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Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.ORCID iD: 0000-0003-2247-8454
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
Massachusetts General Hospital, Harvard Medical School and Broad Institute, Boston, Massachusetts.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Impaired insulin sensitivity (IS) is a major risk factor for cardiovascular disease and type 2 diabetes. Metabolomic profiling during an oral glucose tolerance test (OGTT) can reveal early pathogenic alterations in healthy individuals. Our aim was to identify IS biomarkers and gain new pathophysiologic insights by applying untargeted metabolomics to repeated OGTT plasma samples in association with a hyperinsulinemic-euglycemic clamp assessment. We studied 192 metabolites identified by non-targeted liquid chromatography/mass spectrometry in plasma samples taken at 0, 30, and 120 min during an OGTT in 470 non-diabetic 71-yr-old men. Insulin sensitivity was associated with 35 metabolites at one or more time points in multivariable-adjusted linear regression. The trajectories of nine metabolites during the OGTT were related to IS, six of which (oleic and palmitoleic acid, decanoyl- and dodecanoylcarnitine, deoxycholate-glycine and hexose) showed no associations with IS in the baseline fasting state. The strongest effects were detected for medium-chain acylcarnitines, which increased between 30-120 min in insulin-resistant individuals compared to those with normal IS. In this large community sample, we identified novel associations between clamp-measured IS and metabolite profiles that became apparent only after an oral glucose challenge. Associations of differential medium-chain acylcarnitine and monounsaturated fatty acid trajectories with IS provide new insights into the pathogenesis of insulin resistance.

National Category
Cell and Molecular Biology Physiology Endocrinology and Diabetes Other Medical Biotechnology
Identifiers
URN: urn:nbn:se:uu:diva-316886OAI: oai:DiVA.org:uu-316886DiVA: diva2:1079251
Note

Tove Fall and Erik Ingelsson has contributed equally to this work.

Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2017-05-22Bibliographically 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. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1316
Keyword
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)
Opponent
Supervisors
Available from: 2017-04-28 Created: 2017-03-14 Last updated: 2017-05-05

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Nowak, ChristophSundstrom, JohanSalihovic, SamiraBerne, ChristianGiedraitis, VilmantasÄrnlöv, JohanLind, LarsFall, ToveIngelsson, Erik

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