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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.* ; Ärnlöv, J.* ; Berne, C.* ; Gieger, C. ; Ripatti, S* ; Lind, L.* ; Pedersen, N.L.* ; Sundström, J.* ; Ingelsson, E.* ; Fall, T.*

Effect of insulin resistance on monounsaturated fatty acid levels: A multi-cohort non-targeted metabolomics and mendelian randomization study.

PLoS Genet. 12:e1006379 (2016)

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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 β-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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Stearoyl-coa Desaturase; Homeostasis Model Assessment; Genome-wide Association; Cardiovascular-disease; Diabetes-mellitus; Gene-expression; Obese Mice; Rat-liver; Dysfunction; Heart

ISSN (print) / ISBN 1553-7390

e-ISSN 1553-7404

Journal PLoS Genetics

Quellenangaben Volume: 12, Issue: 10, Article Number: e1006379

Publisher Public Library of Science (PLoS)

Publishing Place San Francisco

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)
Institute of Human Genetics (IHG)