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Molnos, S. ; Wahl, S. ; Haid, M. ; Eekhoff, E.M.W.* ; Pool, R.* ; Floegel, A.* ; Deelen, J.* ; Much, D. ; Prehn, C. ; Breier, M. ; Draisma, H.H.* ; van Leeuwen, N.* ; Simonis-Bik, A.M.C.* ; Jonsson, A.* ; Willemsen, G.* ; Bernigau, W.* ; Wang-Sattler, R. ; Suhre, K. ; Peters, A. ; Thorand, B. ; Herder, C.* ; Rathmann, W.* ; Roden, M.* ; Gieger, C. ; Kramer, M.H.H.* ; van Heemst, D.* ; Pedersen, H.K.* ; Gudmundsdottir, V.* ; Schulze, M.B.* ; Pischon, T.* ; de Geus, E.J.C.* ; Boeing, H.* ; Boomsma, D.I.* ; Ziegler, A.-G. ; Slagboom, P.E.* ; Hummel, S. ; Beekman, M.* ; Grallert, H. ; Brunak, S.* ; McCarthy, M.I.* ; Gupta, R.* ; Pearson, E.R.* ; Adamski, J. ; 't Hart, L.M.*

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

Diabetologia 61, 117-129 (2017)
Verlagsversion DOI
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Epidemiology ; Insulin Secretion ; Metabolomics ; Prediction Of Diabetes ; Type 2 Diabetes; Aromatic-amino-acids; Insulin-resistance; Branched-chain; Nonagenarian Siblings; Genetic-variation; Leiden Longevity; Young-adults; Metabolomics; Risk; Population
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Zeitschrift Diabetologia
Quellenangaben Band: 61, Heft: 1, Seiten: 117-129 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Berlin ; Heidelberg [u.a.]
Begutachtungsstatus Peer reviewed