SAT-LB048 Identification of Pathognomonic Purine Synthesis Biomarkers by Metabolomic Profiling of Youth with Type 2 Diabetes

Abstract

Background: Historically, most individuals affected by type 2 diabetes have been adults. However the incidence of type 2 diabetes is increasing more rapidly in adolescents than in any other age group. Methods: We used a targeted, highly quantitative mass spectrometry (MS)-based approach to identify metabolite signatures in normal weight (NW), obese (OB), and type 2 diabetic (T2D) adolescents (n=30 per group). Fasting plasma and 24-hour urine samples were subjected to LC-MS/MS to quantify 274 analytes, followed by statistical analysis. Diabetic subjects were within 2 years of diagnosis. Findings: We identified 21 urine metabolites that were uniquely associated with T2D when compared to OB and NW groups. Interestingly, the most significantly elevated metabolites in T2D youth included members of the purine synthesis pathway, betaine pathway, and branched-chain amino acids (BCAAs) and their catabolites. Of note, the metabolite pattern in OB and T2D groups differed between urine and plasma, suggesting that urinary BCAAs and their intermediates behaved as a more specific biomarker for T2D, while plasma BCAAs appeared to associate with the obese, insulin resistant state independent of diabetes status. Correlative analysis of metabolites in the T2D signature indicated that betaine metabolites, BCAAs, and aromatic amino acids were associated with hyperglycemia, but BCAA acylglycine derivatives and nucleic acid metabolites were linked to insulin resistance. Of major interest, we found that urine SAICA-riboside was the most significantly elevated urine metabolite in T2D subjects and associated with higher fractional excretion of fumarate. Additionally, several metabolites were associated with increased fractional excretion and higher glomerular filtration rates (GFR) in our early-stage diabetic adolescents. Interpretation: Our results reveal alterations in BCAA oxidative flux, betaine and purine nucleotide metabolism in diabetic youth. We also identify urine SAICA-riboside as a biomarker for type 2 diabetes. Funding: American Diabetes Association, NIH, Endocrine Society Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.