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

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Item Type:Article
Title:Metabolite ratios as potential biomarkers for type 2 diabetes: a DIRECT study
Creators Name:Molnos, S. and Wahl, S. and Haid, M. and Eekhoff, E.M.W. and Pool, R. and Floegel, A. and Deelen, J. and Much, D. and Prehn, C. and Breier, M. and Draisma, H.H. and van Leeuwen, N. and Simonis-Bik, A.M.C. and Jonsson, A. and Willemsen, G. and Bernigau, W. and Wang-Sattler, R. and Suhre, K. and Peters, A. and Thorand, B. and Herder, C. and Rathmann, W. and Roden, M. and Gieger, C. and Kramer, M.H.H. and van Heemst, D. and Pedersen, H.K. and Gudmundsdottir, V. and Schulze, M.B. and Pischon, T. and de Geus, E.J.C. and Boeing, H. and Boomsma, D.I. and Ziegler, A.G. and Slagboom, P.E. and Hummel, S. and Beekman, M. and Grallert, H. and Brunak, S. and McCarthy, M.I. and Gupta, R. and Pearson, E.R. and Adamski, J. and 't Hart, L.M.
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 x 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 x 10-3) and prevalent type 2 diabetes (ORVal_PC ae C32:2 2.64 [beta 0.97 +/- 0.09], p = 1.0 x 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 [beta 0.45 +/- 0.06]; p = 1.3 x 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.
Keywords:Epidemiology, Insulin Secretion, Metabolomics, Prediction of Diabetes, Type 2 Diabetes
Page Range:117-129
Date:January 2018
Official Publication:https://doi.org/10.1007/s00125-017-4436-7
PubMed:View item in PubMed

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