Publications by authors named "Christian Herder"

289 Publications

Novel biomarkers of inflammation, kidney function and chronic kidney disease in the general population.

Nephrol Dial Transplant 2021 Oct 6. Epub 2021 Oct 6.

Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.

Background: Inflammatory processes have been implicated in the development of chronic kidney disease (CKD). We investigated the association of a large panel of inflammatory biomarkers reflecting aspects of immunity with kidney function and CKD incidence.

Methods: We used data from two independent population-based studies, KORA F4 (discovery, n = 1,110, mean age 70.3 years, 48.7% male) and ESTHER (replication, n = 1,672, mean age 61.9 years, 43.6% male). Serum levels of biomarkers were measured using proximity extension assay technology. The association of biomarkers with estimated glomerular filtration rate (eGFR) at baseline and with incident CKD was investigated using linear and logistic regression models adjusted for cardiorenal risk factors. Independent results from prospective analyses of both studies were pooled. The significance level was corrected for multiple testing by false-discovery rate (PFDR < 0.05.).

Results: In the KORA F4 discovery study, 52 out of 71 inflammatory biomarkers were inversely associated with eGFR estimated based on serum creatinine. Top biomarkers included CD40, TNFRSF9 and IL10RB. Forty-two of these 52 biomarkers were replicated in the ESTHER study. Nine of the 42 biomarkers were associated with incident CKD independently of cardiorenal risk factors in the meta-analysis of the KORA (n = 142, mean follow-up of 6.5 years) and ESTHER (n = 103, mean follow-up of 8 years) studies. Pathway analysis revealed the involvement of inflammatory and immunomodulatory processes reflecting cross-communication of innate and adaptive immune cells.

Conclusions: Novel and known biomarkers of inflammation were reproducibly associated with kidney function. Future studies should investigate their clinical utility and underlying molecular mechanisms in independent cohorts.
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http://dx.doi.org/10.1093/ndt/gfab294DOI Listing
October 2021

Natriuretic Peptides and Risk of Type 2 Diabetes: Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium.

Diabetes Care 2021 Sep 14. Epub 2021 Sep 14.

Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.

Objective: Natriuretic peptide (NP) concentrations are increased in cardiovascular diseases (CVDs) but are associated with a lower diabetes risk. We investigated associations of N-terminal pro-B-type NP (NT-proBNP) and midregional proatrial NP (MR-proANP) with incident type 2 diabetes stratified by the presence of CVD.

Research Design And Methods: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium, we included 45,477 participants with NT-proBNP measurements (1,707 developed type 2 diabetes over 6.5 years of median follow-up; among these, 209 had CVD at baseline) and 11,537 participants with MR-proANP measurements (857 developed type 2 diabetes over 13.8 years of median follow-up; among these, 106 had CVD at baseline). The associations were estimated using multivariable Cox regression models.

Results: Both NPs were inversely associated with incident type 2 diabetes (hazard ratios [95% CI] per 1-SD increase of log NP: 0.84 [0.79; 0.89] for NT-proBNP and 0.77 [0.71; 0.83] for MR-proANP). The inverse association between NT-proBNP and type 2 diabetes was significant in individuals without CVD but not in individuals with CVD (0.81 [0.76; 0.86] vs. 1.04 [0.90; 1.19]; multiplicative interaction = 0.001). There was no significant difference in the association of MR-proANP with type 2 diabetes between individuals without and with CVD (0.75 [0.69; 0.82] vs. 0.81 [0.66; 0.99]; multiplicative interaction = 0.236).

Conclusions: NT-proBNP and MR-proANP are inversely associated with incident type 2 diabetes. However, the inverse association of NT-proBNP seems to be modified by the presence of CVD. Further investigations are warranted to confirm our findings and to investigate the underlying mechanisms.
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http://dx.doi.org/10.2337/dc21-0811DOI Listing
September 2021

Leukocyte Counts and T Cell Frequencies Differ Between Novel Subgroups of Diabetes and Associate with Metabolic Parameters and Biomarkers of Inflammation.

Diabetes 2021 Aug 30. Epub 2021 Aug 30.

Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Frequencies of circulating immune cells are altered in type 1 and type 2 diabetes compared with healthy individuals and associate with insulin sensitivity, glycemic control and lipid levels. This study aimed to determine whether specific immune cell types are associated with novel diabetes subgroups. We analyzed automated white blood cell counts (n=669) and flow cytometry data (n=201) of participants of the German Diabetes Study with recent-onset (<1 year) diabetes, who were allocated to five subgroups based on data-driven analysis of clinical variables. Leukocyte numbers were highest in severe insulin-resistant diabetes (SIRD) and moderate obesity-related diabetes (MOD) and lowest in severe autoimmune diabetes (SAID). CD4 T cell frequencies were higher in SIRD vs. SAID, MOD and mild age-related diabetes (MARD), and frequencies of CCR4 regulatory T cells were higher in SIRD vs. SAID and MOD and MARD vs. SAID. Pairwise differences between subgroups were partially explained by differences in clustering variables. Frequencies of CD4 T cells were positively associated with age, BMI, HOMA2-B and HOMA2-IR, and frequencies of CCR4 regulatory T cells with age, HOMA2-B and HOMA2-IR. In conclusion, different leukocyte profiles exist between novel diabetes subgroups and suggest distinct inflammatory processes in these diabetes subgroups.
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http://dx.doi.org/10.2337/db21-0364DOI Listing
August 2021

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

Clin Kidney J 2021 Jun 6;14(6):1618-1625. Epub 2020 Sep 6.

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU, München, Germany.

Background: Uromodulin is a kidney-specific glycoprotein synthesized in tubular cells of Henle's loop exerting nephroprotective and immunomodulatory functions in the urinary tract. A small amount of uromodulin is also released into the systemic circulation, where its physiological role is unknown. Serum uromodulin (sUmod) has been associated with metabolic risk factors and with cardiovascular events and mortality, where these associations were partly stronger in men than in women. In this study, we investigated the associations of sUmod with biomarkers of subclinical inflammation in a population-based sample of women and men.

Methods: Associations of sUmod with 10 biomarkers of subclinical inflammation were assessed in 1065 participants of the Cooperative Health Research in the Region of Augsburg (KORA) F4 study aged 62-81 years using linear regression models adjusted for sex, age, body mass index, estimated glomerular filtration rate and diabetes. Analyses were performed in the total study sample and stratified by sex.

Results: sUmod was inversely associated with white blood cell count, high-sensitive C-reactive protein, interleukin (IL)-6, tumour necrosis factor-α, myeloperoxidase, superoxide dismutase-3, IL-1 receptor antagonist and IL-22 after multivariable adjustment and correction for multiple testing (P < 0.001 for each observation). There was a trend towards a stronger association of sUmod with pro-inflammatory markers in men than in women, with a significant P for sex interaction (<0.001) regarding the relation of sUmod with IL-6.

Conclusions: sUmod was inversely associated with biomarkers of subclinical inflammation in older participants of the KORA F4 study. The association of sUmod with IL-6 differed between women and men. Future research should focus on whether the immunomodulatory properties of sUmod are one explanation for the association of sUmod with cardiovascular outcomes and mortality.
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http://dx.doi.org/10.1093/ckj/sfaa165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248959PMC
June 2021

Chronic Inflammation Mediates the Association between Cortisol and Hyperglycemia: Findings from the Cross-Sectional Population-Based KORA Age Study.

J Clin Med 2021 Jun 22;10(13). Epub 2021 Jun 22.

German Center for Diabetes Research (DZD), München, 85764 Neuherberg, Germany.

(1) Background: The study aimed to investigate the role of subclinical inflammation on the association between diurnal cortisol patterns and glycaemia in an aged population. (2) Methods: Salivary cortisol, interleukin-6 (IL-6) and glycated haemoglobin (HbA1c) were analysed in a sample of 394 men and 364 women (mean age = 5 ± 6.3, 65-90 years). The ratio of morning after awakening and late-night cortisol was calculated as an indication of diurnal cortisol slope (DCS). Multivariable regression models were run to examine whether IL-6 mediates the relationship between the DCS and glycaemia. The Sobel test and bootstrapping methods were used to quantify the mediation analyses. (3) Results: In comparison to normoglycaemic counterparts ( = 676, 89.2%), an increase in IL-6 concentrations, in individuals with hyperglycaemia (HbA1c ≥ 6.5%) ( = 82, 10.8%) ( = 0.04), was significantly associated with a flatter DCS. The link between flatter DCS and elevated HbA1c level was significant mediated by a heightened IL-6 level. Our results do not suggest reverse-directionality, whereby cortisol did not mediate the association of IL-6 with HbA1c. (4) Conclusions: In our sample, the relation between flatter DCS and hyperglycaemia was partly explained by IL-6 levels. The paradigm of subclinical inflammation-mediated cortisol response on glucose metabolism could have widespread implications for improving our understanding of the pathophysiology of type 2 diabetes mellitus.
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http://dx.doi.org/10.3390/jcm10132751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267679PMC
June 2021

Adiponectin Associates with Rheumatoid Arthritis Risk in Overweight and Obesity Independently of Other Adipokines.

J Clin Med 2021 Jun 25;10(13). Epub 2021 Jun 25.

Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden.

We recently reported that increased serum adiponectin was associated with rheumatoid arthritis (RA) risk in subjects with obesity. We hereby aim to determine if other adipokines associate with RA risk and if the association between adiponectin and RA is independent of other adipokines. Two nested-case control studies were performed in two different cohorts: 82 participants of the Swedish Obese Subjects (SOS) study who developed RA during follow-up matched with 410 controls, and 88 matched pairs from the Medical Biobank of Northern Sweden. Baseline levels of circulating adipokines were measured using ELISA. In a multivariable analysis in the SOS cohort, higher adiponectin was associated with an increased risk of RA independently of other adipokines (OR for RA risk: 1.06, 95% CI: 1.01-1.12, = 0.02). No association between leptin, resistin, and visfatin levels and the risk of RA was detected. In the cohort from the Medical Biobank of Northern Sweden, higher adiponectin was associated with an increased risk of RA only in participants with overweight/obesity (OR: 1.17, 95% CI: 1.01-1.36, = 0.03), independently of other adipokines. Our results show that in individuals with overweight/obesity, higher circulating levels of adiponectin, but not leptin, resistin, or visfatin, were associated with an increased RA risk.
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http://dx.doi.org/10.3390/jcm10132791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267689PMC
June 2021

High Depressive Symptoms in Previously Undetected Diabetes - 10-Year Follow-Up Results of the Heinz Nixdorf Recall Study.

Clin Epidemiol 2021 9;13:429-438. Epub 2021 Jun 9.

Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany.

Aim: To determine the 10-year cumulative incidence of high depressive symptoms in people with diagnosed and, in particular, previously undetected diabetes compared to those without diabetes in a population-based cohort study in Germany.

Materials And Methods: We included 2813 participants (52.9% men, mean age (SD) 58.9 (7.7) years, 7.1% diagnosed diabetes, 5.6% previously undetected diabetes) from the Heinz Nixdorf Recall study. We calculated the odds ratios (OR) with 95% confidence intervals (CI) using multiple logistic regression analyses for diagnosed and undetected diabetes.

Results: Cumulative 10-year incidences (95%-CI) of high depressive symptoms in participants with diagnosed diabetes, previously undetected diabetes, and without diabetes were 15.4% (10.7-21.2), 10.1% (5.9-15.9), and 12.4% (11.1-13.8), respectively. Age-sex-adjusted ORs were 1.51 (1.01-2.28) in participants with diagnosed diabetes compared to those without, 1.40 (0.92-2.12) after adjustment for BMI, physical activity, education, and smoking, and 1.33 (0.87-2.02) after further adjustment for stroke and myocardial infarction. ORs in participants with previously undetected diabetes were 0.96 (0.56-1.65), 0.85 (0.49-1.47), and 0.85 (0.49-1.48), respectively, and lower in men than in women.

Conclusion: As expected, we found an increased odds of developing high depressive symptoms in participants with diagnosed diabetes. However, the odds ratios decreased when we considered comorbidities and other covariates. Interestingly, in participants with previously undetected diabetes, the odds was not increased, even 10 years after detection of diabetes. These results support the hypothesis that high depressive symptoms develop due to diabetes-related burdens and comorbidities and not due to hyperglycemia or hyperinsulinemia.
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http://dx.doi.org/10.2147/CLEP.S294342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203301PMC
June 2021

Plasma Proteomics of Renal Function: A Trans-ethnic Meta-analysis and Mendelian Randomization Study.

J Am Soc Nephrol 2021 Jun 16. Epub 2021 Jun 16.

M Prunotto, School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.

Background: Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed.

Methods: A cross-sectional study of 993 plasma proteins among 2,882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified trans-ethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR .

Results: Fifty-seven plasma proteins were associated with eGFR, including one novel protein. Twenty-three of these were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR.

Conclusions: In a discovery-replication setting, we identified 57 proteins trans-ethnically associated with eGFR. The revealed causal relationships are an important stepping-stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.
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http://dx.doi.org/10.1681/ASN.2020071070DOI Listing
June 2021

Comparison of genetic risk prediction models to improve prediction of coronary heart disease in two large cohorts of the MONICA/KORA study.

Genet Epidemiol 2021 Sep 3;45(6):633-650. Epub 2021 Jun 3.

Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.

It is still unclear how genetic information, provided as single-nucleotide polymorphisms (SNPs), can be most effectively integrated into risk prediction models for coronary heart disease (CHD) to add significant predictive value beyond clinical risk models. For the present study, a population-based case-cohort was used as a trainingset (451 incident cases, 1488 noncases) and an independent cohort as testset (160 incident cases, 2749 noncases). The following strategies to quantify genetic information were compared: A weighted genetic risk score including Metabochip SNPs associated with CHD in the literature (GRS ); selection of the most predictive SNPs among these literature-confirmed variants using priority-Lasso (PL ); validation of two comprehensive polygenic risk scores: GRS based on Metabochip data, and GRS (available in the testset only) based on cross-validated genome-wide genotyping data. We used Cox regression to assess associations with incident CHD. C-index, category-free net reclassification index (cfNRI) and relative integrated discrimination improvement (IDI ) were used to quantify the predictive performance of genetic information beyond Framingham risk score variables. In contrast to GRS and PL , GRS significantly improved the prediction (delta C-index [95% confidence interval]: 0.0087 [0.0044, 0.0130]; IDI : 0.0509 [0.0131, 0.0894]; cfNRI improved only in cases: 0.1761 [0.0253, 0.3219]). GRS yielded slightly worse prediction results than GRS .
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http://dx.doi.org/10.1002/gepi.22389DOI Listing
September 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Early life factors and their relevance for markers of cardiometabolic risk in early adulthood.

Nutr Metab Cardiovasc Dis 2021 06 7;31(7):2109-2121. Epub 2021 Apr 7.

Department of Sports and Health, Institute of Nutrition, Consumption and Health, Paderborn University, Germany. Electronic address:

Background And Aims: Early life exposures could be pertinent risk factors of cardiometabolic diseases in adulthood. We assessed the prospective associations of early life factors with markers of cardiometabolic risk among healthy German adults.

Methods And Results: We examined 348 term-born DONALD Study participants with measurement of fasting blood at the age of 18-24 years to assess metabolic indices: fatty liver index (FLI), hepatic steatosis index (HSI), pro-inflammatory score and insulin sensitivity (HOMA2-%S). Early life factors (maternal weight in early pregnancy, maternal early pregnancy BMI, gestational weight gain (GWG), maternal age, birth weight and full breastfeeding (>17 weeks)) were assessed at enrolment of the offspring into the study. Multivariable linear regression models were used to analyze associations between early life factors and markers of cardiometabolic risk in early adulthood with adjustment for potential confounders. A higher early pregnancy BMI was related to notably higher levels of offspring FLI, HSI, pro-inflammatory score and a lower HOMA2-%S (all p < 0.0001). Similarly, a higher gestational weight gain was associated with a higher FLI (p = 0.044), HSI (p = 0.016), pro-inflammatory score (p = 0.032) and a lower HOMA2-%S among females (p = 0.034). Full breastfeeding was associated with a lower adult FLI (p = 0.037). A casual mediation analysis showed that these associations were mediated by offspring adult waist circumference (WC).

Conclusion: This study suggests that early pregnancy BMI, gestational weight gain, and full breastfeeding are relevant for offspring markers of cardiometabolic risk which seems to be mediated by body composition in young adulthood.
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http://dx.doi.org/10.1016/j.numecd.2021.03.024DOI Listing
June 2021

Association of persistent organic pollutants with sensorimotor neuropathy in participants with and without diabetes or prediabetes: Results from the population-based KORA FF4 study.

Int J Hyg Environ Health 2021 06 19;235:113752. Epub 2021 May 19.

Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.

Background: Concentrations of persistent organic pollutants (POPs) have been associated with an increased type 2 diabetes (T2D) risk. It remains unclear whether POPs are also associated with the risk of diabetes complications including neuropathy and evidence on this topic is scarce. We aimed to investigate the hypothesis that low-dose background concentrations of POPs were positively associated with distal sensorimotor polyneuropathy (DSPN).

Methods: This cross-sectional study was based on data from the second follow-up (FF4, 2013-2014, N = 2279) of the population-based KORA S4 study (Augsburg, Germany). The study sample consisted of 200 participants, including four groups of 50 persons each with known T2D, prediabetes, newly diagnosed diabetes, and normal glucose tolerance (NGT) based on an oral glucose tolerance test. We analyzed the association of six most abundant serum concentrations of POPs, including polychlorinated biphenyls (PCBs) as well as organochlorine (OC) pesticides, with DSPN by multivariable logistic regression adjusted for age, sex, glycaemic status, body mass index, physical activity, smoking and alcohol consumption. We assessed effect modification by age, sex, glycaemic status and obesity and conducted two-pollutant models to check the robustness of the estimates.

Results: For all pollutants, the main models indicated no significant association of having DSPN but pointed to rather decreased odds for DSPN. Two-pollutant models supported these findings, though only the association between the combination of PCB-138 and beta-hexachlorocyclohexane (β-HCH) (OR: 0.59; 95% CI: 0.35-0.99) with DSPN became significant. No effect modification was found by age, sex, glycaemic status and obesity.

Conclusion: Low-dose concentrations of POPs were not associated with increased odds of having DSPN in T2D, prediabetes and NGT.
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http://dx.doi.org/10.1016/j.ijheh.2021.113752DOI Listing
June 2021

Risk phenotypes of diabetes and association with COVID-19 severity and death: a living systematic review and meta-analysis.

Diabetologia 2021 07 28;64(7):1480-1491. Epub 2021 Apr 28.

German Center for Diabetes Research (DZD), Partner Düsseldorf, Düsseldorf, Germany.

Aims/hypothesis: Diabetes has been identified as a risk factor for poor prognosis of coronavirus disease-2019 (COVID-19). The aim of this study is to identify high-risk phenotypes of diabetes associated with COVID-19 severity and death.

Methods: This is the first edition of a living systematic review and meta-analysis on observational studies investigating phenotypes in individuals with diabetes and COVID-19-related death and severity. Four different databases were searched up to 10 October 2020. We used a random effects meta-analysis to calculate summary relative risks (SRR) with 95% CI. The certainty of evidence was evaluated by the GRADE tool.

Results: A total of 22 articles, including 17,687 individuals, met our inclusion criteria. For COVID-19-related death among individuals with diabetes and COVID-19, there was high to moderate certainty of evidence for associations (SRR [95% CI]) between male sex (1.28 [1.02, 1.61], n = 10 studies), older age (>65 years: 3.49 [1.82, 6.69], n = 6 studies), pre-existing comorbidities (cardiovascular disease: 1.56 [1.09, 2.24], n = 8 studies; chronic kidney disease: 1.93 [1.28, 2.90], n = 6 studies; chronic obstructive pulmonary disease: 1.40 [1.21, 1.62], n = 5 studies), diabetes treatment (insulin use: 1.75 [1.01, 3.03], n = 5 studies; metformin use: 0.50 [0.28, 0.90], n = 4 studies) and blood glucose at admission (≥11 mmol/l: 8.60 [2.25, 32.83], n = 2 studies). Similar, but generally weaker and less precise associations were observed between risk phenotypes of diabetes and severity of COVID-19.

Conclusions/interpretation: Individuals with a more severe course of diabetes have a poorer prognosis of COVID-19 compared with individuals with a milder course of disease. To further strengthen the evidence, more studies on this topic that account for potential confounders are warranted.

Registration: PROSPERO registration ID CRD42020193692.
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http://dx.doi.org/10.1007/s00125-021-05458-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079163PMC
July 2021

Generalized anxiety disorder symptoms and type 2 diabetes onset: Findings from the Prospective Cooperative Health Research in the Region of Augsburg F4 and FF4 studies.

J Psychosom Res 2021 06 30;145:110480. Epub 2021 Mar 30.

Department of Psychosomatic Medicine and Psychotherapy, University of Gießen and Marburg, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Partner Helmholtz Zentrum München, Germany. Electronic address:

Objective: To investigate the association of generalized anxiety disorder (GAD) symptomology on the incidence of type 2 diabetes.

Research Design & Methods: Participants from the prospective KORA F4/FF4 German cohort were followed for a mean of 6.5 years. Generalized Anxiety Disorder Scale-7 (GAD-7) was used to assess GAD symptoms and incident type 2 diabetes cases were confirmed using a standard oral glucose tolerance test. Multivariate logistic regression models were used to estimate the effect of GAD symptoms on the incidence of type 2 diabetes.

Results: The present study included 1694 participants (51.8% women, 48.2% men) with a mean age of 51.2 years, among whom 113 (6.7%) had high GAD symptoms. During the follow-up period (11,102 person/years), 113 (6.5%) type 2 diabetes cases were confirmed. Participants with GAD symptoms had 2-fold higher incidence of type 2 diabetes than participants without GAD (17.7 vs. 8.7 cases/1000 person-years). Correspondingly, GAD symptoms independently increased the risk of type 2 diabetes by an odds ratio of 2.09 [95%CI 1.02-4.32, p = 0.04] after adjustment for concurrent sociodemographic, lifestyle and cardiometabolic risk factors, high sensitivity C-reactive protein, depression, and the use of antidepressant medications. Additionally, GAD symptoms had an even larger impact on the onset of type 2 diabetes incidence following additional adjustment for prediabetes at baseline (2.68 [1.23-5.88], p=0.01).

Conclusions: Participants with GAD symptoms had 2-times higher odds of type 2 diabetes incidence during 6.5 years of follow-up, highlighting the significant role of dysregulated stress mechanisms in the pathway to developing type 2 diabetes.
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http://dx.doi.org/10.1016/j.jpsychores.2021.110480DOI Listing
June 2021

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.

medRxiv 2021 Apr 7. Epub 2021 Apr 7.

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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http://dx.doi.org/10.1101/2021.04.01.21254789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043484PMC
April 2021

Diagnostic tools, biomarkers, and treatments in diabetic polyneuropathy and cardiovascular autonomic neuropathy.

Curr Diabetes Rev 2021 Apr 12. Epub 2021 Apr 12.

Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf. Germany.

The various manifestations of diabetic neuropathy including distal symmetric sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN) are among to the most prevalent chronic complications of diabetes. Major clinical complications of diabetic neuropathies such as neuropathic pain, chronic foot ulcers, and orthostatic hypotension are associated with considerable morbidity, increased mortality, and diminished quality of life. Despite the substantial individual and socioeconomic burden, the strategies to diagnose and treat diabetic neuropathies remain insufficient. This review provides an overview on the current clinical aspects and recent advances in exploring local and systemic biomarkers of both DSPN and CAN assessed in human studies (such as biomarkers of inflammation and oxidative stress) to better understand the underlying pathophysiology and to improve early detection. Current therapeutic options for DSPN are (I) causal treatment including lifestyle modification, optimal glycemic control, and multifactorial risk intervention; (II) pharmacotherapy derived from pathogenetic concepts; and (III) analgesic treatment against neuropathic pain. Recent advances in each category are discussed including non-pharmacological approaches such as electrical stimulation. Finally, the current therapeutic options for cardiovascular autonomic complications are provided. These insights should contribute to a broader understanding of the various manifestations of diabetic neuropathies from both the research and clinical perspectives.
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http://dx.doi.org/10.2174/1573399817666210412123740DOI Listing
April 2021

Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases.

Clin Epigenetics 2021 03 22;13(1):60. Epub 2021 Mar 22.

The Framingham Heart Study, 73 Mt. Wayte Avenue, Framingham, MA, 01702, USA.

Background: DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases.

Results: We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data.

Conclusions: Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.
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http://dx.doi.org/10.1186/s13148-021-01041-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986283PMC
March 2021

Differences in Biomarkers of Inflammation Between Novel Subgroups of Recent-Onset Diabetes.

Diabetes 2021 05 19;70(5):1198-1208. Epub 2021 Feb 19.

Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

A novel clustering approach identified five subgroups of diabetes with distinct progression trajectories of complications. We hypothesized that these subgroups differ in multiple biomarkers of inflammation. Serum levels of 74 biomarkers of inflammation were measured in 414 individuals with recent adult-onset diabetes from the German Diabetes Study (GDS) allocated to five subgroups based on data-driven cluster analysis. Pairwise differences between subgroups for biomarkers were assessed with generalized linear mixed models before (model 1) and after (model 2) adjustment for the clustering variables. Participants were assigned to five subgroups: severe autoimmune diabetes (21%), severe insulin-deficient diabetes (SIDD) (3%), severe insulin-resistant diabetes (SIRD) (9%), mild obesity-related diabetes (32%), and mild age-related diabetes (35%). In model 1, 23 biomarkers showed one or more pairwise differences between subgroups (Bonferroni-corrected < 0.0007). Biomarker levels were generally highest in SIRD and lowest in SIDD. All 23 biomarkers correlated with one or more of the clustering variables. In model 2, three biomarkers (CASP-8, EN-RAGE, IL-6) showed at least one pairwise difference between subgroups (e.g., lower CASP8, EN-RAGE, and IL-6 in SIDD vs. all other subgroups, all < 0.0007). Thus, novel diabetes subgroups show multiple differences in biomarkers of inflammation, underlining a prominent role of inflammatory pathways in particular in SIRD.
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http://dx.doi.org/10.2337/db20-1054DOI Listing
May 2021

Reversion from prediabetes to normoglycaemia after weight change in older persons: The KORA F4/FF4 study.

Nutr Metab Cardiovasc Dis 2021 02 12;31(2):429-438. Epub 2020 Sep 12.

German Center for Diabetes Research (DZD), München, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Background And Aims: In a non-interventional study of older persons, we assessed the impact of changes in BMI and waist circumference (WC) on reversion from glucose- and HbA1c-defined prediabetes to normoglycaemia (in short: reversion) and on persistence of normoglycaemia. Moreover, we studied whether reversion reduced cardiovascular risk.

Methods And Results: From the population-based KORA S4/F4/FF4 cohort study conducted in Southern Germany, we utilized data from the second and third visit to the study center (median follow-up 6.5 years). We used two overlapping data sets, one with 563 persons with HbA1c<6.5% (mean age 69 years, 51.5% men), one with 510 persons with glucose-based prediabetes or normal glucose tolerance. We calculated proportions of reversion, and estimated adjusted relative risks for the association between initial BMI/WC and change of BMI/WC, respectively, and reversion (and persistence of normoglycaemia, respectively). We estimated 10-year cardiovascular risks using the Framingham 2008 score. Overall, 27.3% of persons with HbA1c-defined prediabetes and 9.2% of persons with glucose-based prediabetes returned to normoglycaemia during follow-up. Lower initial BMI/WC and reduction of BMI/WC were associated with larger probabilities of returning to normoglycaemia (e.g., for HbA1c 5.7-6.4%, RR = 1.24 (95% CI: 1.09-1.41) per 1 kg/m decline of BMI). Moreover, reduction of BMI/WC increased probabilities of maintaining normoglycaemia (e.g., for glucose-based prediabetes, RR = 1.09 (1.02-1.16) per 1 kg/m decline of BMI). 10-year cardiovascular risk was 5.6 (1.7-9.6) percentage points lower after reversion from glucose-based prediabetes to normoglycaemia.

Conclusion: In older adults, even moderate weight reduction contributes to reversion from prediabetes to normoglycaemia and to maintaining normoglycaemia.
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http://dx.doi.org/10.1016/j.numecd.2020.09.008DOI Listing
February 2021

The Prospective Association of Dietary Sugar Intake in Adolescence With Risk Markers of Type 2 Diabetes in Young Adulthood.

Front Nutr 2020 18;7:615684. Epub 2021 Jan 18.

Public Health Nutrition, Paderborn University, Paderborn, Germany.

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. 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 ( = 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). 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 ( > 0.01). On the urinary level, however, higher excreted fructose levels were associated with improved adult HOMA2-%S ( = 0.008) among females only. No associations were observed between dietary or urinary sugars and the adult pro-inflammatory score ( > 0.01). 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.
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http://dx.doi.org/10.3389/fnut.2020.615684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848860PMC
January 2021

Relevance of fructose intake in adolescence for fatty liver indices in young adulthood.

Eur J Nutr 2021 Sep 19;60(6):3029-3041. Epub 2021 Jan 19.

Institute of Nutritional and Food Sciences , Nutritional Epidemiology, University of Bonn, DONALD Study, Heinstück 11, 44225, Dortmund, Germany.

Purpose: To examine the association between fructose intake in adolescence and fatty liver indices (hepatic steatosis index (HSI), fatty liver index (FLI)) in young adulthood.

Methods: Overall, 246 participants of the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study who had a fasting blood sample in adulthood (18-36 years), at least two 3-day weighed dietary records for calculating fructose intakes and other fructose-containing sugars (total (TS), free (FS), added sugar (AS)) as well as two complete 24-h urine samples for calculating sugar excretion (fructose excretion (FE), fructose + sucrose excretion (FE + SE)) in adolescence (males: 9.5-16.5 years; females: 8.5-15.5 years) were analysed using multivariable linear regression analyses.

Results: On the level of dietary intake, no prospective associations were observed between adolescent fructose intake and both adult fatty liver indices, whereas higher FS intakes were associated with lower levels of HSI (P = 0.02) and FLI (P = 0.03). On the urinary excretion level, however, a higher FE (P = 0.03) and FE + SE (P = 0.01) in adolescence were prospectively related to higher adult FLI values. No associations were observed between adolescent sugar excretion and adult HSI.

Conclusion: The present study does not provide unambiguous support for a detrimental impact of adolescent fructose intake on adult liver health. Nonetheless, further examinations estimating exposure by means of urinary excretion as well as dietary intake levels appear warranted.
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http://dx.doi.org/10.1007/s00394-020-02463-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354997PMC
September 2021

Associations of cells from both innate and adaptive immunity with lower nerve conduction velocity: the Maastricht Study.

BMJ Open Diabetes Res Care 2021 01;9(1)

Department of Internal Medicine, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands.

Introduction: Distal sensorimotor polyneuropathy (DSPN) is common in people with diabetes but is also found in pre-diabetes. Peripheral nerve myelin damage, which can be assessed by reduced nerve conduction velocity (NCV), is an essential feature of DSPN. Emerging evidence indicates that the development of DSPN may involve the activation of the immune system. However, available studies have mainly investigated circulating immune mediators, whereas the role of immune cells remains unclear. Therefore, we aimed to test whether leukocyte subsets are associated with NCV.

Research Design And Methods: This cross-sectional study analyzed data from 850 individuals (of whom 252 and 118 had type 2 diabetes and pre-diabetes, respectively) of the Maastricht Study. NCV was measured in the peroneal and tibial motor nerves and the sural sensory nerve and summed to calculate a standardized NCV sum score. Associations between percentages of leukocyte subsets and NCV sum scores were estimated using linear regression models adjusted for demographic, lifestyle, metabolic and clinical covariates.

Results: After adjustment for covariates, higher percentages of basophils and CD4 T cells were associated with lower NCV (p=0.014 and p=0.005, respectively). The percentage of CD8 T cells was positively associated with NCV (p=0.022). These associations were not modified by glucose metabolism status (all p >0.05). No associations were found for monocytes, eosinophils, neutrophils, lymphocytes, total T cells, Treg cells and B cells.

Conclusions: The associations of basophils, CD4 and CD8 T cells with NCV suggest that cell types from both innate and adaptive immunity may be implicated in the development of DSPN.
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http://dx.doi.org/10.1136/bmjdrc-2020-001698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802711PMC
January 2021

Longitudinal associations between ambient air pollution and insulin sensitivity: results from the KORA cohort study.

Lancet Planet Health 2021 01;5(1):e39-e49

Institute of Epidemiology, Helmholtz Centre Munich, German Research Centre for Environmental Health, Neuherberg, Germany; German Centre for Diabetes Research, DZD, Munich-Neuherberg, Germany.

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 PM, by 3·6% (1·0 to 6·3) for PM, 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.
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http://dx.doi.org/10.1016/S2542-5196(20)30275-8DOI Listing
January 2021

DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures.

Clin Epigenetics 2021 01 7;13(1). Epub 2021 Jan 7.

Center for Life Course Health Research, University of Oulu, Oulu University Hospital, Oulu, Finland.

Background: The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances.

Results: We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations.

Conclusion: Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.
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http://dx.doi.org/10.1186/s13148-020-00957-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789600PMC
January 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Reduced Muscle Strength Is Associated With Insulin Resistance in Type 2 Diabetes Patients With Osteoarthritis.

J Clin Endocrinol Metab 2021 03;106(4):1062-1073

Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

Context: Type 2 diabetes is associated with a greater risk for musculoskeletal disorders, yet its impact on joint function remains unclear.

Objective: We hypothesized that patients with type 2 diabetes and osteoarthritis would exhibit musculoskeletal impairment, which would associate with insulin resistance and distinct microRNA profiles.

Methods: Participants of the German Diabetes Study with type 2 diabetes (T2D, n = 39) or normal glucose tolerance (CON, n = 27), both with (+OA) or without osteoarthritis (-OA) underwent intravenous glucose tolerance and hyperinsulinemic-euglycemic clamp tests. Musculoskeletal function was assessed by isometric knee extension strength (KES), grip strength, range of motion (ROM), and balance skills, while neural function was measured by nerve conductance velocity (NCV). Arthritis-related symptoms were quantified using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, serum arthritis-related microRNA using quantitative polymerase chain reaction.

Results: Insulin sensitivity was lower in T2D+OA vs T2D-OA (4.4 ± 2.0 vs 5.7 ± 3.0 mg* kg-1*min-1) and in CON+OA vs CON-OA (8.1 ± 2.0 vs 12.0 ± 2.6 mg*kg-1,*min-1, both P < .05). In T2D+OA, KES and ROM were 60% and 22% lower than in CON+OA, respectively (both P < .05). Insulin sensitivity correlated positively with KES (r = 0.41, P < .05) among T2D, and negatively with symptom severity in CON and T2D (r = -0.60 and r = -0.46, respectively, P < .05). CON+OA and T2D+OA had inferior balance skills than CON-OA, whereas NCV was comparable in T2D+OA and T2D-OA. Expression of arthritis-related microRNAs was upregulated in T2D compared to CON, but downregulated in CON+OA compared to CON-OA (P < .05), and did not differ between T2D+OA and T2D-OA.

Conclusion: Musculoskeletal impairment and osteoarthritis-related symptoms are associated with insulin resistance. Type 2 diabetes can mask changes in arthritis-related microRNA profiles.
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http://dx.doi.org/10.1210/clinem/dgaa912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993587PMC
March 2021

A Panel of 6 Biomarkers Significantly Improves the Prediction of Type 2 Diabetes in the MONICA/KORA Study Population.

J Clin Endocrinol Metab 2021 03;106(4):e1647-e1659

Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.

Context: Improved strategies to identify persons at high risk of type 2 diabetes are important to target costly preventive efforts to those who will benefit most.

Objective: This work aimed to assess whether novel biomarkers improve the prediction of type 2 diabetes beyond noninvasive standard clinical risk factors alone or in combination with glycated hemoglobin A1c (HbA1c).

Methods: We used a population-based case-cohort study for discovery (689 incident cases and 1850 noncases) and an independent cohort study (262 incident cases, 2549 noncases) for validation. An L1-penalized (lasso) Cox model was used to select the most predictive set among 47 serum biomarkers from multiple etiological pathways. All variables available from the noninvasive German Diabetes Risk Score (GDRSadapted) were forced into the models. The C index and the category-free net reclassification index (cfNRI) were used to evaluate the predictive performance of the selected biomarkers beyond the GDRSadapted model (plus HbA1c).

Results: Interleukin-1 receptor antagonist, insulin-like growth factor binding protein 2, soluble E-selectin, decorin, adiponectin, and high-density lipoprotein cholesterol were selected as the most relevant biomarkers. The simultaneous addition of these 6 biomarkers significantly improved the predictive performance both in the discovery (C index [95% CI], 0.053 [0.039-0.066]; cfNRI [95% CI], 67.4% [57.3%-79.5%]) and the validation study (0.034 [0.019-0.053]; 48.4% [35.6%-60.8%]). Significant improvements by these biomarkers were also seen on top of the GDRSadapted model plus HbA1c in both studies.

Conclusion: The addition of 6 biomarkers significantly improved the prediction of type 2 diabetes when added to a noninvasive clinical model or to a clinical model plus HbA1c.
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http://dx.doi.org/10.1210/clinem/dgaa953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993565PMC
March 2021

Association of Long-Term Air Pollution with Prevalence and Incidence of Distal Sensorimotor Polyneuropathy: KORA F4/FF4 Study.

Environ Health Perspect 2020 12 23;128(12):127013. Epub 2020 Dec 23.

Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Background: Air pollution contributes to type 2 diabetes and cardiovascular diseases, but its relevance for other complications of diabetes, in particular distal sensorimotor polyneuropathy (DSPN), is unclear. Recent studies have indicated that DSPN is also increasingly prevalent in obesity.

Objectives: We aimed to assess associations of air pollutants with prevalent and incident DSPN in a population-based study of older individuals with high rates of type 2 diabetes and obesity.

Methods: Cross-sectional analyses on prevalent DSPN were based on 1,075 individuals 62-81 years of age from the German Cooperative Health Research in the Region of Augsburg (KORA) F4 survey (2006-2008). Analyses on incident DSPN included 424 individuals without DSPN at baseline (KORA F4), of whom 188 had developed DSPN by the KORA FF4 survey (2013-2014). Associations of annual average air pollutant concentrations at participants' residences with prevalent and incident DSPN were estimated using Poisson regression models with a robust error variance adjusting for multiple confounders.

Results: Higher particle number concentrations (PNCs) were associated with higher prevalence [risk ratio (RR) per interquartile range (IQR) (95% CI: 1.01, 1.20)] and incidence [1.11 (95% CI: 0.99, 1.24)] of DSPN. In subgroup analyses, particulate (PNC, , , , and ) and gaseous (, ) pollutants were positively associated with prevalent DSPN in obese participants, whereas corresponding estimates for nonobese participants were close to the null [e.g., for an IQR increase in PNC, (95% CI: 1.05, 1.31) vs. 1.06 (95% CI: 0.95, 1.19); ]. With the exception of , corresponding associations with incident DSPN were positive in obese participants but null or inverse for nonobese participants, with [e.g., for PNC, (95% CI: 1.08, 1.51) vs. 1.03 (95% CI: 0.90, 1.18); ].

Discussion: Both particulate and gaseous air pollutants were positively associated with prevalent and incident DSPN in obese individuals. Obesity and air pollution may have synergistic effects on the development of DSPN. https://doi.org/10.1289/EHP7311.
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http://dx.doi.org/10.1289/EHP7311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757787PMC
December 2020
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