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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.

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Cell and Molecular Biology Physiology Endocrinology and Diabetes Other Medical Biotechnology
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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: 2017-03-14Bibliographically approved
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The full text will be freely available from 2017-05-22 03:08
Available from 2017-05-22 03:08

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