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Aruna D. Pradhan, MD,MPH; JoAnn E. Manson, MD,DrPH; Nader Rifai, PhD; Julie E. Buring, ScD; Paul M. Ridker, MD,MPH

JAMA. 2001;286:327-334.

Context  Inflammation is hypothesized to play a role in development of type 2 diabetes mellitus (DM); however, clinical data addressing this issue are limited.

Objective  To determine whether elevated levels of the inflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP) are associated with development of type 2 DM in healthy middle-aged women.

Design  Prospective, nested case-control study.

Setting  The Women's Health Study, an ongoing US primary prevention, randomized clinical trial initiated in 1992.

Participants  From a nationwide cohort of 27 628 women free of diagnosed DM, cardiovascular disease, and cancer at baseline, 188 women who developed diagnosed DM over a 4-year follow-up period were defined as cases and matched by age and fasting status with 362 disease-free controls.

Main Outcome Measures  Incidence of confirmed clinically diagnosed type 2 DM by baseline levels of IL-6 and CRP.

Results  Baseline levels of IL-6 (P<.001) and CRP (P<.001) were significantly higher among cases than among controls. The relative risks of future DM for women in the highest vs lowest quartile of these inflammatory markers were 7.5 for IL-6 (95% confidence interval [CI], 3.7-15.4) and 15.7 for CRP (95% CI, 6.5-37.9). Positive associations persisted after adjustment for body mass index, family history of diabetes, smoking, exercise, use of alcohol, and hormone replacement therapy; multivariate relative risks for the highest vs lowest quartiles were 2.3 for IL-6 (95% CI, 0.9-5.6; P for trend = .07) and 4.2 for CRP (95% CI, 1.5-12.0; P for trend = .001). Similar results were observed in analyses limited to women with a baseline hemoglobin A_1c of 6.0% or less and after adjustment for fasting insulin level.

Conclusions  Elevated levels of CRP and IL-6 predict the development of type 2 DM. These data support a possible role for inflammation in diabetogenesis.

Author Affiliations: Center for Cardiovascular Disease Prevention (Drs Pradhan, Manson, Ridker, Rifai, Buring), the Leducq Center for Molecular and Genetic Epidemiology of Cardiovascular Disorders (Dr Ridker), the Divisions of Cardiology (Dr Ridker) and Preventive Medicine (Drs Pradhan, Manson, Ridker, and Buring), Brigham and Women's Hospital and Harvard Medical School; the Department of Pathology (Dr Rifai), Children's Hospital Medical Center and Harvard Medical School; and the Department of Ambulatory Care and Prevention, Harvard Medical School (Dr Buring), Boston, Mass.

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