Elevated α-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents

Context: Traditional risk factors for type 2 diabetes mellitus are weak predictors of changes in glucose tolerance and insulin sensitivity in youth. Objective: To identify early metabolic features of insulin resistance (IR) in youth and whether they predict deterioration of glycemic control. Design and Setting: A cross-sectional and longitudinal study was conducted at the Yale Pediatric Obesity Clinic. Patients and Intervention: Concentrations of a-hydroxybutyrate, beta-hydroxybutyrate, lactate, and branched-chain amino acids (BCAAs) were measured by nuclear magnetic resonance spectroscopy in 78 nondiabetic adolescents during an oral glucose tolerance test (OGTT). Associations between baseline metabolic alterations and longitudinal changes in glucose control were tested in 16 subjects after a mean follow-up of 2.3 years. Main Outcome Measures: The relationship between metabolite levels, parameters of IR, and glycemic control, and their progression over time. Results: Elevated fasting a-hydroxybutyrate levels were observed in adolescents with reduced insulin sensitivity after adjusting for age, sex, ethnicity, Tanner stage, and body mass index z-score (P = 0.014). Plasmaa-hydroxybutyrate and BCAAs were increased throughout the course of the OGTT in this group (P, 0.03). Notably, borderline IR was associated with a progressive a-hydroxybutyrate decrease from elevated baseline concentrations to normal levels (P = 0.02). Increased baseline a-hydroxybutyrate concentrations were further associated with progressive worsening of glucose tolerance and disposition index. Conclusion: alpha-Hydroxybutyrate and BCAA concentrations during an OGTT characterize insulin-resistant youth and predict worsening of glycemic control. These findings provide potential biomarkers for risk assessment of type 2 diabetes and new insights into IR pathogenesis.