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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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Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Stearoyl-coa Desaturase; Homeostasis Model Assessment; Genome-wide Association; Cardiovascular-disease; Diabetes-mellitus; Gene-expression; Obese Mice; Rat-liver; Dysfunction; Heart
Sprache
Veröffentlichungsjahr 2016
HGF-Berichtsjahr 2016
ISSN (print) / ISBN 1553-7390
e-ISSN 1553-7404
Zeitschrift PLoS Genetics
Quellenangaben Band: 12, Heft: 10, Seiten: , Artikelnummer: e1006379 Supplement: ,
Verlag Public Library of Science (PLoS)
Verlagsort San Francisco
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology (EPI)
Institute of Genetic Epidemiology (IGE)
Institute of Human Genetics (IHG)
POF Topic(s) 30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
90000 - German Center for Diabetes Research
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504091-003
G-504091-004
G-504100-001
G-500700-001
G-501900-402
G-504000-001
DOI 10.1371/journal.pgen.1006379
WOS ID WOS:000386683300041
Scopus ID 84994222203
Erfassungsdatum 2016-11-07
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