Cross-Talk Between Iron Metabolism and Diabetes

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


Diabetes. 2002;51(8) 

In This Article

Abstract and Introduction

Emerging scientific evidence has disclosed unsuspected influences between iron metabolism and type 2 diabetes. The relationship is bi-directional—iron affects glucose metabolism, and glucose metabolism impinges on several iron metabolic pathways. Oxidative stress and inflammatory cytokines influence these relationships, amplifying and potentiating the initiated events. The clinical impact of these interactions depends on both the genetic predisposition and the time frame in which this network of closely related signals acts. In recent years, increased iron stores have been found to predict the development of type 2 diabetes while iron depletion was protective. Iron-induced damage might also modulate the development of chronic diabetes complications. Iron depletion has been demonstrated to be beneficial in coronary artery responses, endothelial dysfunction, insulin secretion, insulin action, and metabolic control in type 2 diabetes. 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. The study of individual susceptibility and of the mechanisms that influence tissue iron deposition and damage are proposed to be valuable in anticipating and treating diabetes complications.

It is increasingly recognized that iron influences glucose metabolism, even in the absence of significant iron overload. In the generalpopulation, body iron stores are positively associated with the development of glucose intolerance, type 2 diabetes,[1,2,3,4,5,6,7] and gestational diabetes.[8,9] Among U.S. adults, men with newly diagnosed diabetes had an odds ratio (OR) of 4.94 (95%confidence interval [CI] 3.05-8.01) and women had an OR of 3.61 (2.01-6.48) of having elevated ferritin concentrations.[6] These figures are especially remarkable when considering the increased prevalence of elevated iron stores in the healthy, free-living U.S. elderly population (28% of men and 12.2% of women showed high iron stores in a recent study).[10]

Frequent blood donations, leading to decreased iron stores, have been demonstrated to reduce postprandial hyperinsulinemia in healthy volunteers,[11] to improve insulin sensitivity,[12] and to constitute a protective factor for the development of type 2 diabetes.[13] Phlebotomy was followed by decreases in serum glucose, cholesterol, triglycerides and a poprotein B,[14] and by improvement in both -cell secretion and peripheral insulin action in patients with type 2 diabetes.[15] A significant impact of tissue iron excess on systemic effects of diabetes is suggested by recent reports in which iron appears to influence the development of diabetic nephropathy and vascular dysfunction. In this sense, intravenous administration of deferoxamine resulted in improved coronary artery responses to cold stress testing in type 2 diabetic subjects[16] and in amelioration of endothelial dysfunction in subjects with coronary heart disease.[17]

All these observations suggest that iron is more intimately linked to human pathophysiology than previously thought. In fact, iron metabolism is closely associated with the clinical presentation of numerous systemic diseases.[18] Tissue iron excess contributes to produce and amplify the injury caused by free radicals as well as to modulate various steps involved in the inflammatory lesion.

In this article, we summarize the relationships between iron, insulin resistance, and type 2 diabetes and discuss the therapeutical and clinical implications of reducing body iron.