Branched-chain amino acids (BCAAs) and aromatic AAs (AAAs) are associated with increased risk for type 2 diabetes in adults. Studies in youth show conflicting results. We hypothesized that an AA metabolomic signature can be defined to identify youth at risk for β-cell failure and the development of type 2 diabetes. We performed targeted AA metabolomics analysis on 127 adolescents (65 girls; 15.5 [SD ±1.9] years old, Tanner stage II–V) with normal weight or obesity across the spectrum of glycemia, with assessment of AA concentrations by mass spectrometry, at fasting, and steady state of a hyperinsulinemic-euglycemic clamp, with determination of insulin sensitivity (IS) per fat-free mass (FFM). We measured insulin secretion during a 2-h hyperglycemic clamp and calculated the disposition index per FFM (DIFFM), a measure of β-cell function. Our results showed that concentration of glycine (Gly) and the glutamine (Gln)-to-glutamate (Glu) ratio were lower, whereas BCAA, tyrosine, and lysine (Lys) concentrations were higher in the groups with obesity and dysglycemia compared with those with normal weight. Gly and Gln-to-Glu ratio were positively related to IS and DIFFM, with opposite relationships observed for BCAAs, AAAs, and Lys. We conclude that a metabolic signature of low Gly concentration and low Gln-to-Glu ratio, and elevated BCAAs, AAAs, and Lys concentrations may constitute a biomarker to identify youth at risk for β-cell failure.

Article Highlights
  • Branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) are associated with increased risk for type 2 diabetes in adults. This relationship is unclear in youth, with studies showing conflicting results.

  • We aimed to determine if an amino acid (AA) profile could be identified to characterize youth at risk for type 2 diabetes.

  • We show that a metabolic signature of low glycine concentration, low glutamine-to-glutamate ratio, and elevated BCAA, AAA and lysine concentrations, as well as increased concentration of short-chain, AA-derived acylcarnitines, may constitute a biomarker profile to identify youth at risk for β-cell failure.

  • Our findings provide support for use of the identified AA profile in metabolomic studies aiming at preventive and therapeutic interventions in youth-onset prediabetes and type 2 diabetes.

This article contains supplementary material online at https://doi.org/10.2337/figshare.24975603.

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