High Glucose Diet Induces Hepatic Iron Overload Contributing to Metabolic Dysfunction

Iron is an essential biometal, critical in processes that include oxygen transport, mitochondrial respiration, and cell signaling. Iron dyshomeostasis is linked with hyperglycemia and associated metabolic disorders, but the underlying mechanisms are poorly understood. To investigate these mechanisms, we conducted a short-term, four-week, in vivo study on mice given water supplemented with glucose. The short time frame was sufficient to cause metabolic shifts in the liver towards triglyceride synthesis. We sought to comprehensively track iron trafficking by analyzing liver and serum markers of iron metabolism alongside LC-ICP-MS analysis of iron speciation, which is a new approach in this context. Glucose supplementation induced changes in iron regulation despite equal dietary iron intake between groups. Specifically, we observed increased uptake of transferrin-bound iron from the serum and an iron overload state in the liver. We developed and applied a cell-based models of this glucose-induced iron overload state and found that, on the one hand, the anti-diabetic drug metformin could restore iron regulation; on the other hand, the iron chelator, deferoxamine, could restore glucose metabolism. Taken together, our studies reveal that early hyperglycemia is sufficient to cause disruptions in iron regulations, pointing to iron overload as viable therapeutic target in metabolic dysfunction.