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Metabolite ratios as potential biomarkers for type 2 diabetes: a DIRECT study

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Title: Metabolite ratios as potential biomarkers for type 2 diabetes: a DIRECT study
Authors: Molnos, S
Wahl, S
Haid, M
Eekhoff, EMW
Pool, R
Floegel, A
Deelen, J
Much, D
Prehn, C
Breier, M
Draisma, HH
Van Leeuwen, N
Simonis-Bik, AMC
Jonsson, A
Willemsen, G
Bernigau, W
Wang-Sattler, R
Suhre, K
Peters, A
Thorand, B
Herder, C
Rathmann, W
Roden, M
Gieger, C
Kramer, MHH
Van Heemst, D
Pedersen, HK
Gudmundsdottir, V
Schulze, MB
Pischon, T
De Geus, EJC
Boeing, H
Boomsma, DI
Ziegler, AG
Slagboom, PE
Hummel, S
Beekman, M
Grallert, H
Brunak, S
McCarthy, MI
Gupta, R
Pearson, ER
Adamski, J
't Hart, LM
Item Type: Journal Article
Abstract: AIMS/HYPOTHESIS: Circulating metabolites have been shown to reflect metabolic changes during the development of type 2 diabetes. In this study we examined the association of metabolite levels and pairwise metabolite ratios with insulin responses after glucose, glucagon-like peptide-1 (GLP-1) and arginine stimulation. We then investigated if the identified metabolite ratios were associated with measures of OGTT-derived beta cell function and with prevalent and incident type 2 diabetes. METHODS: We measured the levels of 188 metabolites in plasma samples from 130 healthy members of twin families (from the Netherlands Twin Register) at five time points during a modified 3 h hyperglycaemic clamp with glucose, GLP-1 and arginine stimulation. We validated our results in cohorts with OGTT data (n = 340) and epidemiological case-control studies of prevalent (n = 4925) and incident (n = 4277) diabetes. The data were analysed using regression models with adjustment for potential confounders. RESULTS: There were dynamic changes in metabolite levels in response to the different secretagogues. Furthermore, several fasting pairwise metabolite ratios were associated with one or multiple clamp-derived measures of insulin secretion (all p < 9.2 × 10-7). These associations were significantly stronger compared with the individual metabolite components. One of the ratios, valine to phosphatidylcholine acyl-alkyl C32:2 (PC ae C32:2), in addition showed a directionally consistent positive association with OGTT-derived measures of insulin secretion and resistance (p ≤ 5.4 × 10-3) and prevalent type 2 diabetes (ORVal_PC ae C32:2 2.64 [β 0.97 ± 0.09], p = 1.0 × 10-27). Furthermore, Val_PC ae C32:2 predicted incident diabetes independent of established risk factors in two epidemiological cohort studies (HRVal_PC ae C32:2 1.57 [β 0.45 ± 0.06]; p = 1.3 × 10-15), leading to modest improvements in the receiver operating characteristics when added to a model containing a set of established risk factors in both cohorts (increases from 0.780 to 0.801 and from 0.862 to 0.865 respectively, when added to the model containing traditional risk factors + glucose). CONCLUSIONS/INTERPRETATION: In this study we have shown that the Val_PC ae C32:2 metabolite ratio is associated with an increased risk of type 2 diabetes and measures of insulin secretion and resistance. The observed effects were stronger than that of the individual metabolites and independent of known risk factors.
Issue Date: 25-Oct-2017
Date of Acceptance: 28-Jul-2017
URI: http://hdl.handle.net/10044/1/58119
DOI: https://dx.doi.org/10.1007/s00125-017-4436-7
ISSN: 0012-186X
Publisher: Springer Verlag
Start Page: 117
End Page: 129
Journal / Book Title: Diabetologia
Volume: 61
Issue: 1
Copyright Statement: © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: Epidemiology
Insulin secretion
Metabolomics
Prediction of diabetes
Type 2 diabetes
1103 Clinical Sciences
1114 Paediatrics And Reproductive Medicine
1117 Public Health And Health Services
Endocrinology & Metabolism
Publication Status: Published
Conference Place: Germany
Appears in Collections:Department of Medicine (up to 2019)