title: Insulin resistance in prepubertal obese children correlates with sex-dependent early onset metabolomic alterations.
abstract: Insulin resistance (IR) is usually the first metabolic alteration diagnosed in obese children and the key risk factor for development of comorbidities. The factors determining whether or not IR develops as a result of excess body mass index (BMI) are still not completely understood.
  
  
  
  This study aimed to elucidate the mechanisms underpinning the predisposition toward hyperinsulinemia-related complications in obese children by using a metabolomic strategy that allows a profound interpretation of metabolic profiles potentially affected by IR.
  
  
  
  Serum from 60 prepubertal obese children (30 girls/30 boys, 50% IR and 50% non-IR in each group, but with similar BMIs) were analyzed by using liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry and capillary electrophoresis-mass spectrometry following an untargeted metabolomics approach. Validation was then performed on a group of 100 additional children with the same characteristics.
  
  
  
  When obese children with and without IR were compared, 47 metabolites out of 818 compounds (P<0.05) obtained after data pre-processing were found to be significantly different. Bile acids exhibit the greatest changes (that is, approximately a 90% increase in IR). 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.
  
  
  
  Inflammation and central carbon metabolism, together with the contribution of the gut microbiota, are the most altered processes in obese children with impaired insulin signaling in a sex-specific fashion despite their prepubertal status.
authors.affiliation: Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, San Pablo CEU University, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Mastrangelo
authors.affiliation: Department of Pediatrics & Pediatric Endocrinology, Instituto de Investigación La Princesa, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.|CIBEROBN, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: G Á
authors.initials: GÁ
authors.lastname: Martos-Moreno
authors.affiliation: Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, San Pablo CEU University, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: García
authors.affiliation: Department of Pediatrics & Pediatric Endocrinology, Instituto de Investigación La Princesa, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.|CIBEROBN, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Barrios
authors.affiliation: Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, San Pablo CEU University, Madrid, Spain.
authors.forename: F J
authors.initials: FJ
authors.lastname: Rupérez
authors.affiliation: Department of Pediatrics & Pediatric Endocrinology, Instituto de Investigación La Princesa, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.|CIBEROBN, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Chowen
authors.affiliation: Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, San Pablo CEU University, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Barbas
authors.affiliation: Department of Pediatrics & Pediatric Endocrinology, Instituto de Investigación La Princesa, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.|CIBEROBN, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Argente
mesh_terms: D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood / Q000150:complications / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D055432:Metabolomics; D063766:Pediatric Obesity / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D013030:Spain / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D001786:Blood Glucose