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Novel biomarkers for pre-diabetes identified by metabolomics.

Wang-Sattler R, Yu Z, Herder C, Messias AC, Floegel A, He Y, Heim K, Campillos M, Holzapfel C, Thorand B, Grallert H, Xu T, Bader E, Huth C, Mittelstrass K, Döring A, Meisinger C, Gieger C, Prehn C, Roemisch-Margl W, Carstensen M, Xie L, Yamanaka-Okumura H, Xing G, Ceglarek U, Thiery J, Giani G, Lickert H, Lin X, Li Y, Boeing H, Joost HG, de Angelis MH, Rathmann W, Suhre K, Prokisch H, Peters A, Meitinger T, Roden M, Wichmann HE, Pischon T, Adamski J, Illig T - Mol. Syst. Biol. (2012)

Bottom Line: We identified three metabolites (glycine, lysophosphatidylcholine (LPC) (18:2) and acetylcarnitine) that had significantly altered levels in IGT individuals as compared to those with normal glucose tolerance, with P-values ranging from 2.4×10(-4) to 2.1×10(-13).Lower levels of glycine and LPC were found to be predictors not only for IGT but also for T2D, and were independently confirmed in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort.Our results may help developing novel strategies to prevent T2D.

View Article: PubMed Central - PubMed

Affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany. rui.wang-sattler@helmholtz-muenchen.de

ABSTRACT
Type 2 diabetes (T2D) can be prevented in pre-diabetic individuals with impaired glucose tolerance (IGT). Here, we have used a metabolomics approach to identify candidate biomarkers of pre-diabetes. We quantified 140 metabolites for 4297 fasting serum samples in the population-based Cooperative Health Research in the Region of Augsburg (KORA) cohort. Our study revealed significant metabolic variation in pre-diabetic individuals that are distinct from known diabetes risk indicators, such as glycosylated hemoglobin levels, fasting glucose and insulin. We identified three metabolites (glycine, lysophosphatidylcholine (LPC) (18:2) and acetylcarnitine) that had significantly altered levels in IGT individuals as compared to those with normal glucose tolerance, with P-values ranging from 2.4×10(-4) to 2.1×10(-13). Lower levels of glycine and LPC were found to be predictors not only for IGT but also for T2D, and were independently confirmed in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort. Using metabolite-protein network analysis, we identified seven T2D-related genes that are associated with these three IGT-specific metabolites by multiple interactions with four enzymes. The expression levels of these enzymes correlate with changes in the metabolite concentrations linked to diabetes. Our results may help developing novel strategies to prevent T2D.

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Population description. Metabolomics screens in the KORA cohort, at baseline S4 (A), overlapped between S4 and F4 (B) and prospective (C, D). Participant numbers are shown. Normal glucose tolerance (NGT), isolated impaired fasting glucose (i-IFG), impaired glucose tolerance (IGT), type 2 diabetes mellitus (T2D) and newly diagnosed T2D (dT2D). Non-T2D individuals include NGT, i-IFG and IGT participants.
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f1: Population description. Metabolomics screens in the KORA cohort, at baseline S4 (A), overlapped between S4 and F4 (B) and prospective (C, D). Participant numbers are shown. Normal glucose tolerance (NGT), isolated impaired fasting glucose (i-IFG), impaired glucose tolerance (IGT), type 2 diabetes mellitus (T2D) and newly diagnosed T2D (dT2D). Non-T2D individuals include NGT, i-IFG and IGT participants.

Mentions: Individuals with known T2D were identified by physician-validated self-reporting (Rathmann et al, 2010) and excluded from our analysis, to avoid potential influence from anti-diabetic medication with non-fasting participants and individuals with missing values (Figure 1A). Based on both fasting and 2-h glucose values (i.e., 2 h post oral 75 g glucose load), individuals were defined according to the WHO diagnostic criteria to have normal glucose tolerance (NGT), isolated IFG (i-IFG), IGT or newly diagnosed T2D (dT2D) (WHO, 1999; Rathmann et al, 2009; Meisinger et al, 2010; Supplementary Table S1). The sample sets include 91 dT2D patients and 1206 individuals with non-T2D, including 866 participants with NGT, 102 with i-IFG and 238 with IGT, in the cross-sectional KORA S4 (Figure 1A; study characteristics are shown in Table I). Of the 1010 individuals in a fasting state who participated at baseline and follow-up surveys (Figure 1B, study characteristics of the KORA F4 survey are shown in Supplementary Table S2), 876 of them were non-diabetic at baseline. Out of these, about 10% developed T2D (i.e., 91 incident T2D) (Figure 1C). From the 641 individuals with NGT at baseline, 18% developed IGT (i.e., 118 incident IGT) 7 years later (Figure 1D). The study characteristics of the prospective KORA S4→F4 are shown in Table II.


Novel biomarkers for pre-diabetes identified by metabolomics.

Wang-Sattler R, Yu Z, Herder C, Messias AC, Floegel A, He Y, Heim K, Campillos M, Holzapfel C, Thorand B, Grallert H, Xu T, Bader E, Huth C, Mittelstrass K, Döring A, Meisinger C, Gieger C, Prehn C, Roemisch-Margl W, Carstensen M, Xie L, Yamanaka-Okumura H, Xing G, Ceglarek U, Thiery J, Giani G, Lickert H, Lin X, Li Y, Boeing H, Joost HG, de Angelis MH, Rathmann W, Suhre K, Prokisch H, Peters A, Meitinger T, Roden M, Wichmann HE, Pischon T, Adamski J, Illig T - Mol. Syst. Biol. (2012)

Population description. Metabolomics screens in the KORA cohort, at baseline S4 (A), overlapped between S4 and F4 (B) and prospective (C, D). Participant numbers are shown. Normal glucose tolerance (NGT), isolated impaired fasting glucose (i-IFG), impaired glucose tolerance (IGT), type 2 diabetes mellitus (T2D) and newly diagnosed T2D (dT2D). Non-T2D individuals include NGT, i-IFG and IGT participants.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472689&req=5

f1: Population description. Metabolomics screens in the KORA cohort, at baseline S4 (A), overlapped between S4 and F4 (B) and prospective (C, D). Participant numbers are shown. Normal glucose tolerance (NGT), isolated impaired fasting glucose (i-IFG), impaired glucose tolerance (IGT), type 2 diabetes mellitus (T2D) and newly diagnosed T2D (dT2D). Non-T2D individuals include NGT, i-IFG and IGT participants.
Mentions: Individuals with known T2D were identified by physician-validated self-reporting (Rathmann et al, 2010) and excluded from our analysis, to avoid potential influence from anti-diabetic medication with non-fasting participants and individuals with missing values (Figure 1A). Based on both fasting and 2-h glucose values (i.e., 2 h post oral 75 g glucose load), individuals were defined according to the WHO diagnostic criteria to have normal glucose tolerance (NGT), isolated IFG (i-IFG), IGT or newly diagnosed T2D (dT2D) (WHO, 1999; Rathmann et al, 2009; Meisinger et al, 2010; Supplementary Table S1). The sample sets include 91 dT2D patients and 1206 individuals with non-T2D, including 866 participants with NGT, 102 with i-IFG and 238 with IGT, in the cross-sectional KORA S4 (Figure 1A; study characteristics are shown in Table I). Of the 1010 individuals in a fasting state who participated at baseline and follow-up surveys (Figure 1B, study characteristics of the KORA F4 survey are shown in Supplementary Table S2), 876 of them were non-diabetic at baseline. Out of these, about 10% developed T2D (i.e., 91 incident T2D) (Figure 1C). From the 641 individuals with NGT at baseline, 18% developed IGT (i.e., 118 incident IGT) 7 years later (Figure 1D). The study characteristics of the prospective KORA S4→F4 are shown in Table II.

Bottom Line: We identified three metabolites (glycine, lysophosphatidylcholine (LPC) (18:2) and acetylcarnitine) that had significantly altered levels in IGT individuals as compared to those with normal glucose tolerance, with P-values ranging from 2.4×10(-4) to 2.1×10(-13).Lower levels of glycine and LPC were found to be predictors not only for IGT but also for T2D, and were independently confirmed in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort.Our results may help developing novel strategies to prevent T2D.

View Article: PubMed Central - PubMed

Affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany. rui.wang-sattler@helmholtz-muenchen.de

ABSTRACT
Type 2 diabetes (T2D) can be prevented in pre-diabetic individuals with impaired glucose tolerance (IGT). Here, we have used a metabolomics approach to identify candidate biomarkers of pre-diabetes. We quantified 140 metabolites for 4297 fasting serum samples in the population-based Cooperative Health Research in the Region of Augsburg (KORA) cohort. Our study revealed significant metabolic variation in pre-diabetic individuals that are distinct from known diabetes risk indicators, such as glycosylated hemoglobin levels, fasting glucose and insulin. We identified three metabolites (glycine, lysophosphatidylcholine (LPC) (18:2) and acetylcarnitine) that had significantly altered levels in IGT individuals as compared to those with normal glucose tolerance, with P-values ranging from 2.4×10(-4) to 2.1×10(-13). Lower levels of glycine and LPC were found to be predictors not only for IGT but also for T2D, and were independently confirmed in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort. Using metabolite-protein network analysis, we identified seven T2D-related genes that are associated with these three IGT-specific metabolites by multiple interactions with four enzymes. The expression levels of these enzymes correlate with changes in the metabolite concentrations linked to diabetes. Our results may help developing novel strategies to prevent T2D.

Show MeSH
Related in: MedlinePlus