Reduced hepcidin expression contributes to iron overload in the pancreas and beta cell stress during the progression of disease in non-obese diabetic mice

Type 1 diabetes (T1D) is a complex disease that is influenced by various genetic and environmental factors. Studies have shown that a dysregulation in iron metabolism contributes to the development of diabetes, and higher dietary iron increases the risk of developing T1D. The underlying mechanism, however, is unclear. Here, we show that beta cells may be protected from iron-mediated oxidative stress through the expression of hepcidin, the main iron-regulatory hormone in the body. Hepcidin binds to ferroportin to block the release of iron from iron-rich cells, such as macrophages in the insulitic lesion. We showed that the hepcidin gene, Hamp, is changed in the islets of non-obese diabetic (NOD) mice prior to the onset of hyperglycemia. A significant increase in Hamp is observed at 4 weeks of age when the insulitic lesions form, but by 12 weeks of age, significant loss of Hamp and hepcidin expression is observed in the beta cells. We showed that acute inflammation increases Hamp expression in isolated islets of control NOD.B10 mice, and studies have shown that chronic inflammation leads to diminished Hamp expression. Interestingly, we observed an accumulation of iron in the pancreas of normoglycemic NOD mice with highly infiltrated islets, and showed that disease incidence in NOD mice correlated with the iron content in the diet. Only 30% of NOD mice fed a standard rodent chow containing 200 ppm iron developed hyperglycemia by 20 weeks of age while 70% of mice developed hyperglycemia if fed a standard diet containing 400 ppm iron. These data demonstrate that a loss of hepcidin expression in the beta cells during disease progression may result in elevated iron levels in the pancreas and contribute to iron-mediated oxidative stress in beta cells. Our findings also suggest that a low-iron diet may be effective in preventing T1D.