Tyrosine Is Associated with Insulin Resistance in Longitudinal Metabolomic Profiling of Obese Children

Christian Hellmuth, Franca Fabiana Kirchberg, Nina Lass, Ulrike Harder, Wolfgang Peissner, Berthold Koletzko, Thomas Reinehr, Christian Hellmuth, Franca Fabiana Kirchberg, Nina Lass, Ulrike Harder, Wolfgang Peissner, Berthold Koletzko, Thomas Reinehr

Abstract

In obese children, hyperinsulinaemia induces adverse metabolic consequences related to the risk of cardiovascular and other disorders. Branched-chain amino acids (BCAA) and acylcarnitines (Carn), involved in amino acid (AA) degradation, were linked to obesity-associated insulin resistance, but these associations yet have not been studied longitudinally in obese children. We studied 80 obese children before and after a one-year lifestyle intervention programme inducing substantial weight loss >0.5 BMI standard deviation scores in 40 children and no weight loss in another 40 children. At baseline and after the 1-year intervention, we assessed insulin resistance (HOMA index), fasting glucose, HbA1c, 2 h glucose in an oral glucose tolerance test, AA, and Carn. BMI adjusted metabolite levels were associated with clinical markers at baseline and after intervention, and changes with the intervention period were evaluated. Only tyrosine was significantly associated with HOMA (p < 0.05) at baseline and end and with change during the intervention (p < 0.05). In contrast, ratios depicting BCAA metabolism were negatively associated with HOMA at baseline (p < 0.05), but not in the longitudinal profiling. Stratified analysis revealed that the children with substantial weight loss drove this association. We conclude that tyrosine alterations in association with insulin resistance precede alteration in BCAA metabolism. This trial is registered with ClinicalTrials.gov Identifier NCT00435734.

Figures

Figure 1
Figure 1
Associations of amino acids (AA) and acylcarnitines (Carn) with HOMA. Associations were calculated at baseline (x-axis) and for changes of AA and Carn to changes of HOMA during the intervention (y-axis) period in all children (n = 80). Displayed are the absolute log⁡(p) values of the applied obesity-independent robust regression models for both associations. AAA, aromatic amino acids; BCAA, branched-chain amino acids.
Figure 2
Figure 2
Estimates (95% CI) for associations of tyrosine with HOMA. Associations were calculated at baseline (Start) and after the intervention (End). Associations were calculated for all obese children (n = 80), children with substantial weight loss (WL, n = 40), and children without substantial weight loss (nWL, n = 40). 95% CI: 95% confidence interval.
Figure 3
Figure 3
Manhattan plot for associations of amino acids (AA) and acylcarnitines (Carn) with HOMA after the one-year lifestyle intervention for all obese children (a), children with substantial weight loss (b), and children without substantial weight loss (c). Plotted are the log10⁡(p) values and the sign is used to indicate the direction of the relationship, as assessed by the robust regression model. The area below or above the dashed lines contains metabolites that are significantly related to HOMA (p values < 0.05). AAA, aromatic amino acids; BCAA, branched-chain amino acids.

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