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Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA.;Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden..
Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany..
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2016 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 10, article id e1006379Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 12, no 10, article id e1006379
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-310027DOI: 10.1371/journal.pgen.1006379ISI: 000386683300041PubMedID: 27768686OAI: oai:DiVA.org:uu-310027DiVA, id: diva2:1055282
Funder
Knut and Alice Wallenberg Foundation, 2015.0327Swedish Diabetes Association, DIA 2013-024Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologySwedish Heart Lung Foundation, 20120197 20150429 20070481EU, European Research Council, 33595 HEALTH-2009-2.2.1-3/242114 HEALTH-2013-2.4.2-1/602936Swedish Research Council, 2012-1397 2015-03477 M-2005-1112 2016-00250The Karolinska Institutet's Research FoundationNIH (National Institute of Health), DK U01-066134Swedish Foundation for Strategic Research Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2018-01-13Bibliographically approved
In thesis
1. Insulin Resistance: Causes, biomarkers and consequences
Open this publication in new window or tab >>Insulin Resistance: Causes, biomarkers and consequences
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The worldwide increasing number of persons affected by largely preventable diseases like diabetes demands better prevention and treatment. Insulin is required for effective utilisation of circulating nutrients. Impaired responsiveness to insulin (insulin resistance, IR) is a hallmark of type 2 diabetes and independently raises the risk of heart attack and stroke. The pathophysiology of IR is incompletely understood. High-throughput measurement of large numbers of circulating biomarkers may provide new insights beyond established risk factors.

The aims of this thesis were to (i) use proteomics, metabolomics and genomics methods in large community samples to identify biomarkers of IR; (ii) assess biomarkers for risk prediction and insights into aetiology and consequences of IR; and (iii) use Mendelian randomisation analysis to assess causality.

In Study I, analysis of 80 circulating proteins in 70-to-77-year-old Swedes identified cathepsin D as a biomarker for IR and highlighted a tentative causal effect of IR on raised plasma tissue plasminogen activator levels. In Study II, nontargeted fasting plasma metabolomics was used to discover 52 metabolites associated with glycaemic traits in non-diabetic 70-year-old men. Replication in independent samples of several thousand persons provided evidence for a causal effect of IR on reduced plasma oleic acid and palmitoleic acid levels. In Study III, nontargeted metabolomics in plasma samples obtained at three time points during an oral glucose challenge in 70-year-old men identified associations between a physiologic measure of IR and concentration changes in medium-chain acylcarnitines, monounsaturated fatty acids, bile acids and lysophosphatidylethanolamines. Study IV provided evidence in two large longitudinal cohorts for causal effects of type 2 diabetes and impaired insulin secretion on raised coronary artery disease risk.

In conclusion, the Studies in this thesis provide new insights into the pathophysiology and adverse health consequences of IR and illustrate the value of combining traditional epidemiologic designs with recent molecular techniques and bioinformatics methods. The results provide limited evidence for the role of circulating proteins and small molecules in IR and require replication in separate studies and validation in experimental designs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 54
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1316
Keywords
insulin resistance, diabetes, insulin secretion, cardiovascular, mendelian randomization, proteomics, metabolomics, genomics, molecular epidemiology, complex disease, risk prediction, coronary heart disease, stroke, hyperglycemia
National Category
Basic Medicine Clinical Medicine Cell and Molecular Biology Endocrinology and Diabetes Public Health, Global Health, Social Medicine and Epidemiology Physiology
Identifiers
urn:nbn:se:uu:diva-316891 (URN)978-91-554-9856-6 (ISBN)
Public defence
2017-05-22, Room E10:1309 (BMC Navet), Biomedicinskt Centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2017-04-28 Created: 2017-03-14 Last updated: 2018-01-13

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Nowak, ChristophSalihovic, SamiraGiedraitis, VilmantasÄrnlöv, JohanBerne, ChristianLind, LarsSundström, JohanIngelsson, ErikFall, Tove

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