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Rui Jiang, MD, DrPH; JoAnn E. Manson, MD, DrPH; James B. Meigs, MD, MPH; Jing Ma, MD, PhD; Nader Rifai, PhD; Frank B. Hu, MD, PhD

JAMA. 2004;291:711-717.

Context  Type 2 diabetes is a common manifestation of hemochromatosis, a disease of iron overload. However, it is not clear whether higher iron stores predict the development of type 2 diabetes in a healthy population.

Objective  To examine plasma ferritin concentration and the ratio of the concentrations of transferrin receptors to ferritin in relation to risk of type 2 diabetes.

Design, Setting, and Participants  Prospective nested case-control study within the Nurses' Health Study cohort. Of the 32 826 women who provided blood samples during 1989-1990 and were free of diagnosed diabetes, cardiovascular disease, and cancer, 698 developed diabetes during 10 years of follow-up. The controls (n = 716) were matched to cases on age, race, and fasting status; and on body mass index (BMI) for cases in the top BMI decile.

Main Outcome Measure  Incident cases of type 2 diabetes.

Results  Among cases, the mean (SD) concentration of ferritin was significantly higher (109 [105] vs 71.5 [68.7] ng/mL for controls; P<.001 for difference) and the mean (SD) ratio of transferrin receptors to ferritin was significantly lower (102 [205] vs 141 [340], respectively; P = .01). In conditional logistic regression stratified on the matching factors and controlled for BMI and other diabetes risk factors, the multivariate relative risks [RRs] of incident type 2 diabetes across increasing quintiles of ferritin were 1.00, 1.09 (95% confidence interval [CI], 0.70-1.70), 1.26 (95% CI, 0.82-1.95), 1.30 (95% CI, 0.83-2.04), and 2.68 (95% CI, 1.75-4.11) (P<.001 for trend). The RRs across increasing quintiles of transferrin receptors to ferritin ratio were 2.44 (95% CI, 1.61-3.71), 1.00 (95% CI, 0.64-1.56), 1.13 (95% CI, 0.73-1.74), 0.99 (95% CI, 0.64-1.53), and 1.00 (P = .01 for trend). Further adjustment for an inflammatory marker (C-reactive protein) did not change the results appreciably. The associations persisted within strata defined by levels of BMI, menopausal status, alcohol consumption, and C-reactive protein.

Conclusion  Higher iron stores (reflected by an elevated ferritin concentration and a lower ratio of transferrin receptors to ferritin) are associated with an increased risk of type 2 diabetes in healthy women independent of known diabetes risk factors.

Author Affiliations: Departments of Nutrition (Drs Jiang and Hu) and Epidemiology (Drs Jiang, Manson, and Hu), Harvard School of Public Health; Division of Preventive Medicine (Dr Manson), Departments of Medicine (Drs Meigs and Rifai) and Pathology (Dr Rifai), Harvard Medical School; General Medicine Division, Brigham and Women's Hospital (Dr Meigs); Channing Laboratory (Drs Manson, Ma, and Hu); and Department of Medicine, Massachusetts General Hospital and Children's Hospital Medical Center (Dr Rifai), Boston.

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