(P22-034-25) The Impact of Prior Iron Deficient Condition on Type 2 Diabetes-Developing Aberrant IRS/PI3K/Akt Signaling, Glucose Transport, and Oxidative Stress

Objectives: This study investigates the impact of diet-induced iron deficiency (ID) and iron overload (IOL) conditions prior to the development of T2DM on glucose homeostasis, insulin signaling, oxidative stress, and iron regulatory pathways.

Methods: To mimic T2DM, high-fat diet (HF) and streptozotocin (STZ)-induced animal models and in vitro IR HepG2 cell line models were generated. The animal study included four groups: (i) Iron-sufficient (IS) group; (ii) IS–HF/STZ group; (iii) ID–HF/STZ group; and (iv) IOL–HF/STZ group. STZ was injected at 8 weeks. High glucose and high insulin treatments were used to induce an IR condition in HepG2 cells, and ID was elicited using DFO treatment.

Results: In animal models, prior ID status alleviated HF/STZ-induced abnormalities by maintaining normal levels of fasting glucose, improving insulin sensitivity, and enhancing IRS1/PI3K/Akt signaling, as evidenced by increased phosphorylation levels. ID also suppressed the expression of liver Pck1 in gluconeogenesis while enhancing the expression of genes involved in glucose transport and glycogen synthesis (liver Slc2a2, muscle Slc2a4, liver Gys2). IOL limited weight gain and hepatic steatosis but had minimal effects on hyperglycemia and insulin resistance. ID further mitigated oxidative stress by reducing lipid peroxidation and maintaining or upregulating antioxidant gene expression (Nfe2l2, Hmox1, Cat, and Sod1), whereas IOL did not. In vitro, DFO-induced ID in IR HepG2 cells was associated with improved IRS1/PI3K/Akt signaling, increased GLUT2 levels on the cell surface, enhanced glucose uptake, and reduced oxidative stress through the lowering of labile iron levels.

Conclusions: These findings highlight the protective effects of ID against T2DM-associated metabolic dysregulation and oxidative stress and provide insights into the differential roles of iron deficiency and overload in glucose metabolism and diabetes pathophysiology.

Funding Sources: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (no. 2023R1A2C1002586).