Identification of pathognomonic purine synthesis biomarkers by metabolomic profiling of adolescents with obesity and type 2 diabetes - PubMed (original) (raw)

Observational Study

Identification of pathognomonic purine synthesis biomarkers by metabolomic profiling of adolescents with obesity and type 2 diabetes

Jennifer Concepcion et al. PLoS One. 2020.

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. A distinct urine metabolomic signature for youth with type 2 diabetes.

A) Heatmap shows relative urinary concentrations of the metabolites in the signature for adolescents with type 2 diabetes. The T2D signature consists of metabolites that met a 5% FDR cutoff with post-hoc Tukey T2D>NW and OB>NW, or T2D

p<0.05. Metabolites were grouped and listed by functional category. Blue boxes indicate metabolites with lower concentrations and red boxes indicate metabolites with higher concentrations. B) Principal components analysis reveals separation of diabetic youth from healthy and obese, non-diabetic controls when the 22 metabolites in the T2D signature were applied to all subjects. The figure shows the plot of principal component 1 (x-axis) versus principal component 2 (y-axis). Black circles represent NW control subjects, green circles represent OB subjects, and red circles represent T2D subjects.

Fig 2. Urinary BCAA metabolites in NW, OB and T2D subjects.

Urinary BCAAs and their immediate catabolites were increased in diabetic youth, but BCAA acylglycine derivatives were decreased in youth with obesity regardless of diabetes status. BCAA degradation pathways are shown. Red triangle symbols with T2D indicate post-hoc Tukey T2D>OB and T2D>NW. Blue triangle symbols with T2D indicate post-hoc Tukey T2D

<nw, and="" blue="" triangle="" symbols="" with="" ob="" indicate="" post-hoc="" tukey="" ob<nw.="" bar="" charts="" show="" mean="" urinary="" metabolite="" concentrations="" ±="" sem="" expressed="" as="" mmol="" creatinine:="" white="" bars,="" nw;="" hatched="" ob;="" solid="" t2d.="" **p<0.01="" t2d="" vs.="" nw="" ob,="" †p<0.05="" compared="" to="" nw,="" ††p<0.01="" nw.<="" div=""> </nw,>

Fig 3. Differences in metabolite profiling between urine and plasma in youth with obesity and type 2 diabetes.

The upper Venn diagram shows urine metabolites that were unique to the T2D signature in the right column (red font indicating T2D>OB and T2D>NW), blue font indicating T2D

TD and OB>NW, blue font indicating OBNW andT2D>NW, blue font indicating OBOB and T2D>NW), blue font indicating T2DNW and T2D>NW, blue font indicating OB

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Identification of pathognomonic purine synthesis biomarkers by metabolomic profiling of adolescents with obesity and type 2 diabetes - PubMed (original) (raw)