Effects of ferric citrate supplementation on advanced glycation end products in a rat model of streptozotocin/nicotinamide-induced diabetes.

Scope: Diabetes is associated with the increased risks of anemia and activation of advanced glycation end products (AGEs) and the receptor for AGEs (RAGE). However, the effects of pharmacological doses of iron supplementation on AGE metabolism are less clear. The aim was to investigate the effect of ferric citrate supplementation on AGE metabolism. Methods and results: Diabetes was induced in overnight starved rats by intraperitoneal injections of 40 mg/kg streptozotocin and 120 mg/kg nicotinamide. Diabetic rats were fed a standard diet or pharmacological doses of ferric citrate (0.5, 1, 2, and 3 g of ferric iron/kg diet) for 10 weeks. Ferric citrate supplementation showed a dose-related effect on the hepatic steatosis score, malondialdehyde, cathepsin D, and glyoxalase I. A Western blot analysis revealed that > 1 g of ferric iron suppressed hepatic AGE receptor 1 and high-mobility group-box 1 expressions but increased heme oxygenase-1 and RAGE expressions. Further analysis showed that high doses of ferric iron triggered sterol regulatory element-binding protein 1c, p38-mitogen-activated protein kinase, and nuclear factor-kappa B protein expressions. Conclusion: Overall, the present results suggest a dose-related effect of ferric citrate supplementation on AGE metabolism, and this effect was more evident at high iron doses (> 1 g of ferric iron/kg diet).