Iron and diabetes risk

Abstract

Iron overload is a risk factor for diabetes. The link between iron and diabetes was first recognized in pathologic conditions-hereditary hemochromatosis and thalassemia-but high levels of dietary iron also impart diabetes risk. Iron plays a direct and causal role in diabetes pathogenesis mediated both by β cell failure and insulin resistance. Iron also regulates metabolism in most tissues involved in fuel homeostasis, with the adipocyte in particular serving an iron-sensing role. The underlying molecular mechanisms mediating these effects are numerous and incompletely understood but include oxidant stress and modulation of adipokines and intracellular signal transduction pathways.

Fig. 1. Overview of iron trafficking

Intestinal free ferric (Fe³⁺) iron is reduced to Fe²⁺ by DCTB and enters the cell through the divalent metal-ion transporter 1 (DMT1) and possibly other carriers. Dietary heme is directly absorbed and iron is released by heme oxygenase (HMOX). Iron exits the enterocyte through the iron export channel ferroportin (FPN). After oxidization by hephaestin (HEPH) iron binds to transferrin (Tf) in the bloodstream which binds to transferrin receptors (TfR)-1 and -2 on the surface of target cells. In most cells, after endocytosis of TfR1 and acidification of the endosome, iron is released, reduced by STEAP, and enters the cytosol through DMT1 where it is used (e.g. for heme or Fe-S-cluster synthesis in the mitochondrion) or if in excess, sequestered by ferritin. Ferritin secreted into the blood serves as a marker for tissue iron stores. In the liver, Tf binds TfR 2 and the protein HFE, and in concert with signaling via GPI-anchored protein hemojuvelin (HJV), bone morphogenic proteins (BMP) and the SMAD signal transduction pathway, production of hepcidin is signaled. Hepcidin induces internalization and degradation of FPN, thus completing a negative feedback regulatory loop.

Fig. 2. Relative risk of diabetes as a function of ferritin or dietary iron intake in four studies

Plotted are the relative risks from four studies (Bowers et al., 2011) (Qiu et al., 2011) (Ford and Cogswell, 1999) (Jiang et al., 2004), with the comparator groups listed on the y-axis.