Cross-Talk Between Iron Metabolism and Diabetes

José Manuel Fernández-Real, Abel López-Bermejo, and Wifredo Ricart


Diabetes. 2002;51(8) 

In This Article


The central role of iron in biology is illustrated by the fact that this is the fourth most abundant element in Earth’s crust as well as the transition element most abundant in living organisms. Iron has additionally proven to be fundamental in the selection imposed by evolution, given its close relationship with oxygen. Although loses of this metal are only a tenth of those found in any other given mammal, iron regulation is maintained within very narrow limits in humans.[71]

Our biochemistry and physiology are tuned to life conditions that existed before the advent of agriculture some 10, 000 years ago. Hunter-gatherer societies obtained more than 56-65%of their subsistence from animal foods.[81] Meat eaters, with a typical high protein and low- carbohydrate diet, have a significant higher plasma concentration of iron[82] and concomitant insulin resistance in the liver and peripheral tissues.[83] It is plausible that the survival advantage of both iron and high protein-induced insulin resistance in our ancestral line was that the little available glucose from carbohydrate consumption was preserved for brain function and reproductive fetal/placental/mammary tissues.[84] Nowadays, with increased life expectancy, this protective mechanism has become detrimental, with iron promoting both insulin resistance and increased oxidative stress.

In the last decades, the impact of transition metals, in general, and iron, in particular, on human physiology has begun to be elucidated. Because iron is a first-line prooxidant, it contributes to regulate the clinical manifestations of numerous systemic diseases, including diabetes and atherosclerosis. Iron regulation of the cell oxidative stress can explain, at least in part, its close association with abnormalities in insulin sensitivity (see Figure 1 for a summary of iron interactions with insulin sensitivity).

Schematic representation of iron interactions with insulin resistance and oxidative stress. Insulin influences iron metabolism. Insulin stimulates ferritin synthesis and facilitates iron uptake by the cell through the translocation of transferrin receptors from the intracellular compartment to the cell surface. Conversely, iron influences glucose metabolism. Iron in a potent prooxidant that increases the cell oxidative stress, causing inhibition of insulin internalization and actions, results in hyperinsulinemia and insulin resistance. Free iron also exerts a positive feedback on ferritin synthesis, while oxidative stress increases the release of iron from ferritin. The increased oxidative stress and insulin resistance cause endothelial and tissue damage. Protein glycation, as seen in diabetes, further amplifies these abnormalities stimulating iron release from transferrin, increasing the cell oxidative stress and directly causing endothelial and tissue damage. NO, nitric oxide; TR, transferrin receptor; (+), stimulation; (-), inhibition; dotted lines, possible trafficking or iron through the cell membrane.

The clarification of the mechanisms that regulate this interaction are proposed to contribute to improve the management of diabetes and to anticipate its possible complications. Here, we show that iron modulates insulin action in healthy individuals and in patients with type 2 diabetes. The extent of this influence should be tested in large-scale clinical trials, searching for the usefulness and cost-effectiveness of therapeutic measures that decrease iron toxicity. Of paramount importance will be the definition of "normal body iron stores" and the establishment of early therapeutical interventions. Simple and inexpensive therapies, such as blood letting and iron chelators, are emerging as alternative and effective treatments for insulin resistance.

It will also be necessary to explore whether important elements of iron metabolism are altered in diabetes, namely the transporters DMT1, ferroportin, and MTP1, which are critical in intestinal absorption and entry of iron into the circulation, and haephastin, which oxidizes Fe2+ to Fe3+ during this process.[85] Interestingly, certain genes appear to be simultaneously involved in iron balance, inflammation, and glucose responsiveness, suggesting a link between these pathways and type 2 diabetes.[85]