title: Circulating branched-chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents.
abstract: What is already known about this subject Circulating concentrations of branched-chain amino acids (BCAAs) can affect carbohydrate metabolism in skeletal muscle, and therefore may alter insulin sensitivity. BCAAs are elevated in adults with diet-induced obesity, and are associated with their future risk of type 2 diabetes even after accounting for baseline clinical risk factors. What this study adds Increased concentrations of BCAAs are already present in young obese children and their metabolomic profiles are consistent with increased BCAA catabolism. Elevations in BCAAs in children are positively associated with insulin resistance measured 18 months later, independent of their initial body mass index.
  
  
  BACKGROUND
  Branched-chain amino acid (BCAA) concentrations are elevated in response to overnutrition, and can affect both insulin sensitivity and secretion. Alterations in their metabolism may therefore play a role in the early pathogenesis of type 2 diabetes in overweight children.
  
  
  OBJECTIVE
  To determine whether paediatric obesity is associated with elevations in fasting circulating concentrations of BCAAs (isoleucine, leucine and valine), and whether these elevations predict future insulin resistance.
  
  
  METHODS
  Sixty-nine healthy subjects, ages 8-18 years, were enrolled as a cross-sectional cohort. A subset of subjects who were pre- or early-pubertal, ages 8-13 years, were enrolled in a prospective longitudinal cohort for 18 months (n = 17 with complete data).
  
  
  RESULTS
  Elevations in the concentrations of BCAAs were significantly associated with body mass index (BMI) Z-score (Spearman's Rho 0.27, P = 0.03) in the cross-sectional cohort. In the subset of subjects that followed longitudinally, baseline BCAA concentrations were positively associated with homeostasis model assessment for insulin resistance measured 18 months later after controlling for baseline clinical factors including BMI Z-score, sex and pubertal stage (P = 0.046).
  
  
  CONCLUSIONS
  Elevations in the concentrations of circulating BCAAs are significantly associated with obesity in children and adolescents, and may independently predict future insulin resistance.
authors.affiliation: Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: McCormack
authors.forename: O
authors.initials: O
authors.lastname: Shaham
authors.forename: M A
authors.initials: MA
authors.lastname: McCarthy
authors.forename: A A
authors.initials: AA
authors.lastname: Deik
authors.forename: T J
authors.initials: TJ
authors.lastname: Wang
authors.forename: R E
authors.initials: RE
authors.lastname: Gerszten
authors.forename: C B
authors.initials: CB
authors.lastname: Clish
authors.forename: V K
authors.initials: VK
authors.lastname: Mootha
authors.forename: S K
authors.initials: SK
authors.lastname: Grinspoon
authors.forename: A
authors.initials: A
authors.lastname: Fleischman
mesh_terms: D000293:Adolescent; D000597:Amino Acids, Branched-Chain / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002648:Child; D015362:Child Nutrition Disorders / Q000097:blood* / Q000453:epidemiology / Q000517:prevention & control; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000453:epidemiology / Q000517:prevention & control; D005215:Fasting / Q000097:blood; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007532:Isoleucine / Q000097:blood; D007930:Leucine / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D009765:Obesity / Q000097:blood* / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control; D011237:Predictive Value of Tests; D014633:Valine / Q000097:blood
chemical_list: D000597:Amino Acids, Branched-Chain; D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D007532:Isoleucine; D007930:Leucine; D014633:Valine