Circulating metabolite biomarkers of glycemic control in youth-onset type 2 diabetes

Objective. We aimed to identify metabolites associated with loss of glycemic control in youth-onset type 2 diabetes. Research design and methods. We measured 480 metabolites in fasting plasma samples from the Treatment Options for type 2 diabetes in Adolescents and Youth (TODAY) study. Participants (n=393, ages 10-17 years) were randomized to metformin, metformin + rosiglitazone, or metformin + lifestyle intervention. Additional metabolomics measurements after 36 months were obtained in n=304. Cox models were used to assess baseline metabolites, the interaction of metabolites and treatment group, and change in metabolites (0-36m), with loss of glycemic control adjusted for age, sex, race, treatment group, and BMI. Metabolite prediction models of glycemic failure were generated using elastic net regression and compared to clinical risk factors. Results. Loss of glycemic control (HbA1c or insulin therapy) occurred in 179/393 participants (mean 12.4 months). Baseline levels of 33 metabolites were associated with loss of glycemic control (q<0.05). Associations of hexose and xanthurenic acid with treatment failure differed by treatment randomization; youth with higher baseline levels of these two compounds had lower risk of treatment failure with metformin alone. For 3 metabolites, changes from 0-36 months associated with loss of glycemic control (q<0.05). Changes in D-gluconic acid and 1,5-AG/1-deoxyglucose, but not baseline levels of measured metabolites, predicted treatment failure better than changes in HbA1c and measures of beta cell function. Conclusion. Metabolomics provides insight into circulating small molecules associated with loss of glycemic control and may highlight metabolic pathways contributing to treatment failure in youth-onset diabetes.