Regulatory Connections between Iron and Glucose Metabolism

Abstract

Iron is essential for energy metabolism, and states of iron deficiency or excess are detrimental for organisms and cells. Therefore, iron and carbohydrate metabolism are tightly regulated. Serum iron and glucose levels are subjected to hormonal regulation by hepcidin and insulin, respectively. Hepcidin is a liver-derived peptide hormone that inactivates the iron exporter ferroportin in target cells, thereby limiting iron efflux to the bloodstream. Insulin is a protein hormone secreted from pancreatic β-cells that stimulates glucose uptake and metabolism via insulin receptor signaling. There is increasing evidence that systemic, but also cellular iron and glucose metabolic pathways are interconnected. This review article presents relevant data derived primarily from mouse models and biochemical studies. In addition, it discusses iron and glucose metabolism in the context of human disease.

Keywords: IRP1; IRP2; adipokines; ferroportin; hepcidin; insulin.

Figure 1

Hormonal regulation of systemic iron traffic by hepcidin. Hepcidin is synthesized in hepatocytes of the liver in response to hyperferremia iron or secretion of bone morphogenetic protein (BMP6) and BMP2 from liver sinusoidal endothelial cells; BMP6 secretion reflects increased body iron stores. It binds to the iron exporter ferroportin in target cells (red arrows) such as tissue macrophages, hepatocytes and intestinal epithelial cells and inhibits ferroportin-mediated iron efflux. Hepcidin binding directly inhibits iron efflux from ferroportin and also promotes ferroportin internalization and degradation. These responses cause cellular iron retention and reduce plasma iron levels.

Figure 2

Hormonal regulation of glucose metabolism by insulin. Insulin is synthesized in pancreatic β cells in response to hyperglycemia. It binds to insulin receptors in target cells (red arrows) such as skeletal muscle cells, hepatocytes and adipocytes and induces signaling pathways that promote glucose uptake, catabolism or storage. This reduces plasma glucose levels.

Figure 3

Iron-dependent regulation of adipokines. Increased adipose tissue iron levels inhibit insulin-sensitizing adiponectin and leptin and stimulate insulin-inhibitory resistin and retinol-binding protein 4 (RBP-4). Conversely, reduced adipose tissue iron levels stimulate insulin-sensitizing adiponectin and leptin and inhibit insulin-inhibitory resistin and RBP-4.

Figure 4

The role of iron in the physiological function of pancreatic β cells. Balanced iron metabolism is critical for proper glucose-stimulated insulin production. Iron deficiency as well as iron overload impair insulin expression.