TY - JOUR A1 - Keller, Johannes A1 - Catala-Lehnen, Philip A1 - Huebner, Antje K. A1 - Jeschke, Anke A1 - Heckt, Timo A1 - Lueth, Anja A1 - Krause, Matthias A1 - Koehne, Till A1 - Albers, Joachim A1 - Schulze, Jochen A1 - Schilling, Sarah A1 - Haberland, Michael A1 - Denninger, Hannah A1 - Neven, Mona A1 - Hermans-Borgmeyer, Irm A1 - Streichert, Thomas A1 - Breer, Stefan A1 - Barvencik, Florian A1 - Levkau, Bodo A1 - Rathkolb, Birgit A1 - Wolf, Eckhard A1 - Calzada-Wack, Julia A1 - Neff, Frauke A1 - Gailus-Durner, Valerie A1 - Fuchs, Helmut A1 - de Angelis, Martin Hrabe A1 - Klutmann, Susanne A1 - Tsourdi, Elena A1 - Hofbauer, Lorenz C. A1 - Kleuser, Burkhard A1 - Chun, Jerold A1 - Schinke, Thorsten A1 - Amling, Michael T1 - Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts JF - Nature Communications N2 - The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P(3). Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P(3)-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts. Y1 - 2014 U6 - https://doi.org/10.1038/ncomms6215 SN - 2041-1723 VL - 5 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Weitkunat, Karolin A1 - Bishop, Christopher Allen A1 - Wittmüss, Maria A1 - Machate, Tina A1 - Schifelbein, Tina A1 - Schulze, Matthias Bernd A1 - Klaus, Susanne T1 - Effect of microbial status on hepatic odd-chain fatty acids is diet-dependent JF - Nutrients / Molecular Diversity Preservation International (MDPI) N2 - Odd-chain fatty acids (OCFA) are inversely associated with type-2-diabetes in epidemiological studies. They are considered as a biomarker for dairy intake because fermentation in ruminants yields high amounts of propionate, which is used as the primer for lipogenesis. Recently, we demonstrated endogenous OCFA synthesis from propionate in humans and mice, but how this is affected by microbial colonization is still unexplored. Here, we investigated the effect of increasing microbiota complexity on hepatic lipid metabolism and OCFA levels in different dietary settings. Germ-free (GF), gnotobiotic (SIH, simplified human microbiota) or conventional (CONV) C3H/HeOuJ-mice were fed a CHOW or high-fat diet with inulin (HFI) to induce microbial fermentation. We found that hepatic lipogenesis was increased with increasing microbiota complexity, independently of diet. In contrast, OCFA formation was affected by diet as well as microbiota. On CHOW, hepatic OCFA and intestinal gluconeogenesis decreased with increasing microbiota complexity (GF > SIH > CONV), while cecal propionate showed a negative correlation with hepatic OCFA. On HFI, OCFA levels were highest in SIH and positively correlated with cecal propionate. The propionate content in the CHOW diet was 10 times higher than that of HFI. We conclude that bacterial propionate production affects hepatic OCFA formation, unless this effect is masked by dietary propionate intake. KW - pentadecanoic acid (C15:0) KW - heptadecanoic acid (C17:0) KW - type-2-diabetes KW - fatty acid synthesis KW - acetate KW - propionate KW - probiotics KW - gut microbiota KW - prebiotics KW - inulin Y1 - 2021 U6 - https://doi.org/10.3390/nu13051546 SN - 2072-6643 VL - 13 IS - 5 PB - MDPI CY - Basel 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 - 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 - Birukov, Anna A1 - Polemiti, Elli A1 - Jaeger, Susanne A1 - Stefan, Norbert A1 - Schulze, Matthias Bernd T1 - Fetuin-A and risk of diabetes-related vascular complications BT - a prospective study JF - Cardiovascular diabetology N2 - Background Fetuin-A is a hepatokine which has the capacity to prevent vascular calcification. Moreover, it is linked to the induction of metabolic dysfunction, insulin resistance and associated with increased risk of diabetes. It has not been clarified whether fetuin-A associates with risk of vascular, specifically microvascular, complications in patients with diabetes. We aimed to investigate whether pre-diagnostic plasma fetuin-A is associated with risk of complications once diabetes develops. Methods Participants with incident type 2 diabetes and free of micro- and macrovascular disease from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (n = 587) were followed for microvascular and macrovascular complications (n = 203 and n = 60, respectively, median follow-up: 13 years). Plasma fetuin-A was measured approximately 4 years prior to diabetes diagnosis. Prospective associations between baseline fetuin-A and risk of complications were assessed with Cox regression. Results In multivariable models, fetuin-A was linearly inversely associated with incident total and microvascular complications, hazard ratio (HR, 95% CI) per standard deviation (SD) increase: 0.86 (0.74; 0.99) for total, 0.84 (0.71; 0.98) for microvascular and 0.92 (0.68; 1.24) for macrovascular complications. After additional adjustment for cardiometabolic plasma biomarkers, including triglycerides and high-density lipoprotein, the associations were slightly attenuated: 0.88 (0.75; 1.02) for total, 0.85 (0.72; 1.01) for microvascular and 0.95 (0.67; 1.34) for macrovascular complications. No interaction by sex could be observed (p > 0.10 for all endpoints). Conclusions Our data show that lower plasma fetuin-A levels measured prior to the diagnosis of diabetes may be etiologically implicated in the development of diabetes-associated microvascular disease. KW - Fetuin-A KW - biomarkers KW - epidemiology KW - Type 2 diabetes KW - vascular disease; KW - vascular calcification KW - microvascular complications Y1 - 2022 U6 - https://doi.org/10.1186/s12933-021-01439-8 SN - 1475-2840 VL - 21 IS - 1 PB - BMC CY - London ER - TY - JOUR A1 - Schulze, Susanne A1 - Merz, Sibille A1 - Thier, Anne A1 - Tallarek, Marie A1 - König, Franziska A1 - Uhlenbrock, Greta A1 - Nübling, Matthias A1 - Lincke, Hans-Joachim A1 - Rapp, Michael A. A1 - Spallek, Jacob A1 - Holmberg, Christine T1 - Psychosocial burden in nurses working in nursing homes during the Covid-19 pandemic BT - a cross-sectional study with quantitative and qualitative data JF - BMC health services research N2 - Background The Covid-19 pandemic led to increased work-related strain and psychosocial burden in nurses worldwide, resulting in high prevalences of mental health problems. Nurses in long-term care facilities seem to be especially affected by the pandemic. Nevertheless, there are few findings indicating possible positive changes for health care workers. Therefore, we investigated which psychosocial burdens and potential positive aspects nurses working in long-term care facilities experience during the Covid-19 pandemic. Methods We conducted a mixed-methods study among nurses and nursing assistants working in nursing homes in Germany. The survey contained the third German version of the Copenhagen Psychosocial Questionnaire (COPSOQ III). Using Welch's t-tests, we compared the COPSOQ results of our sample against a pre-pandemic reference group of geriatric nurses from Germany. Additionally, we conducted semi-structured interviews with geriatric nurses with a special focus on psychosocial stress, to reach a deeper understanding of their experiences on work-related changes and burdens during the pandemic. Data were analysed using thematic coding (Braun and Clarke). Results Our survey sample (n = 177) differed significantly from the pre-pandemic reference group in 14 out of 31 COPSOQ scales. Almost all of these differences indicated negative changes. Our sample scored significantly worse regarding the scales 'quantitative demands', 'hiding emotions', 'work-privacy conflicts', 'role conflicts', 'quality of leadership', 'support at work', 'recognition', 'physical demands', 'intention to leave profession', 'burnout', 'presenteeism' and 'inability to relax'. The interviews (n = 15) revealed six main themes related to nurses' psychosocial stress: 'overall working conditions', 'concern for residents', 'management of relatives', 'inability to provide terminal care', 'tensions between being infected and infecting others' and 'technicisation of care'. 'Enhanced community cohesion' (interviews), 'meaning of work' and 'quantity of social relations' (COPSOQ III) were identified as positive effects of the pandemic. Conclusions Results clearly illustrate an aggravation of geriatric nurses' situation and psychosocial burden and only few positive changes due to the Covid-19 pandemic. Pre-existing hardships seem to have further deteriorated and new stressors added to nurses' strain. The perceived erosion of care, due to an overemphasis of the technical in relation to the social and emotional dimensions of care, seems to be especially burdensome to geriatric nurses. KW - COPSOQ KW - Nurses KW - Nursing home KW - Psychosocial burden KW - Mixed-methods study KW - Covid-19 Y1 - 2022 U6 - https://doi.org/10.1186/s12913-022-08333-3 SN - 1472-6963 VL - 22 IS - 1 PB - BMC CY - London ER - TY - JOUR A1 - Tschorn, Mira A1 - Schulze, Susanne A1 - Förstner, Bernd Rainer A1 - Holmberg, Christine A1 - Spallek, Jacob A1 - Heinz, Andreas A1 - Rapp, Michael A. T1 - Predictors and prevalence of hazardous alcohol use in middle-late to late adulthood in Europe JF - Aging & mental health N2 - Objectives: Even low to moderate levels of alcohol consumption can have detrimental health consequences, especially in older adults (OA). Although many studies report an increase in the proportion of drinkers among OA, there are regional variations. Therefore, we examined alcohol consumption and the prevalence of hazardous alcohol use (HAU) among men and women aged 50+ years in four European regions and investigated predictors of HAU. Methods: We analyzed data of N = 35,042 participants of the European SHARE study. We investigated differences in alcohol consumption (units last week) according to gender, age and EU-region using ANOVAs. Furthermore, logistic regression models were used to examine the effect of income, education, marital status, history of a low-quality parent-child relationship and smoking on HAU, also stratified for gender and EU-region. HAU was operationalized as binge drinking or risky drinking (<12.5 units of 10 ml alcohol/week). Results: Overall, past week alcohol consumption was 5.0 units (+/- 7.8), prevalence of HAU was 25.4% within our sample of European adults aged 50+ years. Male gender, younger age and living in Western Europe were linked to both higher alcohol consumption and higher risks of HAU. Income, education, smoking, a low-quality parent-child relationship, living in Northern and especially Eastern Europe were positively associated with HAU. Stratified analyses revealed differences by region and gender. Conclusions: HAU was highly prevalent within this European sample of OA. Alcohol consumption and determinants of HAU differed between EU-regions, hinting to a necessity of risk-stratified population-level strategies to prevent HAU and subsequent alcohol use disorders. KW - Hazardous alcohol use KW - older adults KW - middle-aged adults KW - Europe KW - alcohol KW - drug and alcohol abuse KW - cross-national KW - international studies KW - environmental factors KW - housing KW - rural-urban factors KW - epidemiology (mental health) Y1 - 2022 U6 - https://doi.org/10.1080/13607863.2022.2076208 SN - 1360-7863 SN - 1364-6915 VL - 27 IS - 5 SP - 1001 EP - 1010 PB - Routledge, Taylor & Francis Group CY - Abingdon ER - TY - JOUR A1 - Polemiti, Elli A1 - Baudry, Julia A1 - Kuxhaus, Olga A1 - Jäger, Susanne A1 - Bergmann, Manuela A1 - Weikert, Cornelia A1 - Schulze, Matthias Bernd T1 - BMI and BMI change following incident type 2 diabetes and risk of microvascular and macrovascular complications BT - the EPIC-Potsdam study JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) N2 - Aims/hypothesis Studies suggest decreased mortality risk among people who are overweight or obese compared with individuals with normal weight in type 2 diabetes (obesity paradox). However, the relationship between body weight or weight change and microvascular vs macrovascular complications of type 2 diabetes remains unresolved. We investigated the association between BMI and BMI change with long-term risk of microvascular and macrovascular complications in type 2 diabetes in a prospective cohort study. Methods We studied participants with incident type 2 diabetes from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, who were free of cancer, cardiovascular disease and microvascular disease at diagnosis (n = 1083). Pre-diagnosis BMI and relative annual change between pre- and post-diagnosis BMI were evaluated in multivariable-adjusted Cox models. Results There were 85 macrovascular (myocardial infarction and stroke) and 347 microvascular events (kidney disease, neuropathy and retinopathy) over a median follow-up of 10.8 years. Median pre-diagnosis BMI was 29.9 kg/m(2) (IQR 27.4-33.2), and the median relative annual BMI change was -0.4% (IQR -2.1 to 0.9). Higher pre-diagnosis BMI was positively associated with total microvascular complications (multivariable-adjusted HR per 5 kg/m(2) [95% CI]: 1.21 [1.07, 1.36], kidney disease 1.39 [1.21, 1.60] and neuropathy 1.12 [0.96, 1.31]) but not with macrovascular complications (HR 1.05 [95% CI 0.81, 1.36]). Analyses according to BMI categories corroborated these findings. Effect modification was not evident by sex, smoking status or age groups. In analyses according to BMI change categories, BMI loss of more than 1% indicated a decreased risk of total microvascular complications (HR 0.62 [95% CI 0.47, 0.80]), kidney disease (HR 0.57 [95% CI 0.40, 0.81]) and neuropathy (HR 0.73 [95% CI 0.52, 1.03]), compared with participants with a stable BMI; no clear association was observed for macrovascular complications (HR 1.04 [95% CI 0.62, 1.74]). The associations between BMI gain compared with stable BMI and diabetes-related vascular complications were less apparent. Associations were consistent across strata of sex, age, pre-diagnosis BMI or medication but appeared to be stronger among never-smokers compared with current or former smokers. Conclusions/interpretation Among people with incident type 2 diabetes, pre-diagnosis BMI was positively associated with microvascular complications, while a reduced risk was observed with weight loss when compared with stable weight. The relationships with macrovascular disease were less clear. KW - BMI KW - CVD KW - Diabetes-related vascular complications KW - Nephropathy KW - Neuropathy KW - T2D KW - Weight change Y1 - 2021 U6 - https://doi.org/10.1007/s00125-020-05362-7 SN - 0012-186X SN - 1432-0428 VL - 64 IS - 4 SP - 814 EP - 825 PB - Springer CY - Berlin ; Heidelberg ER - TY - JOUR A1 - Block, Andrea A1 - Schulze, Susanne A1 - Deeken, Friederike A1 - Häusler, Andreas A1 - Rezo, Anna A1 - Rapp, Michael A. A1 - Wippert, Pia-Maria T1 - Effects of inflammatory markers and biographical stress on treatment response in depression JF - Psychoneuroendocrinology : an international journal ; the official journal of the International Society of Psychoneuroendocrinology N2 - Background Recent research emphasized the role of inflammatory processes in the pathophysiology of depression. Theories hypothesizes that life events (LE) can affect the immune system and trigger depressive symptoms. LE are also considered as one of the best predictors for the onset and course of depressive disorders. Methods Observational study across three treatment settings: n=208 depressive patients (75.5%f, M 46.6 y) were examined on depression (BDI-II), life events (ILE) and inflammatory markers (IL-6, CRP, fibrinogen, ICAM-1, TNF-alpha, E-selectin) at baseline (t0), 5-week(t1) and 5-month(t2) follow-up. Effects and interactions were analyzed with regression models. Results LE were associated with depressive symptoms at t0 (beta=.209; p=.002) and both follow-ups. Except for CRP, which was linked to depression symptoms at t2 (betai=-.190; p=.032), there were no effects of inflammatory markers on depressive symptoms. At t1, an interaction between CRP and LE in total (beta=-.249; p=.041) was found as well as for LE in the past five years (beta=-.122; p=.027). Similar interactions were found between cumulative LE and ICAM-1 (beta=-.197; p=.003) and IL-6 (beta=-.425; p=.001). Conclusion The cumulative burden of LE effects symptoms and treatment outcome in depressive patients. There is some evidence that inflammatory marker may have long-term effects on treatment outcome as they seem to weaken the determining relation between LE and depression. Y1 - 2021 U6 - https://doi.org/10.1016/j.psyneuen.2021.105535 SN - 0306-4530 SN - 1873-3360 VL - 131 IS - Supplement SP - S24 EP - S24 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Wittenbecher, Clemens A1 - Cuadrat, Rafael A1 - Johnston, Luke A1 - Eichelmann, Fabian A1 - Jäger, Susanne A1 - Kuxhaus, Olga A1 - Prada, Marcela A1 - Del Greco, Fabiola M. A1 - Hicks, Andrew A. A1 - Hoffman, Per A1 - Krumsiek, Jan A1 - Hu, Frank B. A1 - Schulze, Matthias B. T1 - Dihydroceramide- and ceramide-profiling provides insights into human cardiometabolic disease etiology JF - Nature communications N2 - Metabolic alterations precede cardiometabolic disease onset. Here we present ceramide- and dihydroceramide-profiling data from a nested case-cohort (type 2 diabetes [T2D, n = 775]; cardiovascular disease [CVD, n = 551]; random subcohort [n = 1137]) in the prospective EPIC-Potsdam study. We apply the novel NetCoupler-algorithm to link a data-driven (dihydro)ceramide network to T2D and CVD risk. Controlling for confounding by other (dihydro)ceramides, ceramides C18:0 and C22:0 and dihydroceramides C20:0 and C22:2 are associated with higher and ceramide C20:0 and dihydroceramide C26:1 with lower T2D risk. Ceramide C16:0 and dihydroceramide C22:2 are associated with higher CVD risk. Genome-wide association studies and Mendelian randomization analyses support a role of ceramide C22:0 in T2D etiology. Our results also suggest that (dh)ceramides partly mediate the putative adverse effect of high red meat consumption and benefits of coffee consumption on T2D risk. Thus, (dihydro)ceramides may play a critical role in linking genetic predisposition and dietary habits to cardiometabolic disease risk. Y1 - 2022 U6 - https://doi.org/10.1038/s41467-022-28496-1 SN - 2041-1723 VL - 13 PB - Nature Research CY - Berlin ER -