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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

Targeted LC-QqQ MS analysis of methionine and methionine sulfoxide.The scatter plots show the abundance of methionine (A) and methionine sulfoxide (B) in controls and HIAE serum samples and trimmed mean (P < 0.05) (controls are depicted in red and HIAE in blue).
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f2: Targeted LC-QqQ MS analysis of methionine and methionine sulfoxide.The scatter plots show the abundance of methionine (A) and methionine sulfoxide (B) in controls and HIAE serum samples and trimmed mean (P < 0.05) (controls are depicted in red and HIAE in blue).

Mentions: Next, all these changes in metabolites were validated and complemented with additional metabolites by targeted analyses of the serum samples using triple-quadrupole mass spectrometry (QqQ MS) with multiple reaction monitoring (MRM) (when chemical standards were commercially available) (Table 2). We confirmed that a drop in methionine levels (Fig. 2A) is accompanied by an increase in MetOx (Fig. 2B) in HIAE girls. To discard that an artifactual conversion of methionine to MetOx during sample preparation and analysis2122 could be the cause of the increased levels of MetOx in HIAE girls, we spiked the same amount of free deuterium labelled methionine (S-methyl-d3) in HIAE and control serum samples, followed by LC-QqQ MS detection. Supplementary Fig. 1 shows no significant differences in the levels of methionine-d3 or the artifactually-produced methionine-d3 sulfoxide (MetOx-d3), nor in the MetOx-d3/Met-d3 ratio, between HIAE and control samples. In both scenarios the percentage of artifactual MetOx-d3 represents less than 2% of the total methionine-d3 signal. Therefore, the minimal artifactual oxidation of methionine in our method does not impact on the relative and biological differences observed between HIAE and the control group.


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)

Targeted LC-QqQ MS analysis of methionine and methionine sulfoxide.The scatter plots show the abundance of methionine (A) and methionine sulfoxide (B) in controls and HIAE serum samples and trimmed mean (P < 0.05) (controls are depicted in red and HIAE in blue).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Targeted LC-QqQ MS analysis of methionine and methionine sulfoxide.The scatter plots show the abundance of methionine (A) and methionine sulfoxide (B) in controls and HIAE serum samples and trimmed mean (P < 0.05) (controls are depicted in red and HIAE in blue).
Mentions: Next, all these changes in metabolites were validated and complemented with additional metabolites by targeted analyses of the serum samples using triple-quadrupole mass spectrometry (QqQ MS) with multiple reaction monitoring (MRM) (when chemical standards were commercially available) (Table 2). We confirmed that a drop in methionine levels (Fig. 2A) is accompanied by an increase in MetOx (Fig. 2B) in HIAE girls. To discard that an artifactual conversion of methionine to MetOx during sample preparation and analysis2122 could be the cause of the increased levels of MetOx in HIAE girls, we spiked the same amount of free deuterium labelled methionine (S-methyl-d3) in HIAE and control serum samples, followed by LC-QqQ MS detection. Supplementary Fig. 1 shows no significant differences in the levels of methionine-d3 or the artifactually-produced methionine-d3 sulfoxide (MetOx-d3), nor in the MetOx-d3/Met-d3 ratio, between HIAE and control samples. In both scenarios the percentage of artifactual MetOx-d3 represents less than 2% of the total methionine-d3 signal. Therefore, the minimal artifactual oxidation of methionine in our method does not impact on the relative and biological differences observed between HIAE and the control group.

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