Association of Oxidative Stress, Insulin Resistance, and Diabetes Risk Phenotypes

The Framingham Offspring Study

  1. James B. Meigs, MD, MPH1,
  2. Martin G. Larson, SD2,
  3. Caroline S. Fox, MD, MPH34,
  4. John F. Keaney, Jr., MD5,
  5. Ramachandran S. Vasan, MD367 and
  6. Emelia J. Benjamin, MD, SCM367
  1. 1General Medicine Division and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
  2. 2Department of Mathematics and Statistics, Boston University, Boston, Massachusetts
  3. 3National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts
  4. 4Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  5. 5Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
  6. 6Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston, Massachusetts
  7. 7Preventive Medicine Section, Boston University School of Medicine, Boston, Massachusetts
  1. Address correspondence and reprint requests to James B. Meigs, MD, General Medicine Division, Massachusetts General Hospital, 50 Staniford St., 9th Floor, Boston, MA 02114. E-mail: jmeigs{at}


OBJECTIVE—Systemic oxidative stress causes insulin resistance in rodents. We tested the hypothesis that oxidative stress and insulin resistance are associated in humans.

RESEARCH DESIGN AND METHODS—We used cross-sectional data from 2,002 nondiabetic subjects of the community-based Framingham Offspring Study. We measured insulin resistance with the homeostasis model and defined categorical insulin resistance as homeostasis model assessment of insulin resistance (HOMA-IR) >75th percentile. We measured oxidative stress using the ratio of urine 8-epi-prostaglandin F (8-epi-PGF) to creatinine and used age- and sex-adjusted regression models to test the association of oxidative stress with insulin resistance in individuals without diabetes and among subgroups at elevated risk of diabetes.

RESULTS—Across 8-epi-PGF/creatinine tertiles, the prevalence of insulin resistance increased (18.0, 27.5, and 29.4% for the first, second, and third tertiles, respectively; P < 0.0001), as did mean levels of HOMA-IR (3.28, 3.83, and 4.06 units; P < 0.0001). The insulin resistance–oxidative stress association was attenuated by additional adjustment for BMI (P = 0.06 across tertiles for insulin resistance prevalence; P = 0.004 for mean HOMA-IR). Twenty-six percent of participants were obese (BMI ≥30 kg/m2), 39% had metabolic syndrome (according to the Adult Treatment Panel III definition), and 37% had impaired fasting glucose (IFG) (fasting glucose 5.6–6.9 mmol/l). Among 528 obese participants, respectively, insulin resistance prevalence was 41.3, 60.6, and 54.2% across 8-epi-PGF/creatinine tertiles (P = 0.005); among 781 subjects with metabolic syndrome, insulin resistance prevalence was 41.3, 56.7, and 51.7% (P = 0.0025); and among 749 subjects with IFG, insulin resistance prevalence was 39.6, 47.2, and 51.6% (P = 0.04).

CONCLUSIONS—Systemic oxidative stress is associated with insulin resistance in individuals at average or elevated risk of diabetes even after accounting for BMI.


  • Published ahead of print at on 22 June 2007. DOI: 10.2337/dc07-0817.

    E.J.B. and R.S.V. contributed equally to this study.

    A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    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.

    • Accepted June 18, 2007.
    • Received April 21, 2007.
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  1. Diabetes Care vol. 30 no. 10 2529-2535
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