Association of oxidative stress, insulin resistance, and diabetes risk phenotypes: The Framingham Offspring Study

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_2α (8-epi-PGF _2α) 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_2α/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_2α/ 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.