Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

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.The mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing β-cells were revised according to their possible influence on the development of type 2 diabetes (T2D).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 β-cells and insulin secretion, although this has been scarcely studied.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.