Relationships Between Circulating Metabolic Intermediates and Insulin Action in Overweight to Obese, Inactive Men and Women

  1. Kim M. Huffman, MD, PHD1,
  2. Svati H. Shah, MD, MHS2,
  3. Robert D. Stevens, PHD3,
  4. James R. Bain, PHD3,
  5. Michael Muehlbauer, PHD3,
  6. Cris A. Slentz, PHD2,
  7. Charles J. Tanner, MS4,
  8. Maragatha Kuchibhatla, PHD5,
  9. Joseph A. Houmard, PHD4,
  10. Christopher B. Newgard, PHD3,6 and
  11. William E. Kraus, MD2
  1. 1Physical Medicine and Rehabilitation, Veterans Affairs Medical Center, Durham, North Carolina;
  2. 2Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina;
  3. 3Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina;
  4. 4Department of Exercise and Sports Science and the Human Performance Laboratory, East Carolina University, Greenville, North Carolina;
  5. 5Division of Geriatrics, Department of Medicine, Duke University Medical Center, Durham, North Carolina;
  6. 6Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.
  1. Corresponding author: Kim M. Huffman, huffm007{at}


OBJECTIVE To determine whether circulating metabolic intermediates are related to insulin resistance and β-cell dysfunction in individuals at risk for type 2 diabetes.

RESEARCH DESIGN AND METHODS In 73 sedentary, overweight to obese, dyslipidemic individuals, insulin action was derived from a frequently sampled intravenous glucose tolerance test. Plasma concentrations of 75 amino acids, acylcarnitines, free fatty acids, and conventional metabolites were measured with a targeted, mass spectrometry–based platform. Principal components analysis followed by backward stepwise linear regression was used to explore relationships between measures of insulin action and metabolic intermediates.

RESULTS The 75 metabolic intermediates clustered into 19 factors comprising biologically related intermediates. A factor containing large neutral amino acids was inversely related to insulin sensitivity (SI) (R2 = 0.26). A factor containing fatty acids was inversely related to the acute insulin response to glucose (R2 = 0.12). Both of these factors, age, and a factor containing medium-chain acylcarnitines and glucose were inversely and independently related to the disposition index (DI) (R2 = 0.39). Sex differences were found for metabolic predictors of SI and DI.

CONCLUSIONS In addition to the well-recognized risks for insulin resistance, elevated concentrations of large, neutral amino acids were independently associated with insulin resistance. Fatty acids were inversely related to the pancreatic response to glucose. Both large neutral amino acids and fatty acids were related to an appropriate pancreatic response, suggesting that these metabolic intermediates might play a role in the progression to type 2 diabetes, one by contributing to insulin resistance and the other to pancreatic failure. These intermediates might exert sex-specific effects on insulin action.


  • Clinical trial reg. nos. NCT00200993 and NCT00275145,

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received January 13, 2009.
    • Accepted May 25, 2009.
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  1. Diabetes Care vol. 32 no. 9 1678-1683
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