title: Sex differences in biomarkers associated with insulin resistance in obese adolescents: metabolomic profiling and principal components analysis.
abstract: OBJECTIVE
  Obesity and insulin resistance (IR) predispose to type 2 diabetes mellitus. Yet only half of obese adolescents have IR and far fewer progress to type 2 diabetes mellitus. We hypothesized that amino acid and fatty acid metabolites may serve as biomarkers or determinants of IR in obese teens.
  
  
  METHODS
  Fasting blood samples were analyzed by tandem mass spectrometry in 82 obese adolescents. A principal components analysis and multiple linear regression models were used to correlate metabolic components with surrogate measures of IR: homeostasis model assessment index of insulin resistance (HOMA-IR), adiponectin, and triglyceride (TG) to high-density lipoprotein (HDL) ratio.
  
  
  RESULTS
  Branched-chain amino acid (BCAA) levels and products of BCAA catabolism were higher (P < .01) in males than females with comparable body mass index (BMI) z-score. In multivariate analyses, HOMA-IR in males correlated positively with BMI z-score and a metabolic signature containing BCAA, uric acid, and long-chain acylcarnitines and negatively with byproducts of complete fatty acid oxidation (R(2) = 0.659, P < .0001). In contrast, only BMI z-score correlated with HOMA-IR in females. Adiponectin correlated inversely with BCAA and uric acid (R(2) = 0.268, P = .0212) in males but not females. TG to HDL ratio correlated with BMI z-score and the BCAA signature in females but not males.
  
  
  CONCLUSIONS
  BCAA levels and byproducts of BCAA catabolism are higher in obese teenage boys than girls of comparable BMI z-score. A metabolic signature comprising BCAA and uric acid correlates positively with HOMA-IR in males and TG to HDL ratio in females and inversely with adiponectin in males but not females. Likewise, byproducts of fatty acid oxidation associate inversely with HOMA-IR in males but not females. Our findings underscore the roles of sex differences in metabolic function and outcomes in pediatric obesity.
authors.affiliation: Divisions of Pediatric Endocrinology and Diabetes (D.N., P.G.B., K.I., M.F.), the Duke Molecular Physiology Institute (J.B., M.M., R.S., O.I., M.F.), the Division of General Pediatrics (D.D., S.A.), Duke University Medical Center, Durham, North Carolina 27710, and Advanced Analytics Division, SAS Institute Inc (M. B.), Cary, North Carolina 27513.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Newbern
authors.forename: Pinar
authors.initials: P
authors.lastname: Gumus Balikcioglu
authors.forename: Metin
authors.initials: M
authors.lastname: Balikcioglu
authors.forename: James
authors.initials: J
authors.lastname: Bain
authors.forename: Michael
authors.initials: M
authors.lastname: Muehlbauer
authors.forename: Robert
authors.initials: R
authors.lastname: Stevens
authors.forename: Olga
authors.initials: O
authors.lastname: Ilkayeva
authors.forename: Diana
authors.initials: D
authors.lastname: Dolinsky
authors.forename: Sarah
authors.initials: S
authors.lastname: Armstrong
authors.forename: Krystal
authors.initials: K
authors.lastname: Irizarry
authors.forename: Michael
authors.initials: M
authors.lastname: Freemark
mesh_terms: D052242:Adiponectin / Q000097:blood; D000293:Adolescent; D000597:Amino Acids, Branched-Chain / Q000097:blood; D000886:Anthropometry; D015415:Biomarkers / Q000097:blood*; D002648:Child; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D020738:Leptin / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008297:Male; D055442:Metabolome; D009765:Obesity / Q000097:blood* / Q000378:metabolism; D025341:Principal Component Analysis; D012727:Sex Characteristics; D014280:Triglycerides / Q000097:blood
chemical_list: D052242:Adiponectin; D000597:Amino Acids, Branched-Chain; D015415:Biomarkers; D020738:Leptin; D008075:Lipoproteins, HDL; D014280:Triglycerides