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Glucose challenge metabolomics implicates medium-chain acylcarnitines in insulin resistance
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.ORCID iD: 0000-0001-5752-4196
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 8691Article in journal (Refereed) Published
Abstract [en]

Insulin resistance (IR) predisposes to type 2 diabetes and cardiovascular disease but its causes are incompletely understood. Metabolic challenges like the oral glucose tolerance test (OGTT) can reveal pathogenic mechanisms. We aimed to discover associations of IR with metabolite trajectories during OGTT. In 470 non-diabetic men (age 70.6 ± 0.6 years), plasma samples obtained at 0, 30 and 120 minutes during an OGTT were analyzed by untargeted liquid chromatography-mass spectrometry metabolomics. IR was assessed with the hyperinsulinemic-euglycemic clamp method. We applied age-adjusted linear regression to identify metabolites whose concentration change was related to IR. Nine trajectories, including monounsaturated fatty acids, lysophosphatidylethanolamines and a bile acid, were significantly associated with IR, with the strongest associations observed for medium-chain acylcarnitines C10 and C12, and no associations with L-carnitine or C2-, C8-, C14- or C16-carnitine. Concentrations of C10- and C12-carnitine decreased during OGTT with a blunted decline in participants with worse insulin resistance. Associations persisted after adjustment for obesity, fasting insulin and fasting glucose. In mouse 3T3-L1 adipocytes exposed to different acylcarnitines, we observed blunted insulin-stimulated glucose uptake after treatment with C10- or C12-carnitine. In conclusion, our results identify medium-chain acylcarnitines as possible contributors to IR.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018. Vol. 8, no 1, article id 8691
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Endocrinology and Diabetes
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URN: urn:nbn:se:oru:diva-74362DOI: 10.1038/s41598-018-26701-0ISI: 000434252600004PubMedID: 29875472Scopus ID: 2-s2.0-85048233782OAI: oai:DiVA.org:oru-74362DiVA, id: diva2:1317351
Funder
Knut and Alice Wallenberg Foundation, 2013.0126Swedish Diabetes Association, 2013–024Swedish Research Council, 2015-03477Swedish Heart Lung Foundation, 20140422NIH (National Institute of Health), 1R01DK106236-01A1Available from: 2019-05-22 Created: 2019-05-22 Last updated: 2019-06-18Bibliographically approved

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