Department of Cell and Tissue Biology, Faculty of Biology, University of Belgrade, Serbia.
Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia.
Front Endocrinol (Lausanne). 2023 Aug 3;14:1227498. doi: 10.3389/fendo.2023.1227498. eCollection 2023.
Recently, the involvement of ferroptotic cell death in the reduction of β-cell mass in diabetes has been demonstrated. To elucidate the mechanisms of β-cell ferroptosis and potential antidiabetic effects of the ferroptosis inhibitor ferrostatin-1 (Fer-1) in vivo, a mouse model of type 1 diabetes (T1D) was used.
Animals were divided into three groups: control (vehicle-treated), diabetic (streptozotocin-treated, 40 mg/kg, from days 1-5), and diabetic treated with Fer-1 (1 mg/kg, from days 1-21). On day 22, glycemia and insulinemia were measured and pancreases were isolated for microscopic analyses.
Diabetes disturbed general parameters of β-cell mass (islet size, β-cell abundance and distribution) and health (insulin and PDX-1 expression), increased lipid peroxidation in islet cells, and phagocytic removal of iron-containing material. It also downregulated the main players of the antiferroptotic pathway - Nrf2, GPX4, and xCT. In contrast, Fer-1 ameliorated the signs of deterioration of β-cell/islets, decreased lipid peroxidation, and reduced phagocytic activity, while upregulated expression of Nrf2 (and its nuclear translocation), GPX4, and xCT in β-cell/islets.
Overall, our study confirms ferroptosis as an important mode of β-cell death in T1D and suggests antiferroptotic agents as a promising strategy for the prevention and treatment of diabetes.
最近，铁死亡细胞死亡在糖尿病中β细胞数量减少中的作用已得到证实。为了阐明β细胞铁死亡的机制以及铁死亡抑制剂 ferrostatin-1（Fer-1）在体内的潜在抗糖尿病作用，使用了 1 型糖尿病（T1D）小鼠模型。
动物分为三组：对照组（给予 vehicle 处理）、糖尿病组（给予链脲佐菌素处理，40mg/kg，从第 1 天至第 5 天）和糖尿病用 Fer-1 治疗组（1mg/kg，从第 1 天至第 21 天）。第 22 天，测量血糖和胰岛素，并分离胰腺进行显微镜分析。
糖尿病扰乱了β细胞数量（胰岛大小、β细胞丰度和分布）和健康（胰岛素和 PDX-1 表达）的一般参数，增加了胰岛细胞中的脂质过氧化，以及含铁物质的吞噬清除。它还下调了抗铁死亡途径的主要参与者 - Nrf2、GPX4 和 xCT。相比之下，Fer-1 改善了β细胞/胰岛的恶化迹象，降低了脂质过氧化，减少了吞噬活性，同时上调了β细胞/胰岛中的 Nrf2（及其核易位）、GPX4 和 xCT 的表达。
总的来说，我们的研究证实了铁死亡是 T1D 中β细胞死亡的一种重要模式，并表明抗铁死亡剂是预防和治疗糖尿病的一种有前途的策略。
