Background: Excess iron has been shown to induce diabetes in animal models. However, the results from human epidemiologic studies linking body iron stores and iron intake to the risk of type 2 diabetes mellitus (T2DM) are conflicting. In this study, we aimed to systematically evaluate the available evidence for associations between iron intake, body iron stores, and the risk of T2DM. Methods: A systematic search of the PubMed/MEDLINE and EMBASE databases to the end of 22 April 2012 was performed, and reference lists of retrieved articles were screened. Two reviewers independently evaluated the eligibility of inclusion and extracted the data. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. Results: We reviewed 449 potentially relevant articles, and 11 prospective studies were included in the analysis. A meta-analysis of five studies gave a pooled RR for T2DM of 1.33 (95% CI 1.19 to 1.48; P<0.001) in individuals with the highest level of heme iron intake, compared with those with the lowest level. The pooled RR for T2DM for a daily increment of 1 mg of heme iron intake was 1.16 (1.09 to 1.23, P<0.001). Body iron stores, as measured by ferritin, soluble transferrin receptor (sTfR) and the sTfR:ferritin ratio, were significantly associated with the risk of T2DM. The pooled RRs for T2DM in individuals with the highest versus the lowest intake of ferritin levels was 1.70 (1.27-2.27, P<0.001) before adjustment for inflammatory markers and 1.63 (1.03-2.56, P = 0.036) after adjustment. We did not find any significant association of dietary intakes of total iron, non-heme, or supplemental iron intake with T2DM risk. Conclusion: Higher heme iron intake and increased body iron stores were significantly associated with a greater risk of T2DM. Dietary total iron, non-heme iron, or supplemental iron intakes were not significantly associated with T2DM risk.

Plasma transthyretin may be engaged in glucose regulation. We aimed to investigate the association between plasma transthyretin levels and the risk of newly diagnosed T2DM and impaired glucose regulation (IGR) in a Chinese population. We conducted a case-control study including 1244 newly diagnosed T2DM patients, 837 newly diagnosed IGR patients, and 1244 individuals with normal glucose tolerance (NGT) matched by sex and age. Multivariate logistic regression analysis was utilized to estimate the independent association of plasma transthyretin concentrations with the risk of T2DM and IGR. Plasma transthyretin concentrations were significantly higher in T2DM and IGR patients compared with control subjects (p < 0.005). After multiple adjustment and comparison with the lowest quartile of plasma transthyretin concentrations, the odds ratios (95% confidence intervals) of T2DM and IGR in the highest quartile were 2.22 (1.66, 2.98) and 2.29 (1.72, 3.05), respectively. Plasma transthyretin concentrations also showed a great performance in predicting the risk of T2DM (AUC: 0.76). Moreover, a potential nonlinear trend was observed. Our results demonstrated that higher plasma transthyretin concentrations, especially more than 290 mg/L, were associated with an increased risk of T2DM and IGR. Further studies are warranted to confirm our findings and elucidate the potential mechanisms.