Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes

The EPIC-InterAct Study

Clara Podmore; Karina Meidtner; Matthias B. Schulze; Robert A. Scott; Anna Ramond; Adam S. Butterworth; Emanuele Di Angelantonio; John Danesh; Larraitz Arriola; Aurelio Barricarte; Heiner Boeing; Françoise Clavel-Chapelon; Amanda J. Cross; Christina C. Dahm; Guy Fagherazzi; Paul W. Franks; Diana Gavrila; Sara Grioni; Marc J. Gunter; Gaelle Gusto; Paula Jakszyn; Verena Katzke; Timothy J. Key; Tilman Kühn; Amalia Mattiello; Peter M. Nilsson; Anja Olsen; Kim Overvad; Domenico Palli; J. Ramón Quirós; Olov Rolandsson; Carlotta Sacerdote; Emilio Sánchez-Cantalejo; Nadia Slimani; Ivonne Sluijs; Annemieke M.W. Spijkerman; Anne Tjonneland; Rosario Tumino; Daphne L. van der A; Yvonne T. van der Schouw; Edith J.M. Feskens; Nita G. Forouhi; Stephen J. Sharp; Elio Riboli; Claudia Langenberg; Nicholas J. Wareham


Diabetes Care. 2016;39(4):572-581. 

In This Article

Abstract and Introduction


Objective Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores in T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigated associations of ferritin, transferrin saturation (TSAT), serum iron, and transferrin with T2D incidence to clarify the role of iron in the pathogenesis of T2D.

Research Design and Methods The European Prospective Investigation into Cancer and Nutrition–InterAct study includes 12,403 incident T2D cases and a representative subcohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron, and transferrin with incident T2D in 11,052 cases and a random subcohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population.

Results Higher levels of ferritin and transferrin were associated with a higher risk of T2D (hazard ratio [HR] [95% CI] in men and women, respectively: 1.07 [1.01–1.12] and 1.12 [1.05–1.19] per 100 μg/L higher ferritin level; 1.11 [1.00–1.24] and 1.22 [1.12–1.33] per 0.5 g/L higher transferrin level) after adjustment for age, center, BMI, physical activity, smoking status, education, hs-CRP, alanine aminotransferase, and γ-glutamyl transferase. Elevated TSAT (≥45% vs. <45%) was associated with a lower risk of T2D in women (0.68 [0.54–0.86]) but was not statistically significantly associated in men (0.90 [0.75–1.08]). Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (P interaction < 0.01).

Conclusions The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D.


Hereditary hemochromatosis (HHC), a genetic disorder characterized by systemic iron overload, is reported to be associated with diabetes.[1] Similarly, an overrepresentation of diabetes cases has also been described among individuals with conditions of acquired iron overload, such as thalassemia major.[2] This raises the question whether high levels of body iron are a risk factor for type 2 diabetes in the general population; this would have implications for the prevention and treatment of type 2 diabetes. Cross-sectional and prospective population studies report a positive association between ferritin and type 2 diabetes.[3,4] However, although ferritin is considered a marker of iron stores in healthy individuals,[5–7] it is also an acute phase reactant and is influenced by inflammation, liver disease, and insulin resistance, which are also associated with type 2 diabetes.[8–11]

Other commonly measured biomarkers of iron metabolism reflect different aspects of the process and are less influenced by the above-mentioned conditions; therefore, their use may provide additional information on the role of iron in the pathogenesis of type 2 diabetes. Transferrin is the iron-binding protein in circulation, and its levels rise with increasing iron requirements. Serum iron is difficult to interpret in isolation because it has a diurnal variation and hence varies significantly without changes in total body iron.[12] Transferrin saturation (TSAT) is the proportion of transferrin bound to serum iron and is in part a marker of iron absorption: it reflects the proportion of circulating iron in the context of iron requirements. TSAT is elevated in the presence of non-transferrin-bound iron, which in turn is responsible for iron-related oxidative damage.[13,14]

We investigated the association of ferritin, TSAT, serum iron, and transferrin with incident type 2 diabetes in a large, prospective European case-cohort study. We also assessed whether these associations have a threshold effect or differ by subgroups of the population, such as individuals not presenting signs of conditions commonly associated with hyperferritinemia.