Circulating branched-chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents

Authors

  • S. E. McCormack,

    1. Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
    2. Division of Endocrinology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, USA
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  • O. Shaham,

    1. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
    2. IBM Research, Haifa, Israel
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  • M. A. McCarthy,

    1. Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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  • A. A. Deik,

    1. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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  • T. J. Wang,

    1. Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    2. Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    3. Framingham Heart Study of the National Heart, Lung, and Blood Institute, Boston University School of Medicine, Framingham, Massachusetts, USA
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  • R. E. Gerszten,

    1. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
    2. Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    3. Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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  • C. B. Clish,

    1. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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  • V. K. Mootha,

    1. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
    2. Diabetes Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    3. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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  • S. K. Grinspoon,

    1. Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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  • A. Fleischman

    Corresponding author
    1. Division of Endocrinology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, USA
    • Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Address for correspondence: Dr A Fleischman, Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, LON 207, Boston, MA 02114, USA. E-mail: afleischman@partners.org

Summary

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.

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