TY - JOUR A1 - Schiborn, Catarina A1 - Schulze, Matthias Bernd T1 - Precision prognostics for the development of complications in diabetes JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) N2 - Individuals with diabetes face higher risks for macro- and microvascular complications than their non-diabetic counterparts. The concept of precision medicine in diabetes aims to optimise treatment decisions for individual patients to reduce the risk of major diabetic complications, including cardiovascular outcomes, retinopathy, nephropathy, neuropathy and overall mortality. In this context, prognostic models can be used to estimate an individual's risk for relevant complications based on individual risk profiles. This review aims to place the concept of prediction modelling into the context of precision prognostics. As opposed to identification of diabetes subsets, the development of prediction models, including the selection of predictors based on their longitudinal association with the outcome of interest and their discriminatory ability, allows estimation of an individual's absolute risk of complications. As a consequence, such models provide information about potential patient subgroups and their treatment needs. This review provides insight into the methodological issues specifically related to the development and validation of prediction models for diabetes complications. We summarise existing prediction models for macro- and microvascular complications, commonly included predictors, and examples of available validation studies. The review also discusses the potential of non-classical risk markers and omics-based predictors. Finally, it gives insight into the requirements and challenges related to the clinical applications and implementation of developed predictions models to optimise medical decision making. KW - Cardiovascular diseases KW - Complications in diabetes KW - Macrovascular KW - complications KW - Microvascular complications KW - Personalised medicine KW - Precision medicine KW - Precision prognostics KW - Review KW - Risk prediction KW - Risk KW - scores Y1 - 2022 U6 - https://doi.org/10.1007/s00125-022-05731-4 SN - 0012-186X SN - 1432-0428 PB - Springer CY - New York ER - TY - JOUR A1 - Wittenbecher, Clemens A1 - Kuxhaus, Olga A1 - Boeing, Heiner A1 - Stefan, Norbert A1 - Schulze, Matthias Bernd T1 - Associations of short stature and components of height with incidence of type 2 diabetes BT - mediating effects of cardiometabolic risk factors JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) N2 - Aims/hypothesis This study aimed to evaluate associations of height as well as components of height (sitting height and leg length) with risk of type 2 diabetes and to explore to what extent associations are explainable by liver fat and cardiometabolic risk markers. Methods A case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study comprising 26,437 participants who provided blood samples was designed. We randomly selected a subcohort of 2500 individuals (2029 diabetes-free at baseline and with anamnestic, anthropometrical and metabolic data for analysis). Of the 820 incident diabetes cases identified in the full cohort during 7 years of follow-up, 698 remained for analyses after similar exclusions. Results After adjustment for age, potential lifestyle confounders, education and waist circumference, greater height was related to lower diabetes risk (HR per 10 cm, men 0.59 [95% CI 0.47, 0.75] and women 0.67 [0.51, 0.88], respectively). Leg length was related to lower risk among men and women, but only among men if adjusted for total height. Adjustment for liver fat and triacylglycerols, adiponectin and C-reactive protein substantially attenuated associations between height and diabetes risk, particularly among women. Conclusions/interpretation We observed inverse associations between height and risk of type 2 diabetes, which was largely related to leg length among men. The inverse associations may be partly driven by lower liver fat content and a more favourable cardiometabolic profile. KW - Adult height KW - Blood pressure KW - Diabetes incidence KW - Leg length KW - Liver fat KW - Short stature KW - Trunk length Y1 - 2019 U6 - https://doi.org/10.1007/s00125-019-04978-8 SN - 0012-186X SN - 1432-0428 VL - 62 IS - 12 SP - 2211 EP - 2221 PB - Springer CY - New York ER - TY - JOUR A1 - Grune, Tilman T1 - Oxidized protein aggregates BT - formation and biological effects JF - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research N2 - The study of protein aggregates has a long history. While in the first decades until the 80ies of the 20th century only the observation of the presence of such aggregates was reported, later the biochemistry of the formation and the biological effects of theses aggregates were described. This review focusses on the complexity of the biological effects of protein aggregates and its potential role in the aging process. Y1 - 2020 U6 - https://doi.org/10.1016/j.freeradbiomed.2020.02.014 SN - 0891-5849 SN - 1873-4596 VL - 150 SP - 120 EP - 124 PB - Elsevier CY - New York ER - TY - JOUR A1 - Bishop, Christopher Allen A1 - Schulze, Matthias Bernd A1 - Klaus, Susanne A1 - Weitkunat, Karolin T1 - The branched-chain amino acids valine and leucine have differential effects on hepatic lipid metabolism JF - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology N2 - Dairy intake, as a source of branched-chain amino acids (BCAA), has been linked to a lower incidence of type-2-diabetes and increased circulating odd-chain fatty acids (OCFA). To understand this connection, we aimed to investigate differences in BCAA metabolism of leucine and valine, a possible source of OCFA, and their role in hepatic metabolism. Male mice were fed a high-fat diet supplemented with leucine and valine for 1 week and phenotypically characterized with a focus on lipid metabolism. Mouse primary hepatocytes were treated with the BCAA or a Ppar alpha activator WY-14643 to systematically examine direct hepatic effects and their mechanisms. Here, we show that only valine supplementation was able to increase hepatic and circulating OCFA levels via two pathways; a PPAR alpha-dependent induction of alpha-oxidation and an increased supply of propionyl-CoA for de novo lipogenesis. Meanwhile, we were able to confirm leucine-mediated effects on the inhibition of food intake and transport of fatty acids, as well as induction of S6 ribosomal protein phosphorylation. Taken together, these data illustrate differential roles of the BCAA in lipid metabolism and provide preliminary evidence that exclusively valine contributes to the endogenous formation of OCFA which is important for a better understanding of these metabolites in metabolic health. KW - fatty acid metabolism KW - leucine KW - liver KW - OCFA KW - valine Y1 - 2020 U6 - https://doi.org/10.1096/fj.202000195R SN - 0892-6638 SN - 1530-6860 VL - 34 IS - 7 SP - 9727 EP - 9739 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Schenk, Matthew A1 - Eichelmann, Fabian A1 - Schulze, Matthias Bernd A1 - Rudovich, Natalia A1 - Pfeiffer, Andreas F. H. A1 - di Giuseppe, Romina A1 - Böing, Heiner A1 - Aleksandrova, Krasimira T1 - Reproducibility of novel immune-inflammatory biomarkers over 4 months BT - an analysis with repeated measures design JF - Biomarkers in medicine N2 - Aim: Assessment of the feasibility and reliability of immune-inflammatory biomarker measurements. Methods: The following biomarkers were assessed in 207 predominantly healthy participants at baseline and after 4 months: MMF, TGF-beta, suPAR and clusterin. Results: Intraclass correlation coefficients (95% CIs) ranged from good for TGF-beta (0.75 [95% CI: 0.33-0.90]) to excellent for MMF (0.81 [95% CI: 0.64-0.90]), clusterin (0.83 [95% CI: 0.78-0.87]) and suPAR (0.91 [95% CI: 0.88-0.93]). Measurement of TGF-beta was challenged by the large number of values below the detection limit. Conclusion: Single measurements of suPAR, clusterin and MMF could serve as feasible and reliable biomarkers of immune-inflammatory pathways in biomedical research. KW - clusterin KW - immune-inflammatory biomarkers KW - MMF KW - repeated measures design KW - reproducibility KW - suPAR KW - TGF-beta Y1 - 2019 U6 - https://doi.org/10.2217/bmm-2018-0351 SN - 1752-0363 SN - 1752-0371 VL - 13 IS - 8 SP - 639 EP - 648 PB - Future Medicine CY - London ER - TY - JOUR A1 - Jannasch, Franziska A1 - Nickel, Daniela A1 - Schulze, Matthias Bernd T1 - The reliability and relative validity of predefined dietary patterns were higher than that of exploratory dietary patterns in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam population JF - British journal of nutrition : BJN : an international journal of nutritional science / published on behalf of The Nutrition Society N2 - The aim of this study was to assess the ability of the FFQ to describe reliable and valid dietary pattern (DP) scores. In a total of 134 participants of the European Prospective Investigation into Cancer and Nutrition-Potsdam study aged 35-67 years, the FFQ was applied twice (baseline and after 1 year) to assess its reliability. Between November 1995 and March 1997, twelve 24-h dietary recalls (24HDR) as reference instrument were applied to assess the validity of the FFQ. Exploratory DP were derived by principal component analyses. Investigated predefined DP were the Alternative Healthy Eating Index (AHEI) and two Mediterranean diet indices. From dietary data of each FFQ, two exploratory DP were retained, but differed in highly loading food groups, resulting in moderate correlations (r 0 center dot 45-0 center dot 58). The predefined indices showed higher correlations between the FFQ (r(AHEI) 0 center dot 62, r(Mediterranean Diet Pyramid Index (MedPyr)) 0 center dot 62 and r(traditional Mediterranean Diet Score (tMDS)) 0 center dot 51). From 24HDR dietary data, one exploratory DP retained differed in composition to the first FFQ-based DP, but showed similarities to the second DP, reflected by a good correlation (r 0 center dot 70). The predefined DP correlated moderately (r 0 center dot 40-0 center dot 60). To conclude, long-term analyses on exploratory DP should be interpreted with caution, due to only moderate reliability. The validity differed extensively for the two exploratory DP. The investigated predefined DP showed a better reliability and a moderate validity, comparable to other studies. Within the two Mediterranean diet indices, the MedPyr performed better than the tMDs in this middle-aged, semi-urban German study population. KW - dietary patterns KW - reliability KW - validity Y1 - 2020 U6 - https://doi.org/10.1017/S0007114520003517 SN - 1475-2662 SN - 0007-1145 VL - 125 IS - 11 SP - 1270 EP - 1280 PB - Cambridge University Press CY - Cambridge ER - TY - JOUR A1 - Eichelmann, Fabian A1 - Sellem, Laury A1 - Wittenbecher, Clemens A1 - Jäger, Susanne A1 - Kuxhaus, Olga A1 - Prada, Marcela A1 - Cuadrat, Rafael A1 - Jackson, Kim G. A1 - Lovegrove, Julie A. A1 - Schulze, Matthias Bernd T1 - Deep lipidomics in human plasma: cardiometabolic disease risk and effect of dietary fat modulation JF - Circulation N2 - Background: In blood and tissues, dietary and endogenously generated fatty acids (FAs) occur in free form or as part of complex lipid molecules that collectively represent the lipidome of the respective tissue. We assessed associations of plasma lipids derived from high-resolution lipidomics with incident cardiometabolic diseases and subsequently tested if the identified risk-associated lipids were sensitive to dietary fat modification. Methods: The EPIC Potsdam cohort study (European Prospective Investigation into Cancer and Nutrition) comprises 27 548 participants recruited within an age range of 35 to 65 years from the general population around Potsdam, Germany. We generated 2 disease-specific case cohorts on the basis of a fixed random subsample (n=1262) and all respective cohort-wide identified incident primary cardiovascular disease (composite of fatal and nonfatal myocardial infarction and stroke; n=551) and type 2 diabetes (n=775) cases. We estimated the associations of baseline plasma concentrations of 282 class-specific FA abundances (calculated from 940 distinct molecular species across 15 lipid classes) with the outcomes in multivariable-adjusted Cox models. We tested the effect of an isoenergetic dietary fat modification on risk-associated lipids in the DIVAS randomized controlled trial (Dietary Intervention and Vascular Function; n=113). Participants consumed either a diet rich in saturated FAs (control), monounsaturated FAs, or a mixture of monounsaturated and n-6 polyunsaturated FAs for 16 weeks. Results: Sixty-nine lipids associated (false discovery rate<0.05) with at least 1 outcome (both, 8; only cardiovascular disease, 49; only type 2 diabetes, 12). In brief, several monoacylglycerols and FA16:0 and FA18:0 in diacylglycerols were associated with both outcomes; cholesteryl esters, free fatty acids, and sphingolipids were largely cardiovascular disease specific; and several (glycero)phospholipids were type 2 diabetes specific. In addition, 19 risk-associated lipids were affected (false discovery rate<0.05) by the diets rich in unsaturated dietary FAs compared with the saturated fat diet (17 in a direction consistent with a potential beneficial effect on long-term cardiometabolic risk). For example, the monounsaturated FA-rich diet decreased diacylglycerol(FA16:0) by 0.4 (95% CI, 0.5-0.3) SD units and increased triacylglycerol(FA22:1) by 0.5 (95% CI, 0.4-0.7) SD units. Conclusions: We identified several lipids associated with cardiometabolic disease risk. A subset was beneficially altered by a dietary fat intervention that supports the substitution of dietary saturated FAs with unsaturated FAs as a potential tool for primary disease prevention. KW - cardiovascular diseases KW - cholesterol KW - diabetes mellitus KW - type 2 KW - diet KW - food KW - and nutrition KW - epidemiology KW - lipids Y1 - 2022 U6 - https://doi.org/10.1161/CIRCULATIONAHA.121.056805 SN - 0009-7322 SN - 1524-4539 VL - 146 IS - 1 SP - 21 EP - 35 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Schröter, David A1 - Neugart, Susanne A1 - Schreiner, Monika A1 - Grune, Tilman A1 - Rohn, Sascha A1 - Ott, Christiane T1 - Amaranth’s 2-Caffeoylisocitric Acid—An Anti-Inflammatory Caffeic Acid Derivative That Impairs NF-κB Signaling in LPS-Challenged RAW 264.7 Macrophages JF - Nutrients N2 - For centuries, Amaranthus sp. were used as food, ornamentals, and medication. Molecular mechanisms, explaining the health beneficial properties of amaranth, are not yet understood, but have been attributed to secondary metabolites, such as phenolic compounds. One of the most abundant phenolic compounds in amaranth leaves is 2-caffeoylisocitric acid (C-IA) and regarding food occurrence, C-IA is exclusively found in various amaranth species. In the present study, the anti-inflammatory activity of C-IA, chlorogenic acid, and caffeic acid in LPS-challenged macrophages (RAW 264.7) has been investigated and cellular contents of the caffeic acid derivatives (CADs) were quantified in the cells and media. The CADs were quantified in the cell lysates in nanomolar concentrations, indicating a cellular uptake. Treatment of LPS-challenged RAW 264.7 cells with 10 µM of CADs counteracted the LPS effects and led to significantly lower mRNA and protein levels of inducible nitric oxide synthase, tumor necrosis factor alpha, and interleukin 6, by directly decreasing the translocation of the nuclear factor κB/Rel-like containing protein 65 into the nucleus. This work provides new insights into the molecular mechanisms that attribute to amaranth’s anti-inflammatory properties and highlights C-IA’s potential as a health-beneficial compound for future research. KW - inflammation KW - caffeic acid derivatives KW - RAW 264 KW - 7 macrophages KW - NF-kappa B KW - amaranth Y1 - 2019 U6 - https://doi.org/10.3390/nu11030571 SN - 2072-6643 VL - 11 IS - 3 PB - MDPI CY - Basel ER - TY - JOUR A1 - Eichelmann, Fabian A1 - Schulze, Matthias Bernd A1 - Wittenbecher, Clemens A1 - Menzel, Juliane A1 - Weikert, Cornelia A1 - di Giuseppe, Romina A1 - Biemann, Ronald A1 - Isermann, Berend A1 - Fritsche, Andreas A1 - Boeing, Heiner A1 - Aleksandrova, Krasimira T1 - Association of Chemerin Plasma Concentration With Risk of Colorectal Cancer JF - JAMA network open N2 - IMPORTANCE Inflammatory processes have been suggested to have an important role in colorectal cancer (CRC) etiology. Chemerin is a recently discovered inflammatory biomarker thought to exert chemotactic, adipogenic, and angiogenic functions. However, its potential link with CRC has not been sufficiently explored. OBJECTIVE To evaluate the prospective association of circulating plasma chemerin concentrations with incident CRC. DESIGN, SETTING, AND PARTICIPANTS Prospective case-cohort study based on 27 548 initially healthy participants from the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Potsdam cohort who were followed for up to 16 years. Baseline study information and samples were collected between August 23, 1994, and September 25, 1998. Recruitment was according to random registry sampling from the geographical area of Potsdam, Germany, and surrounding municipalities. The last date of study follow-up was May 10, 2010. Statistical analysis was conducted in 2018. MAIN OUTCOMES AND MEASURES Incident CRC, colon cancer, and rectal cancer. Baseline chemerin plasma concentrations were measured by enzyme-linked immunosorbent assay. CONCLUSIONS AND RELEVANCE This study found that the association between chemerin concentration and the risk of incident CRC was linear and independent of established CRC risk factors. Further studies are warranted to evaluate chemerin as a novel immune-inflammatory agent in colorectal carcinogenesis. Y1 - 2019 U6 - https://doi.org/10.1001/jamanetworkopen.2019.0896 SN - 2574-3805 VL - 2 IS - 3 PB - American Veterinary Medical Association CY - Chicago ER - TY - JOUR A1 - Johann, Kornelia A1 - Kleinert, Maximilian A1 - Klaus, Susanne T1 - The role of GDF15 as a myomitokine JF - Cells N2 - Growth differentiation factor 15 (GDF15) is a cytokine best known for affecting systemic energy metabolism through its anorectic action. GDF15 expression and secretion from various organs and tissues is induced in different physiological and pathophysiological states, often linked to mitochondrial stress, leading to highly variable circulating GDF15 levels. In skeletal muscle and the heart, the basal expression of GDF15 is very low compared to other organs, but GDF15 expression and secretion can be induced in various stress conditions, such as intense exercise and acute myocardial infarction, respectively. GDF15 is thus considered as a myokine and cardiokine. GFRAL, the exclusive receptor for GDF15, is expressed in hindbrain neurons and activation of the GDF15-GFRAL pathway is linked to an increased sympathetic outflow and possibly an activation of the hypothalamic-pituitary-adrenal (HPA) stress axis. There is also evidence for peripheral, direct effects of GDF15 on adipose tissue lipolysis and possible autocrine cardiac effects. Metabolic and behavioral outcomes of GDF15 signaling can be beneficial or detrimental, likely depending on the magnitude and duration of the GDF15 signal. This is especially apparent for GDF15 production in muscle, which can be induced both by exercise and by muscle disease states such as sarcopenia and mitochondrial myopathy. KW - anorexia KW - appetite regulation KW - cardiokine KW - cytokine KW - exercise KW - mitochondria KW - muscle KW - myokine KW - myopathy KW - sarcopenia Y1 - 2021 U6 - https://doi.org/10.3390/cells10112990 SN - 2073-4409 VL - 10 IS - 11 PB - MDPI CY - Basel ER -