Body Iron Stores in Relation to Risk of Type 2 Diabetes in Apparently Healthy Women

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

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.

Corresponding Author: Rui Jiang, MD, DrPH, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115 ([email protected]).

Author Contributions: Dr Hu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Jiang, Manson, Meigs, Ma, Hu.

Acquisition of data: Manson, Rifai, Hu.

Analysis and interpretation of data: Jiang, Manson, Meigs, Ma, Hu.

Drafting of the manuscript: Jiang.

Critical revision of the manuscript for important intellectual content: Jiang, Manson, Meigs, Ma, Rifai, Hu.

Statistical expertise: Jiang, Meigs, Ma, Hu.

Obtained funding: Manson, Hu.

Administrative, technical, or material support: Manson, Hu.

Supervision: Manson, Hu.

Funding/Support: This work was supported by research grants DK58845, CA87969, and CA78293 from the National Institutes of Health. Dr Meigs is supported in part by a Career Development Award from the American Diabetes Association.

Role of the Sponsor: Funding sources had no role in the design, conduct, and reporting of this study.

JAMA: The Journal of the American Medical Association 291(6):p 711-717, February 11, 2004.

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.