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

Abstract

OBJECTIVEThe 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 METHODSThe 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). RESULTSThe 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. CONCLUSIONSIron 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 diseases. 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 synthesis, 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

Dietary iron intake, iron status, and gestational diabetes

“…For example, oxidative stress from excess iron accumulation can lead to b cell damage and apoptosis and, consequently, contribute to decreased insulin secretion (3). High iron stores in the liver may induce insulin resistance by impairing insulin signaling and by attenuating the liver's ability to extract insulin (4,5). In adipocytes, excess iron can diminish insulininduced glucose transport, whereas in the muscles it may lead to a switch from glucose to fatty acid oxidation (6,7).…”

Hyperferritinemia in patients with nonalcoholic fatty liver disease

“…29 In another line of reasoning, it is suggested that iron depletion allows a more relevant improvement of liver enzyme levels and histological changes present in NAFLD. 6,30 Out of 11 studies evaluated in our review, the only discordant one regarding the interpretation of HPF was that by Chandok et al 3 In the article, HPF was similar in patients with steatosis, NASH or cirrhosis. We speculate whether this finding could be justified by the fact that only 19.3% of the participants in this study were evaluated by liver biopsy and histological analysis.…”

Diabetes inHFEHemochromatosis

“…Favorable effects of phlebotomy on diabetes manifestations suggest that abnormal distribution of normal quantities of body iron contribute to diabetogenesis in some persons without hemochromatosis [143–145]. Iron-related dietary, cellular, and molecular mechanisms may contribute to the development or expression of type 2 diabetes [146] (Table 2). These and other mechanisms may also be associated with or cause impaired glucose metabolism, IR, and MetS.…”