TY - JOUR

T1 - Metabolite ratios as potential biomarkers for type 2 diabetes

T2 - a DIRECT study

AU - Molnos, Sophie

AU - Wahl, Simone

AU - Haid, Mark

AU - Eekhoff, E Marelise W

AU - Pool, René

AU - Floegel, Anna

AU - Deelen, Joris

AU - Much, Daniela

AU - Prehn, Cornelia

AU - Breier, Michaela

AU - Draisma, Harmen H

AU - van Leeuwen, Nienke

AU - Simonis-Bik, Annemarie M C

AU - Jonsson, Anna

AU - Willemsen, Gonneke

AU - Bernigau, Wolfgang

AU - Wang-Sattler, Rui

AU - Suhre, Karsten

AU - Peters, Annette

AU - Thorand, Barbara

AU - Herder, Christian

AU - Rathmann, Wolfgang

AU - Roden, Michael

AU - Gieger, Christian

AU - Kramer, Mark H H

AU - van Heemst, Diana

AU - Pedersen, Helle K.

AU - Gudmundsdottir, Valborg

AU - Schulze, Matthias B

AU - Pischon, Tobias

AU - de Geus, Eco J C

AU - Boeing, Heiner

AU - Boomsma, Dorret I

AU - Ziegler, Anette G

AU - Slagboom, P Eline

AU - Hummel, Sandra

AU - Beekman, Marian

AU - Grallert, Harald

AU - Brunak, Søren

AU - McCarthy, Mark I

AU - Gupta, Ramneek

AU - Pearson, Ewan R

AU - Adamski, Jerzy

AU - 't Hart, Leen M

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1007/s00125-017-4436-7

DO - 10.1007/s00125-017-4436-7

M3 - Journal article

C2 - 28936587

VL - 61

SP - 117

EP - 129

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 1

ER -