Distinct Amino Acid Profile Characterizes Youth With or at Risk for Type 2 Diabetes.

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 ß-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 ß-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 ß-cell failure.

Hyperglycemia: A determinant of cardiac autonomic dysfunction in youth with obesity across the spectrum of glycemic regulation.

OBJECTIVES: To characterize the determinants of heart rate variability (HRV) in youth with obesity across the glycemia spectrum. METHODS: A total of 94 adolescents, 15 ± 2.1 years (21 with normal weight, 23 with overweight-normal glucose tolerance, 26 with prediabetes and 24 with type 2 diabetes [T2D]) underwent an assessment of body composition (dual-energy x-ray absorptiometry), 2-h oral glucose tolerance test with the calculation of indices of glycemia and insulin sensitivity (IS), inflammatory markers (high-sensitivity C-reactive protein [hs-CRP] and tumour necrosis factor-α [TNF-α]), and HRV by peripheral arterial tonometry. RESULTS: The HRV frequency-domain index (low-frequency to high-frequency ratio [LF/HF]), an estimate of the ratio between sympathetic and parasympathetic activity, increased across the glycemic spectrum, and was highest in T2D compared with the other three groups (p = 0.004). LF/HF correlated with %body fat (r = 0.22, p = 0.04); fasting (r = 0.39, p < 0.001), 2-h (r = 0.31, p = 0.004), and area under the curve glucose (r = 0.32, p = 0.003); hs-CRP (r = 0.33, p = 0.002) and TNF-α (r = 0.38, p = 0.006). In a linear regression model, fasting glucose (ß = 0.39, p = 0.003) and hs-CRP (ß = 0.21, p = 0.09) contributed to the variance in Ln LF/HF independent of IS, %body fat, age, sex, race-ethnicity and Tanner stage (R2 = 0.23, p = 0.013). CONCLUSIONS: Youth with impaired glucose regulation have evidence of cardiac autonomic dysfunction with decreased HRV, and sympathetic overdrive (increased LF/HF). This dysfunction is mainly related to glycemia and systemic inflammation.