Sex differences in branched-chain amino acid and tryptophan metabolism and pathogenesis of youth-onset type 2 diabetes.

OBJECTIVES: Insulin resistance is associated with elevations in plasma branched-chain amino acids (BCAAs). BCAAs compete with aromatic amino acids (AAA) including tryptophan for uptake into β-cells. To explore relationships between BCAAs and tryptophan metabolism, adiposity, and glucose tolerance we compared urine metabolites in overweight/obese youth with T2D to those in non-diabetic overweight/obese and lean youth.

METHODS: Metabolites were measured in 24-hr and first-morning urine samples of 56 non-diabetic adolescents with overweight/obesity, 42 adolescents with T2D, and 43 lean controls, ages 12-21 yr. Group differences were assessed by Kruskal Wallis or ANOVA.

RESULTS: Groups were comparable for age, pubertal status, and ethnicity. Youth with T2D were predominantly female and had highest percent body fat. BCAAs, branched-chain ketoacids (BCKAs), tryptophan, and kynurenine were higher in urine of subjects with T2D. There were no differences between lean controls and non-diabetic youth with overweight/obesity. T2D was associated with diversion of tryptophan from the serotonin to the kynurenine pathway, with higher urinary kynurenine/serotonin ratio and lower serotonin/tryptophan and 5-hydroxyindoleacetic acid (5-HIAA)/kynurenine ratios. Urinary BCAAs, BCKAs, tryptophan, and ratios reflecting diversion to the kynurenine pathway correlated positively with metrics of body fat and HbA1c. Increases in these metabolites in the obese T2D group were more pronounced and statistically significant only in adolescent girls.

CONCLUSIONS: Increases in urinary BCAAs and BCKAs in adolescent females with T2D are accompanied by diversion of tryptophan metabolism from the serotonin to the kynurenine pathway. These adaptations associate with higher risks of T2D in obese adolescent females than adolescent males.