Rolle der alimentären und genetischen Modulation des Fettsäurestatus für das Erkrankungsrisiko für Typ 2 Diabetes mellitus
Final Report Abstract
The role of dietary fat in type 2 diabetes has been of interest for many years. Dietary fatty acids are, at least partly, reflected by the fatty acid profile of various biological media. In addition, fatty acid biomarkers also reflect endogenous fatty acid metabolism, thus providing a more proximal and integrated measure of exposure. The project aimed to evaluate the role of fatty acids in the pathogenesis of type 2 diabetes. We have investigated the fatty acid profiles in relation to risk of type 2 diabetes in the EPIC-Potsdam study, a prospective cohort with about 27500 participants. We used a case-cohort consisting of 2500 randomly selected participants and more than 800 incident cases identified during 7 years of follow-up. Blood collected at baseline was used for determination of biochemical markers as well as for genotyping. The proportions of a broad range of individual fatty acids were determined in erythrocyte membranes. We observed a strong association of the fatty acid profile in with diabetes risk. Most notably, palmitoleic acid and γ-linolenic acid and FA ratios reflecting stearoyl CoA desaturase (SCD) and Δ-6 desaturase activity were directly related to risk of diabetes, while linoleic acid and the fatty acid ratio reflecting Δ-5 desaturase activity were inversely associated with risk. Δ-5 desaturase and Δ-6 desaturase regulate the proportions of long-chain polyunsaturated fatty acids in body tissues, and both seem to be regulated inversely resulting in accumulation of γlinolenic acid and dihomo-γ-linolenic acid in body tissues. In the random subpopulation of the EPIC-Potsdam study (n=2500), a higher proportion of linoleic acid in erythrocyte membranes was related to lower CRP and higher adiponectin, whereas a higher proportion of γ-linolenic acid was related to higher CRP and lower adiponectin. These associations mostly did neither strongly nor significantly vary by PPARG genotype. We observed strong positive associations of estimated Δ-6 desaturase and SCD activity with triglyceride concentrations, while estimated Δ-5 desaturase activity showed a strong inverse association with triglycerides. Eicosapentaenoic acid, which is a high-affinity ligand of PPARG, was inversely associated with triglycerides in the PPAR wildtype carriers (Pro12Pro genotype), but not in the Ala12 carriers. Genetic determinants of blood polyunsaturated fatty acid concentrations have received growing interest within the last few years. We observed an association of genetic variation in the FADS1-FADS2 gene cluster (as reflected by rs174546) with the n-6 polyunsaturated fatty acid composition indicating altered Δ-5 desaturase and Δ-6 desaturase activity. Carriers of the minor T allele of rs174546 had significantly higher proportions of linoleic acid and dihomo-γ-linolenic acid, lower proportions of γ-linolenic acid and arachidonic acid, and lower estimated activities of Δ-5 desaturase and Δ-6 desaturase compared to carriers of the major C allele. We used rs174546 to further investigate the relation of Δ-5 and Δ-6 desaturase to diabetes risk by applying a Mendelian randomization approach. Mendelian randomization uses genetic variants as proxies for modifiable exposures. After adjustment for the estimated activity of Δ-5 and Δ-6 desaturase, our Mendelian randomization analyses indicated that the genetically determined low Δ-5 desaturase activity tended to predict higher diabetes risk, whereas a low Δ-6 desaturase activity predicted lower risk and, thus, corroborated results from the analyses on estimated Δ-5 and Δ-6 desaturase activity.
Publications
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“Genetic variation of the FADS1-FADS2-gene-cluster and n-6 polyunsaturated fatty acid composition of erythrocyte membranes in the EPIC-Potsdam Study”. Br J Nutr 2010; 104: 1748-1759
Zietemann V., Kröger J., Enzenbach C., Jansen E., Fritsche A., Weikert C., Boeing H., Schulze M.B.
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“Erythrocyte membrane phospholipid fatty acids, desaturase activities, and dietary fatty acids in relation to the risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study”. Am J Clin Nutr 2011; 93: 127-142
Kröger J., Zietemann V., Enzenbach C., Weikert C., Jansen E., Joost H.G., Boeing H., Schulze M.B.
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“Erythrocyte membrane phospholipid polyunsaturated fatty acids are related to plasma C-reactive protein and adiponectin in middle-aged German women and men”. Eur J Nutr. 2011; 50: 625-636
Enzenbach C., Kröger J., Zietemann V., Jansen E.H., Fritsche A., Döring F., Boeing H., Schulze M.B.
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“Recent insights into the relation of Δ5 desaturase and Δ6 desaturase activity to the development of type 2 diabetes”. Curr Opin Lipidol. 2012; 23: 4-10
Kröger J., Schulze M.B.
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“Associated factors of estimated desaturase activity in the EPIC-Potsdam study”. Nutr Metab Cardiovasc Dis
Schiller K., Jacobs S., Jansen E., Weikert C., di Giuseppe R., Boeing H., Schulze M.B., Kröger J.
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“Omega-3 and omega-6 fatty acids and type 2 diabetes”. Curr Diab Rep. 2013; 13: 279-88
Jeppesen C., Schiller K., Schulze M.B.
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“Association between erythrocyte membrane fatty acids and biomarkers of dyslipidemia in the EPIC-Potsdam study”. Eur J Clin Nutr volume 68, pages 517–525 (2014)
Jacobs S., Schiller K., Jansen E.H., Fritsche A., Weikert C., di Giuseppe R., Boeing H., Schulze M.B., Kröger J.
