Ironing Out the Risk Factors for Diabetes

Abstract & Commentary

Synopsis: Increased iron stores (eg, ferritin levels) are associated with an increased risk of type 2 diabetes in women.

Source: Jiang R, et al. JAMA. 2004;291:711-717.

This paper comes from the Nurses’ Health Study, a prospective evaluation of more than 120,000 registered nurses recruited between 1989 and 1990. This cohort has been described elsewhere;1 in brief, it consists of healthy women, aged 30-55 years at baseline. The current study includes 698 women from the Nurse’s Health Cohort who developed diabetes between 1990 and 2000. Controls were also drawn from the Nurses’ Health Cohort, and were matched for age, race, fasting blood work results at study entry, and Body Mass Index (BMI). The definition of diabetes was in flux during this study. For cases identified prior to 1998, it was based on the National Diabetes Data Group criteria,2 but beginning in 1998, it was based on the report of the American Diabetes Association.3 Essentially, this resulted in a change in threshold of fasting glucose from 140 mg/dL to 126 mg/dL. Women with gestational or Type 1 diabetes were excluded. In addition to fasting, meticulously controlled blood work at study entry, participants completed voluminous questionnaires about family history, lifestyle factors, menopausal status, medication history, physical activity, and diet.

Compared with controls, the women who developed diabetes between 1990 and 2000 were heavier, more likely to have a family history of diabetes, and less likely to exercise and consume alcohol at study entry. Their diet was more likely to include higher amounts of heme iron, transfat, red and processed meats, and calories. They took in smaller amounts of dietary cereal fiber and magnesium. They also had higher plasma concentrations of C-Reactive Protein (CRP), fasting insulin, hemoglobin and A1C at baseline. At baseline, their mean serum ferritin levels were significantly higher than the controls (109 vs 71.5 ng/mL; P < .001), and their ratio of transferrin receptors to ferritin was significantly lower (102 vs 141; P =.01). The Relative Risk (RR) of developing diabetes rose linearly with ferritin levels; for those with the highest levels (> 107.2 ng/mL), the RR was 3.2. Adjusting for important variables including BMI, age, race, family history, activity, caloric intake, menopausal status, CRP levels, and intake of iron supplements reduced the RR only modestly. The authors concluded that total body iron stores are an independent risk factor for type 2 diabetes.

Comment by Barbara A. Phillips, MD, MSPH

Hemachromatosis is a risk factor for diabetes, and iron has long been suspected of causing diabetes and/or cardiovascular disease because of its prooxidant properties.4 Despite this suspected association, only one other small study (in men) has longitudinally evaluated the risk of diabetes in relationship to iron stores.5 The current study is important because it tells us more about risk factors for diabetes (ferritin levels, transferrin to ferritin ratio, and CRP), and because it suggests that even menstruating women could be at risk with oversupplementation of iron.

The study particularly interested me because of the well-established relationship between iron stores and Restless Legs Syndrome (RLS). Individuals with ferritin levels below 45 ng/mL are at increased risk for RLS, and iron supplementation can reduce or eliminate RLS symptoms.6,7 The current study by Jiang and colleagues reminds of us a common theme in medicine and nature: a little bit can be good, but more is not necessarily better!

Dr. Phillips, Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington, KY, is Associate Editor of Internal Medicine Alert.


1. Colditz GA, et al. J Womens Health. 1997;6:49-62.

2. National Diabetes Data Group. Diabetes. 1979;28:1039-1057.

3. American Diabetes Association. Diabetes Care. 1997;20:1183-1197.

4. Ford ES, Cogswell ME. Diabetes Care. 1999;22: 1978-1983.

5. Salonen JT, et al. BMJ. 1998;317-327.

6. Sun ER, et al. Sleep. 1998;21(4):371-377.

7. Hening W, et al. Sleep. 1999;22(7):970-999.