Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes Diabetes Care 2015;38:2169–2176 | DOI: 10.2337/dc14-3082 OBJECTIVE The bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa. RESEARCH DESIGN AND METHODS The mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing b-cells were revised according to their possible influence on the development of type 2 diabetes (T2D). RESULTS The mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucose metabolism in the senescent muscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate b-cells and insulin secretion, although this has been scarcely studied. CONCLUSIONS Iron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted. Iron levels help to modulate the clinical manifestations of numerous systemic dis- eases. The importance of adequate amounts of iron for health and well-being in humans is well known. Iron is involved in binding and transporting oxygen and regulating cell growth and differentiation, as well as electron transport, DNA syn- thesis, and many important metabolic processes (1). From a clinical standpoint, assessing serum ferritin concentrations is a useful measure of iron storage. Ferritin is also an acute-phase reactant and, as such, is 1 University Hospital of Girona "DrJosepTrueta," Department of Diabetes, Endocrinology and Nu- trition, Institut d’Investigaci ´ o Biom` edica de Gi- rona (IdIBGi), Girona, Spain 2 CIBER Fisiopatolog´ ıa de la Obesidad y Nutrici ´ on, Girona, Spain 3 Departments of Biochemistry and Internal Med- icine, University of Utah, Salt Lake City, UT 4 Veterans Administration Research Service, Salt Lake City VAHCS, Salt Lake City, UT 5 Bambino Ges ` u Children’s Hospital and Research Institute, Research Unit for Multifactorial Dis- ease, Rome, Italy Corresponding author: Jos´ e Manuel Fern ´ andez- Real, jmfreal@idibgi.org. Received 29 December 2014 and accepted 21 August 2015. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. Jos´ e Manuel Fern ´ andez-Real, 1,2 Donald McClain, 3,4 and Melania Manco 5 Diabetes Care Volume 38, November 2015 2169 REVIEW Downloaded from http://diabetesjournals.org/care/article-pdf/38/11/2169/623440/dc143082.pdf by guest on 18 October 2022