Abstract
The incidence of type 2 diabetes is increasing more rapidly in adolescents than in any other age group. We identified and compared metabolite signatures in obese children with type 2 diabetes (T2D), obese children without diabetes (OB), and healthy, age- and gender-matched normal weight controls (NW) by measuring 273 analytes in fasting plasma and 24-hour urine samples from 90 subjects by targeted LC-MS/MS. Diabetic subjects were within 2 years of diagnosis in an attempt to capture early-stage disease prior to declining renal function. We found 22 urine metabolites that were uniquely associated with T2D when compared to OB and NW groups. The metabolites most significantly elevated in T2D youth included members of the betaine pathway, nucleic acid metabolism, and branched-chain amino acids (BCAAs) and their catabolites. Notably, 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 associated 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 levels of succinylaminoimidazole carboxamide riboside (SAICA-riboside) were increased in diabetic youth, identifying urine SAICA-riboside as a potential biomarker for T2D.
Highlights
There has been an alarming rise in the prevalence of obesity and type 2 diabetes in children in the past 3 decades. [1] At present, the clinical management of diabetic youth is largely based on therapies used in adults
The metabolite signature for type 2 diabetes was defined by the set of metabolites that met a false discovery rate (FDR) value of less than 5% followed by post-hoc Tukey analysis showing significant differences between the T2D group when compared to both obese children without diabetes (OB) and normal weight controls (NW) groups at p < 0.05
In order to generate a urine metabolome signature for type 2 diabetes, we identified metabolites that met a false discovery rate (FDR) value of less than 5% (q-value < 0.05) using the BH method followed by post-hoc Tukey analysis showing significant differences between the T2D group when compared to both OB and NW groups at p < 0.05
Summary
There has been an alarming rise in the prevalence of obesity and type 2 diabetes in children in the past 3 decades. [1] At present, the clinical management of diabetic youth is largely based on therapies used in adults. [1] At present, the clinical management of diabetic youth is largely based on therapies used in adults. [12, 13] Most prior studies in adolescents have examined obese subjects with insulin resistance, but very few have addressed how metabolic pathways are altered in youth with recent onset type 2 diabetes. [17] We are not aware of any prior studies which examined urine metabolomic profiles in adolescents with obesity or type 2 diabetes. We employed a targeted, quantitative mass spectrometry-based approach to generate unique urine and plasma metabolite signatures that differentiate obese youth with and without type 2 diabetes, as a first step toward identifying novel biomarkers that predict the development of diabetes in children. We used liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and bioinformatic analysis to investigate differences in metabolites concentrations among NW, OB and T2D adolescents, examine differences in excretion, and correlate metabolites to clinical markers of diabetes and renal function
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