TY - THES A1 - Jäger, Susanne T1 - Genetic variants and metabolic pathways of type 2 diabetes within the EPIC-Potsdam study Y1 - 2016 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 - 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 - 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 -