The Role of Iron in Diabetes and Its Complications

The central importance of iron in the pathophysiology of disease is derived from the ease with which iron is reversibly oxidized and reduced. This property, while essential for its metabolic functions, makes iron potentially hazardous because of its ability to participate in the generation of powerful oxidant species such as hydroxyl radical (1). Oxygen normally accepts four electrons and is converted directly to water. However, partial reduction of oxygen can and does occur in biological systems. Thus, the sequential reduction of oxygen along the univalent pathway leads to the generation of superoxide anion, hydrogen peroxide, hydroxyl radical, and water (1,2). Superoxide and hydrogen peroxide appear to be the primary generated species. These species may then play a role in the generation of additional and more reactive oxidants, including the highly reactive hydroxyl radical (or a related highly oxidizing species) in which iron salts play a catalytic role in a reaction. This reaction is commonly referred to as the metal catalyzed Haber-Weiss reaction (1): \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[\frac{\mathrm{Fe}^{3{+}}{+}\mathrm{O}\_{{\dot{2}}}^{{\mbox{--}}} \mathrm{Fe}^{2{+}}{+}\mathrm{O}\_{2}\ \mathrm{Fe}^{2{+}}{+}\mathrm{H}\_{2}\mathrm{O}\_{2} \mathrm{Fe}^{3{+}}{+}{\cdot}\mathrm{OH}{+}\mathrm{OH}{-}}{\mathrm{O}\_{{\dot{2}}}^{{\mbox{--}}}{+}\mathrm{H}\_{2}\mathrm{O}\_{2} \mathrm{O}\_{2}{+}{\cdot}\mathrm{OH}{+}\mathrm{OH}{-}}\] \end{document} Because iron participates in the formation of reactive oxygen species, organisms take great care in the handling of iron. Indeed, iron sequestration in transport and storage proteins may contribute to antioxidant defenses. It is now well established that oxidants can cause the release of catalytic iron (1); thus, a vicious cycle is initiated that leads to the formation of more reactive oxygen species. In this review, we discuss the role tissue iron and elevated body iron stores play in causing type 2 diabetes and the pathogenesis of its important complications, particularly diabetic nephropathy and cardiovascular disease (CVD). In addition, we emphasize that iron overload is not a prerequisite for iron to mediate either diabetes or its complications. Important in its pathophysiology is the availability of so-called catalytic iron or iron that is available to …