Metabolite Profiles During Oral Glucose Challenge

  1. Thomas J. Wang1,5,7
  1. 1Framingham Heart Study of the National Heart, Lung, and Blood Institute and Boston University School of Medicine, Framingham, Massachusetts
  2. 2Cardiovascular Medicine Section, Department of Medicine, Boston University Medical Center, Boston, Massachusetts
  3. 3Department of Mathematics and Statistics, Boston University, Boston, Massachusetts
  4. 4Division of Cardiology and Preventive Medicine, Department of Medicine, Boston University, Boston, Massachusetts
  5. 5Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
  6. 6Division of Cardiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  7. 7Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
  8. 8Renal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
  9. 9Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
  10. 10Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, Massachusetts
  11. 11Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
  12. 12Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  1. Corresponding author: Thomas J. Wang, tjwang{at}partners.org.
  1. R.E.G. and T.J.W. contributed equally to this study.

Abstract

To identify distinct biological pathways of glucose metabolism, we conducted a systematic evaluation of biochemical changes after an oral glucose tolerance test (OGTT) in a community-based population. Metabolic profiling was performed on 377 nondiabetic Framingham Offspring cohort participants (mean age 57 years, 42% women, BMI 30 kg/m2) before and after OGTT. Changes in metabolite levels were evaluated with paired Student t tests, cluster-based analyses, and multivariable linear regression to examine differences associated with insulin resistance. Of 110 metabolites tested, 91 significantly changed with OGTT (P ≤ 0.0005 for all). Amino acids, β-hydroxybutyrate, and tricarboxylic acid cycle intermediates decreased after OGTT, and glycolysis products increased, consistent with physiological insulin actions. Other pathways affected by OGTT included decreases in serotonin derivatives, urea cycle metabolites, and B vitamins. We also observed an increase in conjugated, and a decrease in unconjugated, bile acids. Changes in β-hydroxybutyrate, isoleucine, lactate, and pyridoxate were blunted in those with insulin resistance. Our findings demonstrate changes in 91 metabolites representing distinct biological pathways that are perturbed in response to an OGTT. We also identify metabolite responses that distinguish individuals with and without insulin resistance. These findings suggest that unique metabolic phenotypes can be unmasked by OGTT in the prediabetic state.

Footnotes

  • Received June 6, 2012.
  • Accepted January 29, 2013.

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  1. Diabetes vol. 62 no. 8 2689-2698
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