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| Item Type: | Article |
|---|---|
| Title: | Metabolite ratios as potential biomarkers for type 2 diabetes: a DIRECT study |
| Creators: |
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.  ORCID: https://orcid.org/0000-0003-1568-767X, 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. 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 |
| Source: | Diabetologia |
| ISSN: | 0012-186X |
| Publisher: | Springer |
| Volume: | 61 |
| Number: | 1 |
| 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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