Ferroptosis as a novel determinant of β-cell death in diabetic conditions

Abstract

Diabetes is a complex metabolic disorder which incidence rises in the epidemic fashion, suggesting the urgent need for new therapies. Its main pathological hallmark is loss of functional β-cells, and to date, several types of β-cell death have been described – necrosis, apoptosis, and autophagy. However, the role of ferroptosis in reducing β-cell population in diabetes remains elusive. In this study we aimed to examine whether and how this type of cell death is implicated in regulation of β-cell destiny in diabetes. For that purpose, Rin-5F insulin-producing pancreatic cells were treated with diabetes-mimicking factors – high glucose (HG) and H2O2, as well with commonly used diabetogenic agent streptozotocin (STZ). Results showed that HG, H2O2 and STZ induce the death of Rin-5F cells along with the accumulation of reactive oxygen species, lipid peroxides and iron; inactivation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and decrease in glutathione peroxidase 4 expression. This is consistent with the effect of the treatment with RSL-3, a well-known inducer of ferroptosis. Ferrostatin-1, a ferroptosis inhibitor, diminished above-stated effects and rescued cells from death. Our data revealed that β-cells underwent ferroptotic cell death under diabetogenic conditions. Results also implicate HG and H2O2 as contributing factors to ferroptosis of β-cells and suggest the novel mechanism of STZ diabetogenic action. Furthermore, the results shed a new light on antidiabetic strategy based on Nrf2 activation, putting it into the anti-ferroptotic context. In close, targeting ferroptosis in diabetes might be a new promising therapeutic approach based on preservation of β-cell population.