Abstract
The main pathological hallmark of diabetes is the loss of functional β-cells. Among several types of β-cell death in diabetes, the involvement of ferroptosis remains elusive. Therefore, we investigated the potential of diabetes-mimicking factors: high glucose (HG), proinflammatory cytokines, hydrogen peroxide (H2O2), or diabetogenic agent streptozotocin (STZ) to induce ferroptosis of β-cells in vitro. Furthermore, we tested the contribution of ferroptosis to injury of pancreatic islets in an STZ-induced in vivo diabetic model. All in vitro treatments increased loss of Rin-5F cells along with the accumulation of reactive oxygen species, lipid peroxides and iron, inactivation of NF-E2-related factor 2 (Nrf2), and decrease in glutathione peroxidase 4 expression and mitochondrial membrane potential (MMP). Ferrostatin 1 (Fer-1), ferroptosis inhibitor, diminished the above-stated effects and rescued cells from death in case of HG, STZ, and H2O2 treatments, while failed to increase MMP and to attenuate cell death after the cytokines' treatment. Moreover, Fer-1 protected pancreatic islets from STZ-induced injury in diabetic in vivo model, since it decreased infiltration of macrophages and accumulation of lipid peroxides and increased the population of insulin-positive cells. Such results revealed differences between diabetogenic stimuli in determining the destiny of β-cells, emerging HG, H2O2, and STZ, but not cytokines, as contributing factors to ferroptosis and shed new light on an antidiabetic strategy based on Nrf2 activation. Thus, targeting ferroptosis in diabetes might be a promising new approach for preservation of the β-cell population. Our results obtained from in vivo study strongly justify this approach.
Highlights
Diabetes mellitus is a complex metabolic disorder with a rising incidence, which suggests the urgent need for finding promising therapeutic targets and approaches
We have found here that mimicking the diabetic microenvironment by high glucose (HG), STZ, and H2O2 induced ferroptosis of β-cells since commonly used ferroptosis inhibitor, Ferrostatin 1 (Fer-1), rescued them from death, along with abolishing the effects of those treatments on ROS, lipid peroxides, and iron content
Our results further showed that Fer-1induced activation of NF-E2-related factor 2 (Nrf2) and following increase in GPX4 expression and membrane potential (MMP) protected β-cells from ferroptosis
Summary
Diabetes mellitus is a complex metabolic disorder with a rising incidence, which suggests the urgent need for finding promising therapeutic targets and approaches. The main pathological hallmark of diabetes (both type 1 and type 2) is the decrease of β-cell mass. There is a great effort nowadays to find a way to restore normal β-cell mass under diabetic conditions either by stimulating their proliferation, differentiation/transdifferentiation, or by inhibiting the cell death process. In searching for a successful approach to prevent/diminish diabetes progression, it has become of utmost significance to reveal molecular targets and signaling pathways underlying β-cell loss. Several important regulators of β-cell destiny, responsible for their survival and death, were described. Pancreatic and duodenal homeobox 1 (PDX-1) and mammalian sterile 20like kinase 1 (MST1) play a central role in β-cell survival [1] and apoptosis [2]. Deficiency of the factors controlling PDX-1 and MST1, such as catechol-o-methyltransferase
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