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Metabolomics reveals impaired maturation of HDL particles in adolescents with hyperinsulinaemic androgen excess.

Samino S, Vinaixa M, Díaz M, Beltran A, Rodríguez MA, Mallol R, Heras M, Cabre A, Garcia L, Canela N, de Zegher F, Correig X, Ibáñez L, Yanes O - Sci Rep (2015)

Bottom Line: Here we use NMR and MS-based metabolomics to show that serum levels of methionine sulfoxide in HIAE girls are an indicator of the degree of oxidation of methionine-148 residue in apolipoprotein-A1.Oxidation of apo-A1 in methionine-148, in turn, leads to an impaired maturation of high-density lipoproteins (HDL) that is reflected in a decline of large HDL particles.Notably, such metabolic alterations occur in the absence of impaired glucose tolerance, hyperglycemia and hypertriglyceridemia, and were partially restored after 18 months of treatment with a low-dose combination of pioglitazone, metformin and flutamide.

View Article: PubMed Central - PubMed

Affiliation: 1] Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), C/ Monforte de Lemos 3-5, 28029 Madrid, Spain [2] Centre for Omic Sciences (COS), Rovira i Virgili University, Avinguda Universitat 3, 43204 Reus, Spain.

ABSTRACT
Hyperinsulinaemic androgen excess (HIAE) in prepubertal and pubertal girls usually precedes a broader pathological phenotype in adulthood that is associated with anovulatory infertility, metabolic syndrome and type 2 diabetes. The metabolic derangements that determine these long-term health risks remain to be clarified. Here we use NMR and MS-based metabolomics to show that serum levels of methionine sulfoxide in HIAE girls are an indicator of the degree of oxidation of methionine-148 residue in apolipoprotein-A1. Oxidation of apo-A1 in methionine-148, in turn, leads to an impaired maturation of high-density lipoproteins (HDL) that is reflected in a decline of large HDL particles. Notably, such metabolic alterations occur in the absence of impaired glucose tolerance, hyperglycemia and hypertriglyceridemia, and were partially restored after 18 months of treatment with a low-dose combination of pioglitazone, metformin and flutamide.

No MeSH data available.


Related in: MedlinePlus

Metabolic changes after 18 months of PioFluMet polytherapy.(A) PC1/PC2 scatter scores plot and (B) PC1 loading bar plot of PCA showing all the metabolites measured in HIAE girls after the treatment. (C) Relative intensity of free methionine in serum as measured by LC-QqQ MS. (D) Percentage of large HDL particles in serum as measured by NMR. (E) Relative intensity of free methionine sulfoxide in serum as measured by LC-QqQ MS. (F) Ratio of MetOx-148/Met-148 in apo-A1 calculated from the intensity of the pepide K.LSPLGEEMR.D as measured by MALDI-TOF MS.
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f5: Metabolic changes after 18 months of PioFluMet polytherapy.(A) PC1/PC2 scatter scores plot and (B) PC1 loading bar plot of PCA showing all the metabolites measured in HIAE girls after the treatment. (C) Relative intensity of free methionine in serum as measured by LC-QqQ MS. (D) Percentage of large HDL particles in serum as measured by NMR. (E) Relative intensity of free methionine sulfoxide in serum as measured by LC-QqQ MS. (F) Ratio of MetOx-148/Met-148 in apo-A1 calculated from the intensity of the pepide K.LSPLGEEMR.D as measured by MALDI-TOF MS.

Mentions: The abundance of individual markers was scaled to unit variance and projected using an unsupervised principal component analysis (PCA) (Fig. 5A). The scores plot reveals two clusters along PC1 (~47% of the variance) corresponding to HIAE girls on the one hand, and healthy controls and HIAE girls treated with PioFluMet on the other. This distribution indicates that the metabolic state of HIAE girls after 18 months of PioFluMet treatment more closely resembles the state of healthy girls, suggesting an overall improvement of the metabolic derangements in these girls. To interpret the pattern displayed in the scores plot, Fig. 5B shows a loading bar plot of the PCA using each individual metabolic marker. The relative abundance of large HDL particles and levels of free methionine in serum are the two largest contributing variables to positive values in PC1. After the treatment with PioFluMet, the levels of methionine and large HDL particles recovered to similar levels found in healthy girls (Fig. 5C,D). Likewise, the levels of methionine sulfoxide and the oxidation of Apo-A1 in the Met-148 residue decreased after the treatment, reaching similar or even lower levels than those seen in healthy girls (Fig. 5E,F).


Metabolomics reveals impaired maturation of HDL particles in adolescents with hyperinsulinaemic androgen excess.

Samino S, Vinaixa M, Díaz M, Beltran A, Rodríguez MA, Mallol R, Heras M, Cabre A, Garcia L, Canela N, de Zegher F, Correig X, Ibáñez L, Yanes O - Sci Rep (2015)

Metabolic changes after 18 months of PioFluMet polytherapy.(A) PC1/PC2 scatter scores plot and (B) PC1 loading bar plot of PCA showing all the metabolites measured in HIAE girls after the treatment. (C) Relative intensity of free methionine in serum as measured by LC-QqQ MS. (D) Percentage of large HDL particles in serum as measured by NMR. (E) Relative intensity of free methionine sulfoxide in serum as measured by LC-QqQ MS. (F) Ratio of MetOx-148/Met-148 in apo-A1 calculated from the intensity of the pepide K.LSPLGEEMR.D as measured by MALDI-TOF MS.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4477239&req=5

f5: Metabolic changes after 18 months of PioFluMet polytherapy.(A) PC1/PC2 scatter scores plot and (B) PC1 loading bar plot of PCA showing all the metabolites measured in HIAE girls after the treatment. (C) Relative intensity of free methionine in serum as measured by LC-QqQ MS. (D) Percentage of large HDL particles in serum as measured by NMR. (E) Relative intensity of free methionine sulfoxide in serum as measured by LC-QqQ MS. (F) Ratio of MetOx-148/Met-148 in apo-A1 calculated from the intensity of the pepide K.LSPLGEEMR.D as measured by MALDI-TOF MS.
Mentions: The abundance of individual markers was scaled to unit variance and projected using an unsupervised principal component analysis (PCA) (Fig. 5A). The scores plot reveals two clusters along PC1 (~47% of the variance) corresponding to HIAE girls on the one hand, and healthy controls and HIAE girls treated with PioFluMet on the other. This distribution indicates that the metabolic state of HIAE girls after 18 months of PioFluMet treatment more closely resembles the state of healthy girls, suggesting an overall improvement of the metabolic derangements in these girls. To interpret the pattern displayed in the scores plot, Fig. 5B shows a loading bar plot of the PCA using each individual metabolic marker. The relative abundance of large HDL particles and levels of free methionine in serum are the two largest contributing variables to positive values in PC1. After the treatment with PioFluMet, the levels of methionine and large HDL particles recovered to similar levels found in healthy girls (Fig. 5C,D). Likewise, the levels of methionine sulfoxide and the oxidation of Apo-A1 in the Met-148 residue decreased after the treatment, reaching similar or even lower levels than those seen in healthy girls (Fig. 5E,F).

Bottom Line: Here we use NMR and MS-based metabolomics to show that serum levels of methionine sulfoxide in HIAE girls are an indicator of the degree of oxidation of methionine-148 residue in apolipoprotein-A1.Oxidation of apo-A1 in methionine-148, in turn, leads to an impaired maturation of high-density lipoproteins (HDL) that is reflected in a decline of large HDL particles.Notably, such metabolic alterations occur in the absence of impaired glucose tolerance, hyperglycemia and hypertriglyceridemia, and were partially restored after 18 months of treatment with a low-dose combination of pioglitazone, metformin and flutamide.

View Article: PubMed Central - PubMed

Affiliation: 1] Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), C/ Monforte de Lemos 3-5, 28029 Madrid, Spain [2] Centre for Omic Sciences (COS), Rovira i Virgili University, Avinguda Universitat 3, 43204 Reus, Spain.

ABSTRACT
Hyperinsulinaemic androgen excess (HIAE) in prepubertal and pubertal girls usually precedes a broader pathological phenotype in adulthood that is associated with anovulatory infertility, metabolic syndrome and type 2 diabetes. The metabolic derangements that determine these long-term health risks remain to be clarified. Here we use NMR and MS-based metabolomics to show that serum levels of methionine sulfoxide in HIAE girls are an indicator of the degree of oxidation of methionine-148 residue in apolipoprotein-A1. Oxidation of apo-A1 in methionine-148, in turn, leads to an impaired maturation of high-density lipoproteins (HDL) that is reflected in a decline of large HDL particles. Notably, such metabolic alterations occur in the absence of impaired glucose tolerance, hyperglycemia and hypertriglyceridemia, and were partially restored after 18 months of treatment with a low-dose combination of pioglitazone, metformin and flutamide.

No MeSH data available.


Related in: MedlinePlus