Omics era in type 2 diabetes: From childhood to adulthood

Table 3 Main findings of the omics studies in children

Ref.	Study design	Population (n)	Main findings
Concepcion et al[45]	Cross-sectional study	90 children (30 healthy children, 30 obese children without T2D and 30 obese children with T2D) aged 13-19 yr	In urine samples of T2D patients, 22 metabolites (including succinylaminoimidazole carboxamide riboside (SAICA-riboside), betaine metabolites (betaine and dimethylglycine), branched chain amino acids (valine and leucine) and their direct catabolic derivatives (2-oxoisovaleric acid, 3-methyl-2-oxovaleric acid, 3-hydroxyisobutyrate) and aromatic amino acids (phenylalanine, tyrosine and tryptophan) were significantly associated in obese children. 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 obesity and IR independently of T2D
Perng et al[46]	Cross-sectional study	524 adolescents aged approximately 13 yr, grouped according to both obesity and glucose tolerance status	Five metabolite patterns differed with respect to phenotype: Factor 1 comprised long-chain fatty acids and was lower among non-OW/OB and high MetRisk vs non-OW/OB and low MetRisk. Factors 5 (branched chain amino acids; BCAAs), 8 (diacylglycerols) and 9 (steroid hormones) were highest among OW/OB and high MetRisk. Factor 7 (long-chain acylcarnitines) was higher among non-OWOB and high MetRisk and lower among OW/OB and low MetRisk
Gawlik et al[47]	Observational study	87 obese children divided in 2 groups (IR and Non-IR children) aged 8.5-17.9 yr old	31 steroid metabolites were quantified by GC-MS. IR was diagnosed in 20 (23%) of the examined patients. The steroidal IR signature was characterized by high adrenal androgens, glucocorticoids, and mineralocorticoid metabolites, higher 5a-reductase and 21-hydroxylase activity, and lower 11bHSD1 activity
Müllner et al[48]	Cross sectional study	81 adolescents aged > 10 yr, stratified into four groups based on BMI (lean vs obese), insulin responses (normal)	Two groups of metabolites were identified: (1) Metabolites associated with insulin response level: adolescents with HI (groups 3-4) had higher concentrations of BCAAs and tyrosine, and lower concentrations of serine, glycine, myo-inositol and dimethylsulfone, than adolescents with NI (groups 1-2); and (2) Metabolites associated with obesity status: obese adolescents (groups 2-4) had higher concentrations of acetylcarnitine, alanine, pyruvate and glutamate, and lower concentrations of acetate, than lean adolescents (group 1)
Mastrangelo et al[49]	Observational study	60 prepubertal obese children (30 girls/30 boys, 50% IR and 50% non-IR in each group, but with similar BMI)	47 metabolites out of 818 compounds were found to differ significantly between obese children with and without IR. Bile acids exhibit the greatest changes. The majority of metabolites differing between groups were lysophospholipids (15) and amino acids (17), indicating inflammation and central carbon metabolism as the most altered processes in impaired insulin signaling. Multivariate analysis (OPLS-DA models) showed subtle differences between groups that were magnified when females were analyzed alone
Martos-Moreno et al[50]	Observational study	100 prepubertal obese children (50 girls/50 boys, 50% IR and 50% non-IR in each group)	Twenty-three metabolite sets were enriched in the serum metabolome of IR obese children. The urea cycle, alanine metabolism and glucose-alanine cycle were the most significantly enriched pathways. The high correlation between metabolites related to fatty acid oxidation and amino acids (mainly branched chain and aromatic amino acids) pointed to the possible contribution of mitochondrial dysfunction in IR. The degree of BMI-standard deviation score excess did not correlate with any of the studied metabolomics components. Combination of leptin and alanine showed a high IR discrimination value in the whole cohort in both sexes. However, the specific metabolite/adipokine combinations with highest sensitivity were different between the sexes
Lopez et al[51]	Cross sectional study	28 children (14 obese female subjects with T2D and 14 lean healthy controls) aged 10-17 yr	Children with T2D had higher concentrations of C22:0 and C20:0 ceramides, with a 2-fold increase in C18:0 ceramide and C24:1 dihydroceramide. C22:0, C20:0 and C18:0 ceramide correlated with decreased adiponectin concentrations, increased HOMA-IR, BMI-SDS, triglyceride and fasting blood glucose concentrations. Plasma levels of C18:0, C20:0 and C22:0 ceramide, as well as C24:1 dihydroceramide were elevated in T2D obese female children and adolescents, probably due to tissue IR and low adiponectin levels

T2D: Type 2 diabetes; OB: Obesity; BMI: Body mass index; IR: Insulin resistance; GC-MS: Gas chromatography-mass spectrometry; HOMA-IR: Homeostatic model assessment for insulin resistance; MetRisk: Metabolic risk; 11bHSD1: 11β-Hydroxysteroid dehydrogenase type 1; OPLS-DA: Orthogonal partial least squares discriminant analysis.