Hepcidin in Iron Homeostasis: Diagnostic and Therapeutic Implications in Type 2 Diabetes Mellitus Patients

Abstract

The prevalence of type 2 diabetes is increasing in epidemic proportions worldwide. Evidence suggests body iron overload is frequently linked and observed in patients with type 2 diabetes. Body iron metabolism is based on iron conservation and recycling by which only a part of the daily need is replaced by duodenal absorption. The principal liver-produced peptide called hepcidin plays a fundamental role in iron metabolism. It directly binds to ferroportin, the sole iron exporter, resulting in the internalization and degradation of ferroportin. However, inappropriate production of hepcidin has been shown to play a role in the pathogenesis of type 2 diabetes mellitus and its complications, based on the regulation and expression in iron-abundant cells. Underexpression of hepcidin results in body iron overload, which triggers the production of reactive oxygen species simultaneously thought to play a major role in diabetes pathogenesis mediated both by β-cell failure and insulin resistance. Increased hepcidin expression results in increased intracellular sequestration of iron, and is associated with the complications of type 2 diabetes. Besides, hepcidin concentrations have been linked to inflammatory cytokines, matriptase 2, and chronic hepatitis C infection, which have in turn been reported to be associated with diabetes by several approaches. Either hepcidin-targeted therapy alone or as adjunctive therapy with phlebotomy, iron chelators, or dietary iron restriction may be able to alter iron parameters in diabetic patients. Therefore, measuring hepcidin may improve differential diagnosis and the monitoring of disorders of iron metabolism.

Association of serum ferritin with metabolic syndrome in eight cities in China

“…Iron metabolism in the body, consisting of iron conservation and recycling, is controlled by hepcidin. Meanwhile, hepcidin is homeostatically regulated by iron and erythropoietic activity (Ambachew & Biadgo, ). Therefore, iron in a healthy person is in a state of metabolic balance.…”

Iron Metabolism in Obesity and Metabolic Syndrome

“…In cells like macrophages or hepatocytes, hepcidin binds to ferroportin and leads to its internalization and degradation, so that less ferrous iron is exported to circulation. In enterocytes, hepcidin seems to inhibit DMT1 production transcriptionally, inducing a decrease in ferrous iron uptake in the duodenum [ 98 , 99 ].…”

“…Then, a complex of SMAD proteins enters the nucleus and activates the transcription of the HAMP gene after binding to the BMP responsive element at its promoter. After being cleaved by matriptase-2, HJV is converted into a soluble form that may act as an antagonist in the interaction BMP-BMPR, inhibiting hepcidin expression [ 99 , 100 , 101 ]. The hemochromatosis protein (HFE) and both transferrin receptors (TfR1 and TfR2) are also part of a hepcidin level regulatory pathway via the ERK/MAPK pathway.…”

“…With high plasma iron levels, as TfR1 presents a higher affinity for holo-Tf than for HFE, HFE dissociates and binds to TfR2. Thereafter, the holo-Tf-HFE-TfR2 complex activates the ERK signaling pathway, resulting in HAMP expression [ 99 , 101 ]. Erythropoiesis also inhibits hepcidin synthesis in hepatocytes, because erythroid precursors release erythroferrone (ERFE), which suppress hepcidin expression to facilitate iron acquisition for hemoglobin synthesis [ 102 , 103 ].…”

“…Increased levels of cytokines such as IL-6 after infection lead to the activation of Janus kinases (JAK), which phosphorylate signal transducers and activators of transcription (STAT) proteins. STAT3 can now enter the nucleus and activate HAMP expression [ 99 , 104 ].…”