244 with T2D: 116 total, 62 cardiovascular, 31 cancer-related and 23 other-cause deaths; 1301 without T2D: 321 total, 114 cardiovascular, 120 cancer-related and 87 other-cause deaths). The validation cohort comprised 1031 participants (median follow-up 6.9 years; 203 with T2D: 76 total, 45 cardiovascular, 19 cancer-related and 12 other-cause deaths; 828 without T2D: 169 total, 74 cardiovascular, 39 cancer-related and 56 other-cause deaths). We used Cox regression to examine associations of 233 plasma proteins with all-cause and cause-specific mortality and Lasso regression to construct prediction models for all-cause mortality stratifying by baseline T2D. C-index, category-free net reclassification index (cfNRI), and integrated discrimination improvement (IDI) were conducted to evaluate the predictive performance of built prediction models. Results Thirty-five and 62 proteins, with 29 overlapping, were positively associated with all-cause mortality in the group with and without T2D, respectively. Out of these, in the group with T2D, 35, eight, and 26 were positively associated with cardiovascular, cancer-related, and other-cause mortality, while in the group without T2D, 55, 41, and 47 were positively associated with respective cause-specific outcomes in the pooled analysis of both cohorts. Regulation of insulin-like growth factor (IGF) transport and uptake by IGF-binding proteins emerged as a unique pathway enriched for all-cause and cardiovascular mortality in individuals with T2D. The combined model containing the selected proteins (five and 12 proteins, with four overlapping, in the group with and without T2D, respectively) and clinical risk factors improved the prediction of all-cause mortality by C-index, cfNRI, and IDI. Conclusions This study uncovered shared and unique mortality-related proteins in persons with and without T2D and emphasized the role of proteins in improving the prediction of mortality in different T2D subgroups.

Abstract Background Coronary heart disease (CHD) is a major global health concern, especially among individuals with type 2 diabetes (T2D). Given the crucial role of proteins in various biological processes, this study aimed to elucidate the aetiological role and predictive performance of protein biomarkers on incident CHD in individuals with and without T2D. Methods The discovery cohort included 1492 participants from the Cooperative Health Research in the Region of Augsburg (KORA) S4 study with 147 incident CHD cases (45 vs. 102 cases in the group with T2D and without T2D, respectively) during 15.6 years of follow-up. The validation cohort included 888 participants from the KORA-Age1 study with 70 incident CHD cases (19 vs. 51 cases in the group with T2D and without T2D, respectively) during 6.9 years of follow-up. We measured 233 plasma proteins related to cardiovascular disease and inflammation using proximity extension assay technology. Associations of proteins with incident CHD were assessed using Cox regression and Mendelian randomization (MR) analysis. Predictive models were developed using priority-Lasso and were evaluated on top of Framingham risk score variables using the C-index, category-free net reclassification index (cfNRI), and relative integrated discrimination improvement (IDI). Results We identified two proteins associated with incident CHD in individuals with and 29 in those without baseline T2D, respectively. Six of these proteins are novel candidates for incident CHD. MR suggested a potential causal role for hepatocyte growth factor in CHD development. The developed four-protein-enriched model for individuals with baseline T2D (ΔC-index: 0.017; cfNRI: 0.253; IDI: 0.051) and the 12-protein-enriched model for individuals without baseline T2D (ΔC-index: 0.054; cfNRI: 0.462; IDI: 0.024) consistently improved CHD prediction in the discovery cohort, while in the validation cohort, significant improvements were only observed for selected performance measures (with T2D: cfNRI: 0.633; without T2D: ΔC-index: 0.038; cfNRI: 0.465). Conclusions This study identified novel protein biomarkers associated with incident CHD in individuals with and without T2D and reaffirmed previously reported protein candidates. These findings enhance our understanding of CHD pathophysiology and provide potential targets for prevention and treatment.

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.

Abstract Objective: The aim of this analysis was to investigate whether habitual intake of total dairy (TD) or different dairy types (liquid, solid, fermented, non-fermented, low-fat, high-fat, low-sugar and high-sugar dairy) during adolescence is associated with biomarkers of low-grade inflammation as well as risk factors of type 2 diabetes in young adulthood. Design: Multivariable linear regression analyses were used to investigate prospective associations between estimated TD intake as well as intake of different types of dairy and a pro-inflammatory score, based on high-sensitivity C-reactive protein, IL-6, IL-18, leptin and adiponectin, and insulin resistance assessed as Homeostasis Model Assessment Insulin Resistance in an open-cohort study. Setting: Dortmund, Germany. Participants: Data from participants (n 375) of the DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study were included, for whom at least two 3-d weighed dietary records during adolescence (median age: 11 years) and one blood sample in young adulthood (>18 years) were available. Results: There was no statistically significant association between TD intake or intake of any dairy type and the pro-inflammatory score (all P > 0·05). TD intake as well as each dairy type intake and insulin resistance also showed no association (all P > 0·05). Conclusions: The habitual intake of dairy or individual types of dairy during adolescence does not seem to have a major impact on low-grade systemic inflammation and insulin resistance in the long term. There was no indication regarding a restriction of dairy intake for healthy children and adolescents in terms of diabetes risk reduction.

Abstract Background Molecular measurements of the genome, the transcriptome, and the epigenome, often termed multi-omics data, provide an in-depth view on biological systems and their integration is crucial for gaining insights in complex regulatory processes. These data can be used to explain disease related genetic variants by linking them to intermediate molecular traits (quantitative trait loci, QTL). Molecular networks regulating cellular processes leave footprints in QTL results as so-called trans-QTL hotspots. Reconstructing these networks is a complex endeavor and use of biological prior information can improve network inference. However, previous efforts were limited in the types of priors used or have only been applied to model systems. In this study, we reconstruct the regulatory networks underlying trans-QTL hotspots using human cohort data and data-driven prior information. Methods We devised a new strategy to integrate QTL with human population scale multi-omics data. State-of-the art network inference methods including BDgraph and glasso were applied to these data. Comprehensive prior information to guide network inference was manually curated from large-scale biological databases. The inference approach was extensively benchmarked using simulated data and cross-cohort replication analyses. Best performing methods were subsequently applied to real-world human cohort data. Results Our benchmarks showed that prior-based strategies outperform methods without prior information in simulated data and show better replication across datasets. Application of our approach to human cohort data highlighted two novel regulatory networks related to schizophrenia and lean body mass for which we generated novel functional hypotheses. Conclusions We demonstrate that existing biological knowledge can improve the integrative analysis of networks underlying trans associations and generate novel hypotheses about regulatory mechanisms.

Abstract Background Air pollutants can activate low-grade subclinical inflammation which further impairs respiratory health. We aimed to investigate the role of polygenic susceptibility to chronic air pollution-induced subclinical airway inflammation. Methods We used data from 296 women (69–79 years) enrolled in the population-based SALIA cohort (Study on the influence of Air pollution on Lung function, Inflammation and Aging). Biomarkers of airway inflammation were measured in induced-sputum samples at follow-up investigation in 2007–2010. Chronic air pollution exposures at residential addresses within 15 years prior to the biomarker assessments were used to estimate main environmental effects on subclinical airway inflammation. Furthermore, we calculated internally weighted polygenic risk scores based on genome-wide derived single nucleotide polymorphisms. Polygenic main and gene-environment interaction (GxE) effects were investigated by adjusted linear regression models. Results Higher exposures to nitrogen dioxide (NO2), nitrogen oxides (NOx), particulate matter with aerodynamic diameters of ≤ 2.5 μm, ≤ 10 μm, and 2.5–10 µm significantly increased the levels of leukotriene (LT)B4 by 19.7% (p-value = 0.005), 20.9% (p = 0.002), 22.1% (p = 0.004), 17.4% (p = 0.004), and 23.4% (p = 0.001), respectively. We found significant effects of NO2 (25.9%, p = 0.008) and NOx (25.9%, p-value = 0.004) on the total number of cells. No significant GxE effects were observed. The trends were mostly robust in sensitivity analyses. Conclusions While this study confirms that higher chronic exposures to air pollution increase the risk of subclinical airway inflammation in elderly women, we could not demonstrate a significant role of polygenic susceptibility on this pathway. Further studies are required to investigate the role of polygenic susceptibility. Graphical Abstract

Introduction To investigate the associations of a lifestyle score with various cardiovascular risk markers, indicators for fatty liver disease as well as MRI-determined total, subcutaneous and visceral adipose tissue mass in adults with new-onset diabetes.Research design and methods This cross-sectional analysis included 196 individuals with type 1 (median age: 35 years; median body mass index (BMI): 24 kg/m²) and 272 with type 2 diabetes (median age: 53 years; median BMI: 31 kg/m²) from the German Diabetes Study. A healthy lifestyle score was generated based on healthy diet, moderate alcohol consumption, recreational activity, non-smoking and non-obese BMI. These factors were summed to form a score ranging from 0 to 5. Multivariable linear and non-linear regression models were used.Results In total, 8.1% of the individuals adhered to none or one, 17.7% to two, 29.7% to three, 26.7% to four, and 17.7% to all five favorable lifestyle factors. High compared with low adherence to the lifestyle score was associated with more favorable outcome measures, including triglycerides (β (95% CI) −49.1 mg/dL (−76.7; −21.4)), low-density lipoprotein (−16.7 mg/dL (−31.3; −2.0)), and high-density lipoprotein cholesterol (13.5 mg/dL (7.6; 19.4)), glycated hemoglobin (−0.5% (−0.8%; −0.1%)), high-sensitivity C reactive protein (−0.4 mg/dL (−0.6; −0.2)), as well as lower hepatic fat content (−8.3% (−11.9%; −4.7%)), and visceral adipose tissue mass (−1.8 dm³ (−2.9; −0.7)). The dose–response analyses showed that adherence to every additional healthy lifestyle factor was associated with more beneficial risk profiles.Conclusions Adherence to each additional healthy lifestyle factor was beneficially associated with cardiovascular risk markers, indicators of fatty liver disease and adipose tissue mass. Strongest associations were observed for adherence to all healthy lifestyle factors in combination.Trial registration number NCT01055093.

High dietary phosphorus intake (P-In) and high acid loads may adversely affect kidney function. In animal models, excessive phosphorus intake causes renal injury, which, in humans, is also inducible by chronic metabolic acidosis. We thus examined whether habitually high P-In and endogenous acid production during childhood and adolescence may be early indicators of incipient renal inflammatory processes later in adulthood. P-In and acid–base status were longitudinally and exclusively determined by biomarker-based assessment in 277 healthy children, utilizing phosphate and net acid excretion (NAE) measurements in 24 h urine samples repeatedly collected between the ages of 3 and 17 years. Standard deviation scores (by sex and age) were calculated for anthropometric data and for the urinary biomarkers available within age range 3–17 years. Multivariable linear regression was used to analyze the relations of phosphate excretion and NAE with the adulthood outcome circulating interleukin-18 (IL-18), a marker of inflammation and kidney dysfunction. After adjusting for growth- and adulthood-related covariates and pro-inflammatory biomarkers to rule out confounding by non-renal inflammatory processes, regression models revealed a significant positive relationship of long-term NAE (p = 0.01), but not of long-term phosphate excretion with adult serum IL-18. Similar significant positive regression results were obtained after replacing NAE with 24 h urinary ammonium excretion as the exposition variable. Our results suggest that even moderate elevations in renal ammonia production, as caused by habitually higher acid loading during growth, may affect the intrarenal pro-inflammatory system in the long-term, known to be boosted by acidosis-induced raised ammoniagenesis.

Abstract Background Endothelin-1 (ET-1) and adrenomedullin (ADM) are commonly known as vasoactive peptides that regulate vascular homeostasis. Less recognised is the fact that both peptides could affect glucose metabolism. Here, we investigated whether ET-1 and ADM, measured as C-terminal-proET-1 (CT-proET-1) and mid-regional-proADM (MR-proADM), respectively, were associated with incident type 2 diabetes. Methods Based on the population-based Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium data, we performed a prospective cohort study to examine associations of CT-proET-1 and MR-proADM with incident type 2 diabetes in 12,006 participants. During a median follow-up time of 13.8 years, 862 participants developed type 2 diabetes. The associations were examined in Cox proportional hazard models. Additionally, we performed two-sample Mendelian randomisation analyses using published data. Results CT-proET-1 and MR-proADM were positively associated with incident type 2 diabetes. The multivariable hazard ratios (HRs) [95% confidence intervals (CI)] were 1.10 [1.03; 1.18], P = 0.008 per 1-SD increase of CT-proET-1 and 1.11 [1.02; 1.21], P = 0.016 per 1-SD increase of log MR-proADM, respectively. We observed a stronger association of MR-proADM with incident type 2 diabetes in obese than in non-obese individuals (P-interaction with BMI

Serum urate concentration can be studied in large datasets to find genetic and epigenetic loci that may be related to cardiometabolic traits. Here the authors identify and replicate 100 urate-associated CpGs, which provide insights into urate GWAS loci and shared CpGs of urate and cardiometabolic traits.

Many genetic loci have been identified to be associated with kidney disease, but the molecular mechanisms are not well understood. Here, the authors perform epigenome-wide association studies on kidney function measures to identify epigenetic marks and pathways involved in kidney function.

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Abstract Background High N-terminal pro-brain-type natriuretic peptide levels have been associated with a lower risk of type 2 diabetes mellitus (T2D). However, less is known about other cardiac stress biomarkers in this context. Here we evaluated the association of mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM) with incident T2D and changes in glucose metabolism. Methods We performed a prospective cohort study using data from the population-based KORA F4/FF4 study. 1773 participants (52.3% women) with MR-proANP measurements and 960 (52.7% women) with copeptin, CT-proET-1 and MR-proADM measurements were included. We examined associations of circulating plasma levels of MR-proANP, copeptin, CT-proET-1 and MR-proADM with incident T2D, the combined endpoint of incident prediabetes/T2D and with fasting and 2 h-glucose, fasting insulin, HOMA-IR, HOMA-B and HbA1c at follow-up. Logistic and linear regression models adjusted for age, sex, waist circumference, height, hypertension, total/HDL cholesterol ratio, triglycerides, smoking, physical activity and parental history of diabetes were used to compute effect estimates. Results During a median follow-up time of 6.4 years (25th and 75th percentiles: 6.0 and 6.6, respectively), 119 out of the 1773 participants and 72 out of the 960 participants developed T2D. MR-proANP was inversely associated with incident T2D (odds ratio [95% confidence interval]: 0.75 [0.58; 0.96] per 1-SD increase of log MR-proANP). Copeptin was positively associated with incident prediabetes/T2D (1.29 [1.02; 1.63] per 1-SD increase of log copeptin). Elevated levels of CT-proET-1 were associated with increased HOMA-B at follow-up, while elevated MR-proADM levels were associated with increased fasting insulin, HOMA-IR and HOMA-B at follow-up. These associations were independent of previously described diabetes risk factors. Conclusions High plasma concentrations of MR-proANP contributed to a lower risk of incident T2D, whereas high plasma concentrations of copeptin were associated with an increased risk of incident prediabetes/T2D. Furthermore, high plasma concentrations of CT-proET-1 and MR-proADM were associated with increased insulin resistance. Our study provides evidence that biomarkers implicated in cardiac stress are associated with incident T2D and changes in glucose metabolism.

Objectives: To investigate the impact of omentin on the release of inflammation-related biomarkers and inflammatory pathways in primary human adipocytes. Methods: Adipocytes were treated with or without omentin (500 and 2,000 ng/mL), and the supernatants were analyzed for inflammation-related biomarkers using proximity extension assay technology. Potential upstream regulators of the omentin-stimulated proteins were identified using Ingenuity Pathway Analysis. Protein levels of components of inflammatory pathways were measured using Western blotting. Results: 2,000 ng/mL omentin induced the release of 30 biomarkers 97.1 ± 31.1-fold in the supernatants (all p < 0.05). Most biomarkers were proin­flammatory chemokines and cytokines. We identified the transcription factor nuclear factor “kappa-light-chain-enhancer” of activated B cells (NFĸB) and the kinases p38 and extracellular signal-regulated kinase (ERK)1/2 as potential upstream regulators in silico. On the cellular level, treatment with 2,000 ng/mL omentin for 24 h enhanced the phosphorylation levels of NFĸB 2.1 ± 0.3-fold (p < 0.05), of p38 2.6 ± 0.4-fold (p < 0.05), and of ERK1/2 1.8 ± 0.2-fold (p < 0.05). Conclusions: These data argue that omentin exerts proinflammatory effects through the activation of the inflammatory NFĸB, p38, and ERK1/2 pathways in cultured primary adipocytes.

Abstract Background Biomarkers may contribute to our understanding of the pathophysiology of various diseases. Type 2 diabetes (T2D) and coronary heart disease (CHD) share many clinical and lifestyle risk factors and several biomarkers are associated with both diseases. The current analysis aims to assess the relevance of biomarkers combined to pathway groups for the development of T2D and CHD in the same cohort. Methods Forty-seven serum biomarkers were measured in the MONICA/KORA case-cohort study using clinical chemistry assays and ultrasensitive molecular counting technology. The T2D (CHD) analyses included 689 (568) incident cases and 1850 (2004) non-cases from three population-based surveys. At baseline, the study participants were 35–74 years old. The median follow-up was 14 years. We computed Cox regression models for each biomarker, adjusted for age, sex, and survey. Additionally, we assigned the biomarkers to 19 etiological pathways based on information from literature. One age-, sex-, and survey-controlled average variable was built for each pathway. We used the R2 PM coefficient of determination to assess the explained disease risk. Results The associations of many biomarkers, such as several cytokines or the iron marker soluble transferrin receptor (sTfR), were similar in strength for T2D and CHD, but we also observed important differences. Lipoprotein (a) (Lp(a)) and N-terminal pro B-type natriuretic peptide (NT-proBNP) even demonstrated opposite effect directions. All pathway variables together explained 49% of the T2D risk and 21% of the CHD risk. The insulin-like growth factor binding protein 2 (IGFBP-2, IGF/IGFBP system pathway) best explained the T2D risk (about 9% explained risk, independent of all other pathway variables). For CHD, the myocardial-injury- and lipid-related-pathways were most important and both explained about 4% of the CHD risk. Conclusions The biomarker-derived pathway variables explained a higher proportion of the T2D risk compared to CHD. The ranking of the pathways differed between the two diseases, with the IGF/IGFBP-system-pathway being most strongly associated with T2D and the myocardial-injury- and lipid-related-pathways with CHD. Our results help to better understand the pathophysiology of the two diseases, with the ultimate goal of pointing out targets for lifestyle intervention and drug development to ideally prevent both T2D and CHD development.

Introduction Diabetic sensorimotor polyneuropathy (DSPN) affects approximately 30% of people with diabetes, while around half of cases are symptomatic. Currently, there are only few pathogenetically oriented pharmacotherapies for DSPN, one of which is benfotiamine, a prodrug of thiamine with a high bioavailability and favourable safety profile. While benfotiamine has shown positive effects in preclinical and short-term clinical studies, no long-term clinical trials are available to demonstrate disease-modifying effects on DSPN using a comprehensive set of disease-related endpoints.Methods and analysis The benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes trial is a randomised double-blind, placebo-controlled parallel group monocentric phase II clinical trial to assess the effects of treatment with benfotiamine compared with placebo in participants with type 2 diabetes and mild to moderate symptomatic DSPN. Sixty participants will be 1:1 randomised to treatment with benfotiamine 300 mg or placebo two times a day over 12 months. The primary endpoint will be the change in corneal nerve fibre length assessed by corneal confocal microscopy (CCM) after 12 months of benfotiamine treatment compared with placebo. Secondary endpoints will include other CCM measures, skin biopsy and function indices, variables from somatic and autonomic nerve function tests, clinical examination and questionnaires, general health, health-related quality of life, cost, safety and blood tests.Ethics and dissemination The trial was approved by the competent authority and the local independent ethics committee. Trial results will be published in peer-reviewed journals, conference abstracts, and via online and print media.Trial registration number DRKS00014832.

Background and aimDespite its vasodilatory effect, adrenomedullin and its surrogate mid-regional pro-adrenomedullin (MR-proADM) have been found to be positively associated with all-cause and cardiovascular mortality. However, the underlying mechanisms thereof remain unclear and the associations were mostly shown in geriatric cohorts or in patients with chronic diseases. Therefore, we aimed to investigate the possible involvement of abdominal obesity, selected adipokines, and biomarkers of subclinical inflammation in the association of MR-proADM with mortality in a population based study cohort.MethodsProspective analysis of the KORA F4 study; median follow-up 9.1 (8.8-9.4) years. Complete data on MR-proADM and mortality was available for 1551 participants, aged 56.9±12.9 years (mean±SD). Correlation and regression analyses of MR-proADM with overall (BMI) and abdominal obesity (waist circumference), selected adipokines and biomarkers of subclinical inflammation. Cox proportional hazard models on the association of MR-proADM with all-cause and cardiovascular mortality with adjustment for cardiovascular risk factors and selected biomarkers in study subgroups (n = 603-1551).ResultsMR-proADM associated with all-cause (HR (95%CI): 2.37 (1.72-3.26) and 2.31 (1.67-3.20)) and cardiovascular mortality (4.28 (2.19-8.39) and 4.44 (2.25-8.76)) after adjustment for traditional cardiovascular risk factors including BMI or waist circumference, respectively. MR-proADM was further associated with four out of seven examined adipokines (leptin, retinol-binding protein-4, chemerin, and adiponectin) and with five out of eleven examined biomarkers of subclinical inflammation (high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, interleukin-22, and interleukin-1 receptor antagonist) after multivariable adjustment and correction for multiple testing. However, only IL-6 substantially attenuated the association of MR-proADM with all-cause mortality.ConclusionsWe found an association of MR-proADM with (abdominal) obesity, selected adipokines, and biomarkers of subclinical inflammation. However, the association of MR-proADM with mortality was independent of these parameters. Future studies should investigate the role of IL-6 and further characteristics of subclinical inflammation in the association between MR-proADM and all-cause mortality.

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 t issue-specific biomarker for kidney function. In contrast to the commonly used markers creatinine and cystatin C, serum uromodulin does not primarily depend on glomerular filtrat ion. 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, p hysical 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.

Surgical weight-loss interventions improve insulin sensitivity via incompletely understood mechanisms. Here the authors assess skeletal muscle epigenetic changes in individuals with obesity following metabolic surgery and compare them with data from individuals without obesity.

Our understanding of the functional link between differential DNA methylation and type 2 diabetes and obesity remains limited. Here the authors present a blood-based EWAS of fasting glucose and insulin among 4808 non-diabetic Europeans and identify nine CpGs not previously implicated in glucose, insulin homeostasis and diabetes.

Background: While prior studies have linked air pollution (AP) to diabetes prevalence and incidence, few have investigated whether AP exposure is also associated with alterations in diabetes-related biomarkers in metabolically healthy adults. Objective: To evaluate the associations between short-, medium-, and long-term AP and diabetes-related biomarkers (adiponectin, interleukin-1 receptor antagonist [IL-1RA], high sensitivity C-reactive protein [hsCRP], fibrinogen) in persons without diabetes. Methods: Adiponectin, IL-1RA, hsCRP, and fibrinogen were measured in blood samples collected at the baseline (t0; 2000–2003) and first follow-up (t1; 2006–2008) examinations of the prospective Heinz Nixdorf Recall (HNR) cohort study in Germany. Participants' residential mean exposures to PM10, PM2.5, NO2, and accumulation mode particle number concentration (PNAM) were estimated for several time windows (1- to 365-day) prior to examination using a dispersion and chemistry transport model. We fitted covariate-adjusted linear mixed effects models using a random participant intercept and investigated effect modification by obesity status. Results: We analyzed 6727 observations (nt0 = 3626, nt1 = 3101) from 4052 participants of the HNR study (52% women; ages 45–76 years at t0). For all air pollutants, medium-term exposures (60- to 120-day) were negatively associated with adiponectin (e.g., 91-day PNAM: −2.51% change [−3.40%, −1.53%] per interquartile [IQR] increase). Several short-, medium-, and long-term AP exposures were positively associated with IL-1RA (e.g., 365-day PM10: 2.64% change [1.25%, 4.22%] per IQR increase). Long-term exposures were positively associated with hsCRP level while no consistent patterns were observed for fibrinogen. Stronger associations for adiponectin were observed among non-obese participants. Conclusion: In persons without diabetes, we observed differing patterns of association between AP and diabetes-related biomarkers across a range of exposure windows, supporting the hypothesis that AP may play a role in the development of diabetes. Keywords: Particulate matter, NO2, Air pollution, Inflammation, Diabetes, Metabolism

Abstract Background Reports on body mass index (BMI) trajectories from childhood into late adolescence, their determinants, and subsequent cardiometabolic risk markers, particularly among European populations have been few. Moreover, sex-specific investigation is necessary considering the sex difference in BMI, and the sex-specific association between BMI and some cardiometabolic risk markers. Methods Using a sample from the DOrtmund Nutritional and Anthropometric Longitudinally Designed study, we explored sex-specific trajectories of the BMI standard deviation score (SDS) from 4 to 18 years of age in 354 males and 335 females by latent (class) growth models. The determinants of trajectory were assessed by logistic regression. We identified cardiometabolic risk markers that were highly associated with BMI SDS trajectory by random forest regression, and finally we used generalized linear models to investigate differences in the identified cardiometabolic risk markers between pairs of trajectories. Results We observed four: ‘low-normal weight’, ‘mid-normal weight’, ‘high-normal weight’, and ‘overweight’, and three: ‘‘low-normal weight’, ‘mid-normal weight’, and ‘high-normal weight’ trajectories in males and females, respectively. Higher maternal prepregnancy BMI was associated with the ‘overweight’ trajectory, and with ‘high-normal weight’ trajectory in both sexes. In addition, employed mothers and first-born status were associated with ‘high-normal weight’ trajectory in females. BMI SDS trajectory was associated with high-density lipoprotein-cholesterol and interleukin-18 (IL-18) in males, and diastolic blood pressure and interleukin-6 (IL-6) in females. However, only males following the ‘overweight’ trajectory had significantly higher IL-18 when compared to their ‘low-normal weight’ counterpart. Conclusions We identified sex-specific distinct trajectories of BMI SDS from childhood into late adolescence, higher maternal prepregnancy BMI as a common determinant of the ‘high-normal weight’ and ‘overweight’ trajectories, and ‘overweight’ trajectory being associated with elevated IL-18 in late adolescence–young adulthood. This study emphasizes the role of maternal prepregnancy BMI in overweight, and highlights IL-18 as a cardiometabolic signature of overweight across life.

Abstract Background Previous studies found regional differences in the prevalence and incidence of type 2 diabetes between Northeast and South of Germany. The aim of this study was to investigate if regional variations are also present for macrovascular disease in people with type 2 diabetes and in the general population. A further aim was to investigate if traditional risk factors of macrovascular complications can explain these regional variations. Methods Data of persons aged 30–79 from two regional population-based studies, SHIP-TREND (Northeast Germany, 2008–2012, n = 2539) and KORA-F4 (South Germany, 2006–2008, n = 2932), were analysed. Macrovascular disease was defined by self-reported previous myocardial infarction, stroke or coronary angiography. Multivariable logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI) for prevalence of macrovascular disease in persons with type 2 diabetes and in the general population. Results The prevalence of macrovascular disease in persons with type 2 diabetes and in the general population was considerably higher in the Northeast (SHIP-TREND: 32.8 and 12.0%) than in the South of Germany (KORA-F4: 24.9 and 8.8%), respectively. The odds of macrovascular disease in persons with type 2 diabetes was 1.66 (95% CI: 1.11–2.49) in the Northeast in comparison to the South after adjustment for sex, age, body mass index, hypertension, hyperlipidemia and smoking. In the general population, SHIP-TREND participants also had a significantly increased odds of macrovascular disease compared to KORA-F4 participants (OR = 1.63, 95% CI: 1.33–2.00). After excluding coronary angiography (myocardial infarction or stroke only), the ORs for region decreased in all models, but the difference between SHIP-TREND and KORA-F4 participants was still significant in the age- and sex-adjusted model for the general population (OR = 1.34, 95% CI: 1.01–1.78). Conclusions This study provides an indication for regional differences in macrovascular disease, which is not explained by traditional risk factors. Further examinations of other risk factors, such as regional deprivation or geographical variations in medical care services are needed.

Abstract Background Higher dietary intake of fibers and coffee, but lower red meat intake is associated with reduced risk for type 2 diabetes in epidemiological studies. We hypothesized that a calorie-restricted diet, which is high in fiber and coffee, but free of red meat, improves beta-cell function in patients with T2D. Methods In a randomized parallel-group pilot trial, obese type 2 diabetes patients were randomly allocated to consume either a diet high in cereal fiber and coffee, but free of red meat (n = 17) (L-RISK) or a diet low in fiber, free of coffee but high in red meat (n = 20) (H-RISK) for 8 weeks. Insulin secretion was assessed from glucagon stimulation tests (GST) and mixed-meal tolerance tests (MMTT) before and after dietary intervention. Results Both diets resulted in comparable reduction of fasting concentrations of insulin (H-RISK -28% vs. L-RISK -32%, both p

Objectives: An inverse relationship between education and cardiovascular risk has been described, however, the combined association of education, income, and neighborhood socioeconomic status with macrovascular disease is less clear. The aim of this study was to evaluate the association of educational level, equivalent household income and area deprivation with macrovascular disease in Germany.Methods: Cross-sectional data from two representative German population-based studies, SHIP-TREND (n = 3,731) and KORA-F4 (n = 2,870), were analyzed. Multivariable logistic regression models were applied to estimate odds ratios and 95% confidence intervals for the association between socioeconomic determinants and macrovascular disease (defined as self-reported myocardial infarction or stroke).Results: The study showed a higher odds of prevalent macrovascular disease in men with low and middle educational level compared to men with high education. Area deprivation and equivalent income were not related to myocardial infarction or stroke in any of the models.Conclusion: Educational level, but not income or area deprivation, is significantly related to the macrovascular disease in men. Effective prevention of macrovascular disease should therefore start with investing in individual education.

Lifestyle score approaches combining individual lifestyle factors, e.g. favourable diet, physical activity or normal body weight, showed inverse associations with cardiovascular disease (CVD) risk. However, research mainly focussed on adult behaviour and is scarce for vulnerable time windows for adult health like adolescence. We investigated associations between an adolescent lifestyle score and CVD risk markers in young adulthood. Overall, we analysed 270 participants of the open DONALD cohort study with 1–6 complete measurements of five lifestyle factors (healthy diet, moderate-to-vigorous physical activity, sedentary behaviour, sleep duration and BMI standard deviation score) during adolescence (females: 8⋅5–15⋅5 years and males: 9⋅5–16⋅5 years). Multivariable linear regression models were used to investigate the prospective association between the adolescent lifestyle score (0–5 points) and CVD risk markers in young adulthood (18–30 years). On average, participants obtained a mean adolescent lifestyle score of 2⋅9 (0–5) points. Inverse associations between the adolescent lifestyle score and waist circumference, waist-to-height ratio and percentage of body fat were observed (4⋅1, 4⋅1 and 9⋅2 % decrease per 1 point increase in adolescent lifestyle score, respectively, P < 0⋅05). For the remaining CVD risk markers (glucose, blood lipids, blood pressure and a proinflammatory score), no associations were observed. A healthy adolescent lifestyle is particularly associated with CVD risk-related favourable anthropometric markers in adulthood. A more comprehensive understanding of lifestyle patterns in the life course might enable earlier, targeted preventive measures to assist vulnerable groups in prevention of chronic diseases.

Summary: Background: Impaired insulin sensitivity could be an intermediate step that links exposure to air pollution to the development of type 2 diabetes. However, longitudinal associations of air pollution with insulin sensitivity remain unclear. Our study investigated the associations of long-term air pollution exposure with the degree and rate of change of insulin sensitivity. Methods: In this longitudinal study, we analysed data from the Cooperative Health Research in the Region of Augsburg (KORA) cohort from Augsburg, Germany, which recruited participants aged 25–74 years in the survey between 1999 and 2001 (KORA S4), with two follow-up examinations in 2006–08 (KORA F4) and 2013–14 (KORA FF4). Serum concentrations of fasting insulin and glucose, and homoeostasis model assessment of insulin resistance (HOMA-IR, a surrogate measure of insulin sensitivity) and β-cell function (HOMA-B, a surrogate marker for fasting insulin secretion) were assessed at up to three visits between 1999 and 2014. Annual average air pollutant concentrations at the residence were estimated by land-use regression models. We examined the associations of air pollution with repeatedly assessed biomarker levels using mixed-effects models, and we assessed the associations with the annual rate of change in biomarkers using quantile regression models. Findings: Among 9620 observations from 4261 participants in the KORA cohort, we included 6008 (62·5%) observations from 3297 (77·4%) participants in our analyses. Per IQR increment in annual average air pollutant concentrations, HOMA-IR significantly increased by 2·5% (95% CI 0·3 to 4·7) for coarse particulate matter, by 3·1% (0·9 to 5·3) for PM2·5, by 3·6% (1·0 to 6·3) for PM2·5absorbance, and by 3·2% (0·6 to 5·8) for nitrogen dioxide, and borderline significantly increased by 2·2% (–0·1 to 4·5) for ozone, whereas it did not significantly increase for the whole range of ultrafine particles. Similar positive associations in slightly smaller magnitude were observed for HOMA-B and fasting insulin levels. In addition, air pollutant concentrations were positively associated with the annual rate of change in HOMA-IR, HOMA-B, and fasting insulin. Neither the level nor the rate of change of fasting glucose were associated with air pollution exposure. Interpretation: Our study indicates that long-term air pollution exposure could contribute to the development of insulin resistance, which is one of the key factors in the pathogenesis of type 2 diabetes. Funding: German Federal Ministry of Education and Research.

Purpose: To examine the prospective relevance of dietary sugar intake (based on dietary data as well as urinary excretion data) in adolescent years for insulin sensitivity and biomarkers of inflammation in young adulthood.Methods: Overall 254 participants of the DONALD study who had at least two 3-day weighed dietary records for calculating intakes of fructose, glucose, sucrose, total, free, added sugars, total sugars from sugar-sweetened beverages (SSB), juice, and sweets/sugar or at least two complete 24 h urine samples (n = 221) for calculating sugar excretion (urinary fructose and urinary fructose + sucrose) in adolescence (females: 9–15 years, males: 10–16 years) and a fasting blood sample in adulthood (18–36 years), were included in multivariable linear regression analyses assessing their prospective associations with adult homeostasis model assessment insulin sensitivity (HOMA2-%S) and a pro-inflammatory score (based on CRP, IL-6, IL-18, leptin, chemerin, adiponectin).Results: On the dietary intake level, no prospective associations were observed between adolescent fructose, sucrose, glucose, added, free, total sugar, or total sugar from SSB, juice or sweets/sugar intake and adult HOMA2-%S (p > 0.01). On the urinary level, however, higher excreted fructose levels were associated with improved adult HOMA2-%S (p = 0.008) among females only. No associations were observed between dietary or urinary sugars and the adult pro-inflammatory score (p > 0.01).Conclusion: The present study did not provide support that dietary sugar consumed in adolescence is associated with adult insulin sensitivity. The one potential exception was the moderate dietary consumption of fructose, which showed a beneficial association with adult fasting insulin and insulin sensitivity.

Introduction Sphingolipid accumulation has been linked to obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). A recent study showed that depletion of dihydroceramide desaturase-1 (DES-1) in adipose and/or liver tissue decreases ceramide-to-dihydroceramide ratios (ceramide/dihydroceramide) in several tissues and improves the metabolic profile in mice. We tested the hypothesis that ceramide/dihydroceramide would also be elevated and relate positively to liver fat content and insulin resistance in humans.Research design and methods Thus, we assessed total and specific ceramide/dihydroceramide in various biosamples of 7 lean and 21 obese volunteers without or with different NAFLD stages, who were eligible for abdominal or bariatric surgery, respectively. Biosamples were obtained from serum, liver, rectus abdominis muscle as well as subcutaneous abdominal and visceral adipose tissue during surgery.Results Surprisingly, certain serum and liver ceramide/dihydroceramide ratios were reduced in both obesity and non-alcoholic steatohepatitis (NASH) and related inversely to liver fat content. Specifically, hepatic ceramide/dihydroceramide (species 16:0) related negatively to hepatic mitochondrial capacity and lipid peroxidation. In visceral adipose tissue, ceramide/dihydroceramide (species 16:0) associated positively with markers of inflammation.Conclusion These results failed to confirm the relationships of ceramide/dihydroceramide in humans with different degree of insulin resistance. However, the low hepatic ceramide/dihydroceramide favor a role for dihydroceramide accumulation in NASH, while a specific ceramide/dihydroceramide ratio in visceral adipose tissue suggests a role of ceramides in obesity-associated low-grade inflammation.

Background: An increasing number of studies have been published recently on the association between ambient air pollution (AP) and incident diabetes mellitus (DM), but studies investigating source-specific AP toxicity and potential mediating pathways are rare. We investigated the associations of all-source, traffic-specific, and industry-specific outdoor AP exposure with 10-year incidence of DM and potential mediation via inflammation-associated biomarkers. Methods: Data from participants of the prospective Heinz Nixdorf Recall cohort study who attended the baseline (t0; 2000–2003), 5-year follow-up (t1; 2006–2008), and 10-year follow-up (t2; 2011–2015) examinations was used. For participants without DM at baseline (determined using information on physician diagnosis and glucose-lowering medication), residential long-term exposure (total, traffic-specific, and industry-specific) to particulate matter (PM2.5, PM10), nitrogen dioxide (NO2), and accumulation mode particle number concentration (PNAM) were estimated using a chemistry transport model. Covariate-adjusted modified Poisson regression models with robust standard errors were applied to estimate relative risks (RR) for the associations between baseline AP and incident DM at t2. Mediation analyses for adiponectin, high-sensitivity C-reactive protein (hsCRP), and interleukin-1 receptor antagonist (IL-1RA) were conducted to estimate natural direct and indirect effects. Results: Of the 4,814 participants at t0, 2,451 participants (mean baseline age: 58.2 years) were included in the main analysis. Interquartile range (IQR) increases in total PM10 and PNAM were associated with increased risk of DM (e.g., RR: 1.25 [95% Confidence Interval (CI): 1.02, 1.53] per 3.8 µg/m3 PM10). Whereas traffic-specific exposures were associated with DM risk for all air pollutants (e.g., RR: 1.24 [95% CI: 1.06, 1.46] per 0.3 µg/m3 PM10), significant associations for industry exposures were limited to NO2 and PNAM (e.g., RR: 1.24 [95% CI: 1.03, 1.49] per 230 particles/mL PNAM). Potential mediation of the association between AP and DM was observed for adiponectin but not for hsCRP and IL-1RA. Conclusion: Our study shows that long-term exposure to total and source-specific ambient AP may increase DM risk, with consistent results observed across traffic-specific exposures. Decreases in adiponectin may play a potential role along the causal pathway. Keywords: Ambient air pollution, Incident diabetes, Mediation, Particulate matter, Inflammation

Abstract Background Biomarkers of inflammation and adiponectin are associated with cardiovascular autonomic neuropathy (CAN) in cross-sectional studies, but prospective data are scarce. This study aimed to assess the associations of biomarkers of subclinical inflammation and adiponectin with subsequent changes in heart rate (HR) and heart rate variability (HRV) in non-diabetic and diabetic individuals. Methods Data are based on up to 25,050 person-examinations for 8469 study participants of the Whitehall II cohort study. Measures of CAN included HR and several HRV indices. Associations between baseline serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra) and adiponectin and 5-year changes in HR and six HRV indices were estimated using mixed-effects models adjusting for age, sex, ethnicity, body mass index (BMI), metabolic covariates and medication. A modifying effect of diabetes was tested. Results Higher levels of IL-1Ra were associated with higher increases in HR. Additional associations with measures of HRV were observed for hsCRP, IL-6 and IL-1Ra, but these associations were explained by BMI and other confounders. Associations between adiponectin, HR and HRV differed depending on diabetes status. Higher adiponectin levels were associated with more pronounced decreases in HR and increases in three measures of HRV reflecting both sympathetic and vagal activity, but these findings were limited to individuals with type 2 diabetes. Conclusions Higher IL-1Ra levels appeared as novel risk marker for increases in HR. Higher adiponectin levels were associated with a more favourable development of cardiovascular autonomic function in individuals with type 2 diabetes independently of multiple confounders.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21276-3

Abstract  In this paper we present HySAT, a bounded model checker for linear hybrid systems, incorporating a tight integration of a DPLL–based pseudo–Boolean SAT solver and a linear programming routine as core engine. In contrast to related tools like MathSAT, ICS, or CVC, our tool exploits the various optimizations that arise naturally in the bounded model checking context, e.g.isomorphic replication of learned conflict clauses or tailored decision strategies, and extends them to the hybrid domain. We demonstrate that those optimizations are crucial to the performance of the tool. [ABSTRACT FROM AUTHOR]

Abstract Aims Secreted frizzled-related protein (Sfrp)5 has beneficial effects on insulin sensitivity, inflammation and cardiovascular risk in different mouse models, but its relevance for cardiometabolic diseases in humans is controversial. We aimed to characterise associations of circulating SFRP5 with cardiometabolic risk factors and prediabetes/type 2 diabetes in a large population-based cohort. Methods Cross-sectional associations between serum SFRP5 and cardiometabolic risk factors as well as prediabetes/type 2 diabetes were investigated in 1096 participants aged 62–81 years from the German KORA F4 study, of whom 666 had prediabetes or type 2 diabetes. Multivariable linear regression models were adjusted for potential confounders including age, sex, body mass index (BMI), lifestyle factors, lipids, hypertension, kidney function and myocardial infarction. Results Higher serum SFRP5 levels were associated with lower HbA1c, BMI, systolic blood pressure, estimated glomerular filtration rate and high-sensitivity C-reactive protein levels and with higher levels of high-density lipoprotein cholesterol and adiponectin in the fully adjusted model (all P

Previous studies reported that secreted frizzled-related protein-5 (Sfrp5) decreases beta cell proliferation and increases fasting insulin levels, but studies on direct effects of Sfrp5 on insulin secretion and its underlying mechanisms are missing. This study examined effects of Sfrp5 on (i) beta cell viability and proliferation, (ii) basal and glucose-stimulated insulin secretion and (iii) canonical and non-canonical Wnt signalling pathways. We incubated rat INS-1E cells with 0.1, 1 or 5 μg/ml recombinant Sfrp5 for 24h. We measured basal and glucose-stimulated insulin secretion at glucose concentrations of 2.5 and 20 mmol/l. Phosphorylated and total protein content as well as mRNA levels of markers of cell proliferation, canonical and non-canonical Wnt signalling pathways were examined using Western blotting and real-time PCR. Differences between treatments were analysed by repeated measurement one-way ANOVA or Friedman's test followed by correction for multiple testing using the Benjamini-Hochberg procedure. At 5 μg/ml, Sfrp5 reduced mRNA levels of cyclin-B1 by 25% (p

This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.

The present study describes time and age trends in morning and evening protein intakes and sources among German children and adolescents from 1985 to 2014. A total of 9757 three-day weighed dietary records of 1246 3- to 18-year-old participants of the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study were analysed using polynomial mixed-effects regression models. Morning protein intake increased over the study period by approximately 1 % of morning energy intake (linear trend P < 0·0001), with the youngest and the oldest children having the highest protein intake (linear, quadratic trend P < 0·0001). Evening protein intake increased over time by approximately 2 % of evening energy intake in girls (linear trend P < 0·0001) and 1 % of evening energy intake in boys (quadratic trend P = 0·0313), with decreasing intake with age (girls: linear trend P < 0·0001; boys: linear trend P = 0·0963). Time trends were largely due to increases in protein from ‘starchy foods’. In conclusion, morning and evening protein intakes increased modestly between 1985 and 2014; these increases were, however, not accompanied by increases in traditional protein sources (i.e. meat or dairy products).

BackgroundGlycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findingsUsing genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.ConclusionsAs G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

OBJECTIVE:Early detection of diabetes and prediabetic states is beneficial for patients, but may be delayed by patients´ being overly optimistic about their own health. Therefore, we assessed how persons without known diabetes perceive their risk of having or developing diabetes, and we identified factors associated with perception of diabetes risk. RESEARCH DESIGN AND METHODS:1,953 participants without previously known diabetes from the population-based, German KORA FF4 Study (59.1 years, 47.8% men) had an oral glucose tolerance test. They estimated their probability of having undiagnosed diabetes mellitus (UDM) on a six category scale, and assessed whether they were at risk of developing diabetes in the future. We cross-tabulated glycemic status with risk perception, and fitted robust Poisson regression models to identify determinants of diabetes risk perception. RESULTS:74% (95% CI: 65-82) of persons with UDM believed that their probability of having undetected diabetes was low or very low. 72% (95% CI: 69-75) of persons with prediabetes believed that they were not at risk of developing diabetes. In people with prediabetes, seeing oneself at risk of diabetes was associated with self-rated poor general health (prevalence ratio (PR) = 3.1 (95% CI: 1.4-6.8), parental diabetes (PR = 2.6, 1.9-3.4), high educational level (PR = 1.9 (1.4-2.5)), lower age (PR = 0.7, 0.6-0.8, per 1 standard deviation increase), female sex (PR = 1.2, 0.9-1.5) and obesity (PR = 1.5, 1.2-2.0). CONCLUSIONS:People with undiagnosed diabetes or prediabetes considerably underestimate their probability of having or developing diabetes. Contrary to associations with actual diabetes risk, perceived diabetes risk was lower in men, lower educated and older persons.

Coffee is widely consumed and contains many bioactive compounds, any of which may impact pathways related to disease development. Our objective was to identify individual lipid changes in response to coffee drinking. We profiled the lipidome of fasting serum samples collected from a previously reported single blinded, three-stage clinical trial. Forty-seven habitual coffee consumers refrained from drinking coffee for 1 month, consumed 4 cups of coffee/day in the second month and 8 cups/day in the third month. Samples collected after each coffee stage were subject to quantitative lipidomic profiling using ion-mobility spectrometry⁻mass spectrometry. A total of 853 lipid species mapping to 14 lipid classes were included for univariate analysis. Three lysophosphatidylcholine (LPC) species including LPC (20:4), LPC (22:1) and LPC (22:2), significantly decreased after coffee intake (p < 0.05 and q < 0.05). An additional 72 species mapping to the LPC, free fatty acid, phosphatidylcholine, cholesteryl ester and triacylglycerol classes of lipids were nominally associated with coffee intake (p < 0.05 and q > 0.05); 58 of these decreased after coffee intake. In conclusion, coffee intake leads to lower levels of specific LPC species with potential impacts on glycerophospholipid metabolism more generally.

Epigenetic regulation has been postulated to affect glucose metabolism, insulin sensitivity and the risk of type 2 diabetes. Therefore, we performed an epigenome-wide association study for measures of glucose metabolism in whole blood samples of the population-based Cooperative Health Research in the Region of Augsburg F4 study using the Illumina HumanMethylation 450 BeadChip. We identified a total of 31 CpG sites where methylation level was associated with measures of glucose metabolism after adjustment for age, sex, smoking, and estimated white blood cell proportions and correction for multiple testing using the Benjamini-Hochberg (B-H) method (four for fasting glucose, seven for fasting insulin, 25 for homeostasis model assessment-insulin resistance [HOMA-IR]; B-H-adjusted p-values between 9.2x10(-5) and 0.047). In addition, DNA methylation at cg06500161 (annotated to ABCG1) was associated with all the aforementioned phenotypes and 2-hour glucose (B-H-adjusted p-values between 9.2x10(-5) and 3.0x10(-3)). Methylation status of additional three CpG sites showed an association with fasting insulin only after additional adjustment for body mass index (BMI) (B-H-adjusted p-values = 0.047). Overall, effect strengths were reduced by around 30% after additional adjustment for BMI, suggesting that this variable has an influence on the investigated phenotypes. Furthermore, we found significant associations between methylation status of 21 of the aforementioned CpG sites and 2-hour insulin in a subset of samples with seven significant associations persisting after additional adjustment for BMI. In a subset of 533 participants, methylation of the CpG site cg06500161 (ABCG1) was inversely associated with ABCG1 gene expression (B-H-adjusted p-value = 1.5x10(-9)). Additionally, we observed an enrichment of the top 1,000 CpG sites for diabetes-related canonical pathways using Ingenuity Pathway Analysis. In conclusion, our study indicates that DNA methylation and diabetes-related traits are associated and that these associations are partially BMI-dependent. Furthermore, the interaction of ABCG1 with glucose metabolism is modulated by epigenetic processes.

Insulin resistance plays a key role in the development of type 2 diabetes. It arises from a combination of genetic predisposition and environmental and lifestyle factors including lack of physical exercise and poor nutrition habits. The increased risk of type 2 diabetes is molecularly based on defects in insulin signaling, insulin secretion, and inflammation. The present review aims to give an overview on the molecular mechanisms underlying the uptake of glucose and related signaling pathways after acute and chronic exercise. Physical exercise, as crucial part in the prevention and treatment of diabetes, has marked acute and chronic effects on glucose disposal and related inflammatory signaling pathways. Exercise can stimulate molecular signaling pathways leading to glucose transport into the cell. Furthermore, physical exercise has the potential to modulate inflammatory processes by affecting specific inflammatory signaling pathways which can interfere with signaling pathways of the glucose uptake. The intensity of physical training appears to be the primary determinant of the degree of metabolic improvement modulating the molecular signaling pathways in a dose-response pattern, whereas training modality seems to have a secondary role.

Abstract 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.