Sex-Specific Association of Circulating Ferritin Level and Risk of Type 2 Diabetes: A Dose-Response Meta-Analysis of Prospective Studies

Abstract

Context: Although the role of iron in the development of type 2 diabetes (T2D) has long been a concern, prospective studies directly linking body iron stores to T2D risk in a sex-dependent context have been inconsistent. Objective: A systematic meta-analysis was conducted to explore the sex-specific association of circulating ferritin with T2D risk. Data Sources: We searched PubMed, Web of Science, and EMBASE databases to identify available prospective studies through 1 August 2018. Results: Fifteen prospective studies comprising 77,352 participants and 18,404 patients with T2D, aged 20 to 80 years, and with ∼3 to 17 years of follow-up were identified. For each 100-μg/L increment in ferritin levels of overall participants, T2D risk increased by 22% (RR, 1.22; 95% CI, 1.14 to 1.31). Of note, major heterogeneities by sex were identified, with increased ferritin level having an apparently greater effect on T2D risk in women (RR, 1.53; 95% CI, 1.29 to 1.82) than in men (RR, 1.21; 95% CI, 1.15 to 1.27) after exclusion of a study with high heterogeneity (41,512 men and 6974 women for sex-specific analyses; P = 0.020 for sex difference). Further nonlinear analysis between circulating ferritin and T2D risk also showed sex-dimorphic association in that the T2D risk of women was twice as strong in magnitude as that of men at the same ferritin level. Conclusions: Greater circulating ferritin levels were independently associated with increased T2D risk, which appeared stronger among women than men. Our findings provide prospective evidence for further testing of the utility of ferritin levels in predicting T2D risk in a sex-specific manner.