title: Association of oxidative stress, insulin resistance, and diabetes risk phenotypes: the Framingham Offspring Study.
abstract: OBJECTIVE
  Systemic oxidative stress causes insulin resistance in rodents. We tested the hypothesis that oxidative stress and insulin resistance are associated in humans.
  
  
  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 F2alpha (8-epi-PGF2alpha) 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-PGF2alpha/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 > or = 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-PGF2alpha/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.
authors.affiliation: General Medicine Division and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. jmeigs@partners.org
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D049628:Body Size; D002318:Cardiovascular Diseases / Q000453:epidemiology*; D003404:Creatinine / Q000097:blood; D003920:Diabetes Mellitus / Q000453:epidemiology* / Q000235:genetics*; D015237:Dinoprost / Q000097:blood; D005260:Female; D006306:Health Surveys; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D008875:Middle Aged; D009679:Nuclear Family; D018384:Oxidative Stress / Q000502:physiology*; D010641:Phenotype; D011236:Prediabetic State / Q000453:epidemiology; D015995:Prevalence
chemical_list: D015415:Biomarkers; D003404:Creatinine; D015237:Dinoprost