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 4-week study on mice given glucose-supplemented water. The supplementation induced metabolic shifts in the liver towards triglyceride synthesis. We tracked iron trafficking by analyzing liver and serum markers of iron metabolism alongside iron speciation analysis as determined by liquid chromatography with inductively-coupled plasma mass spectrometry (LC-ICP-MS). Glucose supplementation induced changes in iron regulation despite equal dietary iron intake. Specifically, we observed increased uptake of transferrin-bound iron and liver iron overload. We developed cell-based models recapitulating this state. Metformin restored iron regulation while the iron chelator, deferoxamine, restored glucose metabolism. Taken together, our studies reveal that early hyperglycemia disrupts iron homeostasis, identifying iron overload as a viable therapeutic target in metabolic dysfunction.