Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels : A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study

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dc.contributor.author Nowak, Christoph
dc.contributor.author Salihovic, Samira
dc.contributor.author Ganna, Andrea
dc.contributor.author Brandmaier, Stefan
dc.contributor.author Tukiainen, Taru
dc.contributor.author Broeckling, Corey D.
dc.contributor.author Magnusson, Patrik K.
dc.contributor.author Prenni, Jessica E.
dc.contributor.author Wang-Sattler, Rui
dc.contributor.author Peters, Annette
dc.contributor.author Strauch, Konstantin
dc.contributor.author Meitinger, Thomas
dc.contributor.author Giedraitis, Vilmantas
dc.contributor.author Arnlov, Johan
dc.contributor.author Berne, Christian
dc.contributor.author Gieger, Christian
dc.contributor.author Ripatti, Samuli
dc.contributor.author Lind, Lars
dc.contributor.author Pedersen, Nancy L.
dc.contributor.author Sundstrom, Johan
dc.contributor.author Ingelsson, Erik
dc.contributor.author Fall, Tove
dc.date.accessioned 2016-12-08T07:28:02Z
dc.date.available 2016-12-08T07:28:02Z
dc.date.issued 2016-10
dc.identifier.citation Nowak , C , Salihovic , S , Ganna , A , Brandmaier , S , Tukiainen , T , Broeckling , C D , Magnusson , P K , Prenni , J E , Wang-Sattler , R , Peters , A , Strauch , K , Meitinger , T , Giedraitis , V , Arnlov , J , Berne , C , Gieger , C , Ripatti , S , Lind , L , Pedersen , N L , Sundstrom , J , Ingelsson , E & Fall , T 2016 , ' Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels : A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study ' , PLoS Genetics , vol. 12 , no. 10 , 1006379 . https://doi.org/10.1371/journal.pgen.1006379
dc.identifier.other PURE: 72609838
dc.identifier.other PURE UUID: e442e2bd-d26d-4c9d-90d6-caeea34bf78e
dc.identifier.other WOS: 000386683300041
dc.identifier.other Scopus: 84994222203
dc.identifier.uri http://hdl.handle.net/10138/170069
dc.description.abstract Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or beta-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development. en
dc.format.extent 19
dc.language.iso eng
dc.relation.ispartof PLoS Genetics
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject OBESE MICE
dc.subject RAT-LIVER
dc.subject DYSFUNCTION
dc.subject HEART
dc.subject 3142 Public health care science, environmental and occupational health
dc.subject 3111 Biomedicine
dc.title Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels : A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study en
dc.type Article
dc.contributor.organization Institute for Molecular Medicine Finland
dc.contributor.organization Clinicum
dc.contributor.organization Samuli Olli Ripatti / Principal Investigator
dc.contributor.organization Department of Public Health
dc.contributor.organization Biostatistics Helsinki
dc.contributor.organization Complex Disease Genetics
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1371/journal.pgen.1006379
dc.relation.issn 1553-7404
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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