title: Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study.
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 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.
authors: Department of Medical Sciences and Science for Life Laboratory, Molecular Epidemiology Unit, Uppsala University, Uppsala, Sweden.
authors: Christoph
authors: http://orcid.org/0000-0003-2071-5866
authors: C
authors: Nowak
authors: Department of Medical Sciences and Science for Life Laboratory, Molecular Epidemiology Unit, Uppsala University, Uppsala, Sweden.
authors: Samira
authors: http://orcid.org/0000-0001-5752-4196
authors: S
authors: Salihovic
authors: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States of America.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA,United States of America.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States of America.|Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet, Stockholm, Sweden.
authors: Andrea
authors: A
authors: Ganna
authors: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, München-Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, München-Neuherberg, Germany.
authors: Stefan
authors: S
authors: Brandmaier
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: Taru
authors: http://orcid.org/0000-0002-5404-8398
authors: T
authors: Tukiainen
authors: Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Corey D
authors: CD
authors: Broeckling
authors: Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet, Stockholm, Sweden.
authors: Patrik K
authors: http://orcid.org/0000-0002-7315-7899
authors: PK
authors: Magnusson
authors: Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Jessica E
authors: JE
authors: Prenni
authors: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, München-Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, München-Neuherberg, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors: Rui
authors: R
authors: Wang-Sattler
authors: Institute of Epidemiology II, Helmholtz Zentrum München, München-Neuherberg, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors: Annette
authors: A
authors: Peters
authors: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Konstantin
authors: K
authors: Strauch
authors: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors: Thomas
authors: T
authors: Meitinger
authors: Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
authors: Vilmantas
authors: V
authors: Giedraitis
authors: School of Health and Social Studies, Dalarna University, Falun, Sweden.|Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
authors: Johan
authors: J
authors: Ärnlöv
authors: Department of Medical Sciences, Clinical Diabetology and Metabolism, Uppsala University, Uppsala, Sweden.
authors: Christian
authors: C
authors: Berne
authors: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, München-Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, München-Neuherberg, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors: Christian
authors: C
authors: Gieger
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors: Samuli
authors: S
authors: Ripatti
authors: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
authors: Lars
authors: L
authors: Lind
authors: Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet, Stockholm, Sweden.
authors: Nancy L
authors: http://orcid.org/0000-0001-8057-3543
authors: NL
authors: Pedersen
authors: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
authors: Johan
authors: J
authors: Sundström
authors: Department of Medical Sciences and Science for Life Laboratory, Molecular Epidemiology Unit, Uppsala University, Uppsala, Sweden.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States of America.
authors: Erik
authors: E
authors: Ingelsson
authors: Department of Medical Sciences and Science for Life Laboratory, Molecular Epidemiology Unit, Uppsala University, Uppsala, Sweden.
authors: Tove
authors: http://orcid.org/0000-0003-2071-5866
authors: T
authors: Fall
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001647:Bile Acids and Salts / Q000378:metabolism; D002110:Caffeine / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D020404:Glycerophospholipids / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D055432:Metabolomics; D008875:Middle Aged; D014443:Tyrosine / Q000097:blood
chemical_list: D001647:Bile Acids and Salts; D005229:Fatty Acids, Monounsaturated; D020404:Glycerophospholipids; D007328:Insulin; D002110:Caffeine; D014443:Tyrosine; D005947:Glucose