Publications by authors named "Michael Roden"

442 Publications

Novel Antidiabetic Strategies and Diabetologists' Views in Nonalcoholic Steatohepatitis.

Semin Liver Dis 2021 Jul 21. Epub 2021 Jul 21.

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

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide with high prevalence, especially in individuals with obesity and type 2 diabetes. Among individuals with type 2 diabetes, the severe insulin resistant subgroup has the greatest risk of NAFLD, likely due to dysfunctional adipose tissue mass but also genetic factors, and may progress earlier to inflammatory and profibrotic nonalcoholic steatohepatitis (NASH). NASH has been associated with increased liver-related as well as cardiovascular morbidity and mortality. International diabetes associations recommend certain screening and treatment strategies for NASH in type 2 diabetes, which, however, bear several limitations such as lack of accurate noninvasive diagnostic tools and targeted treatments. Currently, antihyperglycemic drug concepts based on glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors offer metabolic as well as cardiorenal benefits and provide treatment options for both hyperglycemia and NASH in type 2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0041-1732354DOI Listing
July 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ckj/sfaa165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248959PMC
June 2021

Meta-analysis of genome-wide DNA methylation and integrative omics of age in human skeletal muscle.

J Cachexia Sarcopenia Muscle 2021 Jun 30. Epub 2021 Jun 30.

Institute for Health and Sport (iHeS), Victoria University, Footscray, Melbourne, Vic., Australia.

Background: Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans.

Methods: We conducted a large-scale epigenome-wide association study meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 muscle methylomes from men and women aged 18-89 years old). We explored the genomic context of age-related DNA methylation changes in chromatin states, CpG islands, and transcription factor binding sites and performed gene set enrichment analysis. We then integrated the DNA methylation data with known transcriptomic and proteomic age-related changes in skeletal muscle. Finally, we updated our recently developed muscle epigenetic clock (https://bioconductor.org/packages/release/bioc/html/MEAT.html).

Results: We identified 6710 differentially methylated regions at a stringent false discovery rate <0.005, spanning 6367 unique genes, many of which related to skeletal muscle structure and development. We found a strong increase in DNA methylation at Polycomb target genes and bivalent chromatin domains and a concomitant decrease in DNA methylation at enhancers. Most differentially methylated genes were not altered at the mRNA or protein level, but they were nonetheless strongly enriched for genes showing age-related differential mRNA and protein expression. After adding a substantial number of samples from five datasets (+371), the updated version of the muscle clock (MEAT 2.0, total n = 1053 samples) performed similarly to the original version of the muscle clock (median of 4.4 vs. 4.6 years in age prediction error), suggesting that the original version of the muscle clock was very accurate.

Conclusions: We provide here the most comprehensive picture of DNA methylation ageing in human skeletal muscle and reveal widespread alterations of genes involved in skeletal muscle structure, development, and differentiation. We have made our results available as an open-access, user-friendly, web-based tool called MetaMeth (https://sarah-voisin.shinyapps.io/MetaMeth/).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcsm.12741DOI Listing
June 2021

Defining comprehensive models of care for NAFLD.

Nat Rev Gastroenterol Hepatol 2021 Jun 25. Epub 2021 Jun 25.

Metabolic Liver Research Program, I. Department of Medicine, University Medical Centre Mainz, Mainz, Germany.

Non-alcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease globally. Despite the increased demand placed on health-care systems, little attention has been given to the design and implementation of efficient and effective models of care for patients with NAFLD. In many health-care settings, no formal pathways exist and, where pathways are in place, they are often not standardized according to good practices. We systematically searched the peer-reviewed literature with the aim of identifying published examples of comprehensive models of care that answered four key questions: what services are provided? Where are they provided? Who is offering them? How are they coordinated and integrated within health-care systems? We identified seven models of care and synthesized the findings into eight recommendations nested within the 'what, where, who and how' of care models. These recommendations, aimed at policy-makers and practitioners designing and implementing models of care, can help to address the increasing need for the provision of good practice care for patients with NAFLD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41575-021-00477-7DOI Listing
June 2021

Non-alcoholic fatty liver disease in type 2 diabetes - A specific entity?

Liver Int 2021 06;41 Suppl 1:105-111

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

Individuals with obesity or type 2 diabetes (T2D) have an increased risk of developing non-alcoholic fatty liver disease (NAFLD). In insulin-resistant states, altered adipose tissue function may be the initial abnormality underlying NAFLD. Hepatic lipid oversupply interferes with insulin signalling and mitochondrial function. In obese individuals, adaptation of hepatic mitochondrial respiration fails with the progression of NAFLD and can activate pro-inflammatory pathways. T2D as well as type 1 diabetes are associated with altered hepatic mitochondrial function. Screening for NAFLD remains challenging especially in those with diabetes because liver enzymes are often in the normal range and the performance of NAFLD scores is limited. Patients with T2D and severe insulin-resistant diabetes (SIRD) have the highest prevalence of NAFLD at diagnosis and the greatest risk of progression. In this subgroup, the single-nucleotide-polymorphism (SNP) rs738409(G) of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is associated with high liver fat content and adipose tissue insulin resistance. This frequent SNP is also known to be associated with lean NAFLD so that genetic testing for this and other SNPs could improve future screening strategies to identify high-risk individuals. Although lifestyle modifications are effective, this approach is limited owing to difficulties with compliance and several classes of drugs are being tested to treat NAFLD. Antihyperglycaemic drugs such as glucagon-like peptide 1 receptor agonists (GLP-1 RA), sodium-glucose cotransporter 2 inhibitors (SGLT2i) and pioglitazone are promising and halt the progression of NAFLD. In conclusion, although NAFLD in diabetes may not be a separate entity, there are specific features to its pathogenesis and clinical management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.14846DOI Listing
June 2021

Dapagliflozin reduces thrombin generation and platelet activation: implications for cardiovascular risk reduction in type 2 diabetes mellitus.

Diabetologia 2021 Aug 16;64(8):1834-1849. Epub 2021 Jun 16.

Institute of Pharmacology and Clinical Pharmacology, Medical Faculty and University Hospital of Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Aims/hypothesis: People with diabetes have an increased cardiovascular risk with an accelerated development of atherosclerosis and an elevated mortality rate after myocardial infarction. Therefore, cardioprotective effects of glucose-lowering therapies are of major importance for the pharmacotherapy of individuals with type 2 diabetes. For sodium-glucose cotransporter 2 inhibitors (SGLT2is), in addition to a reduction in blood glucose, beneficial effects on atherosclerosis, obesity, renal function and blood pressure have been observed. Recent results showed a reduced risk of worsening heart failure and cardiovascular deaths under dapagliflozin treatment irrespective of the diabetic state. However, the underlying mechanisms are yet unknown. Platelets are known drivers of atherosclerosis and atherothrombosis and disturbed platelet activation has also been suggested to occur in type 2 diabetes. Therefore, the present study investigates the impact of the SGLT2i dapagliflozin on the interplay between platelets and inflammation in atherogenesis.

Methods: Male, 8-week-old LDL-receptor-deficient (Ldlr) mice received a high-fat, high-sucrose diabetogenic diet supplemented without (control) or with dapagliflozin (5 mg/kg body weight per day) for two time periods: 8 and 25 weeks. In a first translational approach, eight healthy volunteers received 10 mg dapagliflozin/day for 4 weeks.

Results: Dapagliflozin treatment ameliorated atherosclerotic lesion development, reduced circulating platelet-leucocyte aggregates (glycoprotein [GP]IbCD45: 29.40 ± 5.94 vs 17.00 ± 5.69 cells, p < 0.01; GPIblymphocyte antigen 6 complex, locus G (Ly6G): 8.00 ± 2.45 vs 4.33 ± 1.75 cells, p < 0.05) and decreased aortic macrophage infiltration (1.31 ± 0.62 vs 0.70 ± 0.58 ×10 cells/aorta, p < 0.01). Deeper analysis revealed that dapagliflozin decreased activated CD62P-positive platelets in Ldlr mice fed a diabetogenic diet (3.78 ± 1.20% vs 2.83 ± 1.06%, p < 0.01) without affecting bleeding time (85.29 ± 37.27 vs 89.25 ± 16.26 s, p = 0.78). While blood glucose was only moderately affected, dapagliflozin further reduced endogenous thrombin generation (581.4 ± 194.6 nmol/l × min) × 10 thrombin vs 254.1 ± 106.4 (nmol/l × min) × 10 thrombin), thereby decreasing one of the most important platelet activators. We observed a direct inhibitory effect of dapagliflozin on isolated platelets. In addition, dapagliflozin increased HDL-cholesterol levels. Importantly, higher HDL-cholesterol levels (1.70 ± 0.58 vs 3.15 ± 1.67 mmol/l, p < 0.01) likely contribute to dapagliflozin-mediated inhibition of platelet activation and thrombin generation. Accordingly, in line with the results in mice, treatment with dapagliflozin lowered CD62P-positive platelet counts in humans after stimulation by collagen-related peptide (CRP; 88.13 ± 5.37% of platelets vs 77.59 ± 10.70%, p < 0.05) or thrombin receptor activator peptide-6 (TRAP-6; 44.23 ± 15.54% vs 28.96 ± 11.41%, p < 0.01) without affecting haemostasis.

Conclusions/interpretation: We demonstrate that dapagliflozin-mediated atheroprotection in mice is driven by elevated HDL-cholesterol and ameliorated thrombin-platelet-mediated inflammation without interfering with haemostasis. This glucose-independent mechanism likely contributes to dapagliflozin's beneficial cardiovascular risk profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-021-05498-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245397PMC
August 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 Jun 3. 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 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22389DOI Listing
June 2021

Branched-Chain Amino Acids Associate Negatively With Postprandial Insulin Secretion in Recent-Onset Diabetes.

J Endocr Soc 2021 Jun 20;5(6):bvab067. Epub 2021 Apr 20.

Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany.

Context: In addition to unfavorable effects on insulin sensitivity, elevated plasma branched-chain amino acids (BCAA) stimulate insulin secretion, which, over the long-term, could impair pancreatic β-cell function.

Objective: To investigate cross-sectional and prospective associations between circulating BCAA and postprandial β-cell function in recently diagnosed type 1 and type 2 diabetes.

Methods: The study included individuals with well-controlled type 1 and type 2 diabetes (known diabetes duration <12 months) and glucose-tolerant participants (controls) of similar age, sex, and body mass index (n = 10/group) who underwent mixed meal tolerance tests. Plasma BCAA levels were quantified by gas chromatography-mass spectrometry, postprandial β-cell function was assessed from serum C-peptide levels, and insulin sensitivity was determined from PREDIM index (PREDIcted M-value).

Results: In type 1 diabetes, postprandial total BCAA, valine, and leucine levels were 25%, 18%, and 19% higher vs control, and total as well as individual postprandial BCAA were related inversely to C-peptide levels. In type 2 diabetes, postprandial isoleucine was 16% higher vs the respective controls, while neither total nor individual BCAA correlated with C-peptide levels. Whole-body insulin sensitivity was lower in both diabetes groups than in corresponding controls.

Conclusion: Insulin deficiency associates with sustained high BCAA concentrations, which could contribute to exhausting the insulin secretory reserve in early type 1 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jendso/bvab067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130764PMC
June 2021

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

Nutr Metab Cardiovasc Dis 2021 Jun 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 Jun 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijheh.2021.113752DOI Listing
June 2021

The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments.

Nat Rev Gastroenterol Hepatol 2021 May 10. Epub 2021 May 10.

Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions worldwide. NAFLD and type 2 diabetes mellitus (T2DM) are known to frequently coexist and act synergistically to increase the risk of adverse (hepatic and extra-hepatic) clinical outcomes. T2DM is also one of the strongest risk factors for the faster progression of NAFLD to nonalcoholic steatohepatitis, advanced fibrosis or cirrhosis. However, the link between NAFLD and T2DM is more complex than previously believed. Strong evidence indicates that NAFLD is associated with an approximate twofold higher risk of developing T2DM, irrespective of obesity and other common metabolic risk factors. This risk parallels the severity of NAFLD, such that patients with more advanced stages of liver fibrosis are at increased risk of incident T2DM. In addition, the improvement or resolution of NAFLD (on ultrasonography) is associated with a reduction of T2DM risk, adding weight to causality and suggesting that liver-focused treatments might reduce the risk of developing T2DM. This Review describes the evidence of an association and causal link between NAFLD and T2DM, discusses the putative pathophysiological mechanisms linking NAFLD to T2DM and summarizes the current pharmacological treatments for NAFLD or T2DM that might benefit or adversely affect the risk of T2DM or NAFLD progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41575-021-00448-yDOI Listing
May 2021

Impact of mixed meal tolerance test composition on measures of beta-cell function in type 2 diabetes.

Nutr Metab (Lond) 2021 May 4;18(1):47. Epub 2021 May 4.

Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany.

Background: Application of mixed meal tolerance tests (MMTT) to measure beta-cell function in long-term studies is limited by modification of the commercial products occurring over time. This study assessed the intra-individual reliability of MMTTs and compared the effects of liquid meals differing in macronutrient composition on the estimation of beta-cell function in type 2 diabetes (T2DM).

Methods: To test the reliability of MMTTs, 10 people with T2DM (age 58 ± 11 years, body mass index 30.0 ± 4.9 kg/m) received Boost® high Protein 20 g protein three times. For comparing different meals, another 10 persons with T2DM (58 ± 5 years, 31.9 ± 5.3 kg/m) ingested either Boost® high Protein 20 g protein or the isocaloric Boost® high Protein 15 g protein containing 35% less protein and 18% more carbohydrates. C-peptide, insulin and glucose release were assessed from the incremental area under the concentration time curve (iAUC) and the intra- and inter-individual variation of these parameters from the coefficients of variations (CV).

Results: Repetitive ingestion of one meal revealed intra-individual CVs for the iAUCs of C-peptide, insulin and glucose, which were at least 3-times lower than the inter-individual variation of these parameters (18.2%, 19.7% and 18.9% vs. 74.2%, 70.5% and 207.7%) indicating a good reliability. Ingestion of two different meals resulted in comparable intra-individual CVs of the iAUCs of C-peptide and insulin (16.9%, 20.5%).

Conclusion: MMTTs provide reliable estimation of beta-cell function in people with T2DM. Furthermore, moderate differences in the protein and carbohydrate contents in a standardized liquid meal do not result in relevant changes of C-peptide and insulin responses.

Trial Registration: Clinicaltrials.gov, Identifier number: NCT01055093. Registered 22 January 2010 - Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/study/NCT01055093.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12986-021-00556-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097850PMC
May 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 Jun 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychores.2021.110480DOI Listing
June 2021

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020).

Front Hum Neurosci 2020 23;14:568051. Epub 2021 Mar 23.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnhum.2020.568051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040977PMC
March 2021

Improving insulin sensitivity, liver steatosis and fibrosis in type 2 diabetes by a food-based digital education-assisted lifestyle intervention program: a feasibility study.

Eur J Nutr 2021 Apr 11. Epub 2021 Apr 11.

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

Purpose: Recent trials demonstrated remission of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) following formula diet-induced weight loss. To improve the outreach for populations in need, many mobile health apps targeting weight loss have been developed with limited scientific evaluation of these apps. The present feasibility study investigated the effects of a novel approach incorporating a regular 'whole food-based' low-calorie diet combined with app-based digital education and behavioral change program on glucose metabolism and disease management.

Methods: Twenty-four individuals with type 2 diabetes followed this approach supported by weekly coaching calls for 12 weeks. Phenotyping included bioimpedance analysis, mixed-meal tolerance test, magnetic resonance spectroscopy and transient elastography for assessing liver fat content and liver stiffness.

Results: Over 12 weeks, participants reduced their body weight by 9% (97 ± 13 to 88 ± 12 kg), body mass index (BMI; 33 ± 5 to 29 ± 4 kg/m), total fat mass (31 ± 10 to 27 ± 10%) (all p < 0.01) and liver fat by 50% alongside with decreased liver stiffness. Target HbA1c (< 6.5%) was achieved by 38% and resolution of NAFLD (liver fat content < 5.6%) was observed in 30% of the participants.

Conclusion: This novel approach combining digital education with a low-calorie diet results in effective improvements of body weight, glycemic control and NAFLD and could complement existing care for patients with type 2 diabetes.

Trial Registration: NCT04509245.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00394-021-02521-3DOI Listing
April 2021

Prevalence and Factors Associated With Statin Use Among Patients With Nonalcoholic Fatty Liver Disease in the TARGET-NASH Study.

Clin Gastroenterol Hepatol 2021 Mar 26. Epub 2021 Mar 26.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. Electronic address:

Patients with nonalcoholic fatty liver disease (NAFLD) are at an increased risk of cardiovascular disease. Hydoxy-3-methyglutaryl-coenzyme reductase inhibitors, statins, reduce the risk of cardiovascular events. Studies have shown that statins are safe among patients with liver disease, including those with compensated cirrhosis, and their use is associated with lower mortality, hepatic decompensation, and possibly hepatocellular carcinoma. Despite these data, statins are under prescribed among patients with liver disease due to concerns about hepatotoxicity. This study aimed to assess prevalence and patient factors associated with indicated statin use in patients with NAFLD in a real-world cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cgh.2021.03.031DOI Listing
March 2021

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

Diabetes 2021 May 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.numecd.2020.09.008DOI Listing
February 2021

[Acute metabolic complications in diabetes].

Dtsch Med Wochenschr 2021 Feb 16;146(4):266-278. Epub 2021 Feb 16.

Over time, diabetes patients are at increased risk for microvascular and macrovascular complications leading to increased morbidity and mortality compared to metabolically healthy people. In addition, acute life-threatening metabolic derangements at first manifestation as well as during the course of the disease may occur, comprising diabetic ketoacidosis, hyperosmolar hyperglycaemic state and hypoglycaemia. Diabetes-related emergencies require fast diagnosis and early treatment initiation as well as close monitoring of vital signs and laboratory parameters. The present article gives an overview on the acute metabolic complications in diabetes, focussing on diagnostic work-up and treatment goals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1270-8878DOI Listing
February 2021

Nonalcoholic Fatty Liver Disease and Cardiovascular Disease.

Clin Liver Dis (Hoboken) 2021 Jan 1;17(1):19-22. Epub 2021 Feb 1.

Liver Center Division of Gastroenterology Department of Medicine Massachusetts General Hospital Boston MA.

Watch a video presentation of this article Answer questions and earn CME.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cld.1017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849297PMC
January 2021

Apolipoprotein A5 controls fructose-induced metabolic dysregulation in mice.

Nutr Metab Cardiovasc Dis 2021 03 17;31(3):972-978. Epub 2020 Nov 17.

Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria; Christan Doppler Laboratory for Metabolic Crosstalk, Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Background And Aims: Western dietary habits are partially characterized by increased uptake of fructose, which contributes to metabolic dysregulation and associated liver diseases. For example, a diet enriched with fructose drives insulin resistance and non-alcoholic fatty liver disease (NAFLD). The molecular hubs that control fructose-induced metabolic dysregulation are poorly understood. Apolipoprotein A5 (apoA5) controls triglyceride metabolism with a putative role in hepatic lipid deposition. We explored apoA5 as a rheostat for fructose-induced hepatic and metabolic disease in mammals.

Methods And Results: ApoA5 knock out (-/-) and wildtype (wt) mice were fed with high fructose diet or standard diet for 10 weeks. Afterwards, we conducted a metabolic characterization by insulin tolerance test as well as oral glucose tolerance test. Additionally, hepatic lipid content as well as transcription patterns of key enzymes and transcription factors in glucose and lipid metabolism were evaluated. Despite comparable body weight, insulin sensitivity was significantly improved in high fructose diet fed apoA5 (-/-) when compared to wildtype mice on the same diet. In parallel, hepatic triglyceride content was significantly lower in apoA5 (-/-) mice than in wt mice. No difference was seen between apoA5 (-/-) and wt mice on a standard diet.

Conclusion: ApoA5 is involved in fructose-induced metabolic dysregulation and associated hepatic steatosis suggesting that apoA5 may be a novel target to treat metabolic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.numecd.2020.11.008DOI Listing
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 Jan 19. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00394-020-02463-2DOI Listing
January 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-020-00957-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789600PMC
January 2021

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

J Clin Endocrinol Metab 2021 Mar;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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 Mar;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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993565PMC
March 2021