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Simin Liu, MD, ScD; Lesley Tinker, PhD, RD; Yiqing Song, MD, ScD; Nader Rifai, PhD; Denise E. Bonds, MD; Nancy R. Cook, ScD; Gerardo Heiss, MD; Barbara V. Howard, PhD; Gokhan S. Hotamisligil, MD, PhD; Frank B. Hu, MD, PhD; Lewis H. Kuller, MD, DrPH; JoAnn E. Manson, MD, DrPH

Arch Intern Med. 2007;167(15):1676-1685.

Background  Inflammatory cytokines, including tumor necrosis factor , IL-6 (interleukin 6), and high-sensitivity C-reactive protein (hsCRP), have been related to both insulin resistance and type 2 diabetes mellitus. However, prospective studies that comprehensively assess their roles in the development of type 2 diabetes are few, especially in minority populations.

Methods  Among 82 069 postmenopausal women aged 50 to 79 years without cardiovascular disease or diabetes mellitus who participated in the Women's Health Initiative Observational Study, we prospectively examined the relationships of plasma levels of tumor necrosis factor receptor 2, IL-6, and hsCRP to diabetes risk. During a median follow-up period of 5.9 years, 1584 women who had clinical diabetes were matched by age, ethnicity, clinical center, time of blood draw, and duration of follow-up to 2198 study participants who were free of the disease.

Results  After adjustment for matching factors and known diabetes risk factors, all 3 markers were significantly associated with increased diabetes risk; the estimated relative risks comparing the highest with the lowest quartiles were 1.47 (95% confidence interval [CI], 1.10-1.97) for tumor necrosis factor receptor 2, 3.08 (95% CI, 2.25-4.23) for IL-6, and 3.46 (95% CI, 2.50-4.80) for hsCRP (P for trend, <.01 for all biomarkers). When mutually adjusted, IL-6 and hsCRP remained significant in each ethnic group. While no statistically significant interactions were observed between ethnicity and these biomarkers on diabetes risk, there were consistent trends for the associations of hsCRP and IL-6 with increased diabetes risk in all ethnic groups.

Conclusion  These prospective data showed that elevated levels of IL-6 and hsCRP were consistently and significantly associated with an increased risk of clinical diabetes in postmenopausal women.

Author Affiliations: Departments of Epidemiology (Dr Liu) and Medicine (Dr Liu), University of California, Los Angeles; Division of Preventive Medicine (Drs Liu, Song, and Manson) and Channing Laboratory (Drs Hu and Manson), Department of Medicine, Brigham and Women's Hospital, and Department of Laboratory Medicine, Children's Hospital (Dr Rifai), Harvard Medical School, and Departments of Epidemiology (Drs Liu, Cook, Hu, and Manson) and Genetics and Complex Diseases (Dr Hotamisligil), Harvard School of Public Health, Boston, Massachusetts; Public Health Division, Fred Hutchinson Cancer Research Center, Seattle, Washington (Dr Tinker); Departments of Public Health Sciences (Dr Bonds) and Medicine (Dr Bonds), University of Virginia, Charlottesville; Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill (Dr Heiss); MedStar Research Institute, Washington, DC (Dr Howard); and Department of Epidemiology, University of Pittsburgh, School of Public Health, Pittsburgh, Pennsylvania (Dr Kuller).

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