Association of Oxidative Stress, Insulin Resistance, and Diabetes Risk Phenotypes: The Framingham Offspring Study

doi:10.2337/dc07-0817

Association of Oxidative Stress, Insulin Resistance, and Diabetes Risk Phenotypes: The Framingham Offspring Study

James B. Meigs, MD, MPH (jmeigs{at}partners.org)¹,
Martin G. Larson, SD²,
Caroline S. Fox, MD, MPH³,
John F. Keaney, Jr., MD⁴,
Ramachandran S. Vasan, MD⁵ and
Emelia J. Benjamin, MD, ScM⁵

¹ General Medicine Division and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
² Department of Mathematics and Statistics, Boston University, Boston, and the National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA
³ The NHLBI's Framingham Heart Study and the Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
⁴ Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, MA
⁵ The NHLBI's Framingham Heart Study and the Evans Department of Medicine, Whitaker Cardiovascular Institute, and Preventive Medicine Section, Boston University School of Medicine, Boston, MA

Abstract

Objective: Systemic oxidative stress causes insulin resistance (IR) in rodents. We tested the hypothesis that oxidative stress and IR are associated in humans.

Research Design and Methods: We used cross-sectional data from 2002 non-diabetic subjects of the community-based Framingham Offspring Study. We measured IR with the homeostasis model and defined categorical IR as HOMA-IR >75%ile. We measured oxidative stress using the ratio of urine 8-epi-PGF_2a/creatinine, and used age-sex-adjusted regression models to test the association of oxidative stress with IR in people without diabetes and among subgroups at elevated risk of diabetes.

Results: Across 8-epi-PGF_2a/creatinine tertile the prevalence of IR increased (18.0%, 27.5%, and 29.4%; p <0.0001), as did mean levels of HOMA-IR (3.28, 3.83, 4.06 units; p<0.0001). The IR-oxidative stress association was attenuated by additional adjustment for BMI (p=0.06 across tertile for IR prevalence, p=0.004 for mean HOMA-IR). Twenty-six percent of participants were obese (BMI ≥30 kg/m2), 39% had metabolic syndrome (ATP3 definition) and 37% had IFG (fasting glucose 5.6-6.9 mmol/l). Among 528 obese participants, IR prevalence was 41.3%, 60.6%, and 54.2% across 8-epi-PGF_2a/creatinine tertile (p=0.005); among 781 with metabolic syndrome, IR prevalence was 41.3%, 56.7%, and 51.7% (p=0.0025); and among 749 with IFG, IR prevalence was 39.6%, 47.2%, and 51.6% (p=0.04).

Conclusions: Systemic oxidative stress is associated with IR in people at average or elevated risk of diabetes, even after accounting for BMI.