Defining the ferroptotic phenotype of beta cells in type 1 diabetes and its inhibition as a potential antidiabetic strategy

Frontiers in Endocrinology

Endocrinology

Ksenija Velickovic¹  Milica Markelic¹  Tamara Saksida²  Dragica Micanovic²  Vesna Otasevic³  Vesna Martinovic³  Ilijana Grigorov³  Nevena Savic³  Andjelija Gudelj³  Ana Stancic³ 

[1] Department of Cell and Tissue Biology, Faculty of Biology, University of Belgrade, Serbia;Department of Immunology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia;Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia;

关键词: ferroptosis;    β-cell death;    diabetes;    ferroptosis inhibitor;    ferrostatin-1;   

DOI  :  10.3389/fendo.2023.1227498

 received in 2023-05-25, accepted in 2023-07-19,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionRecently, 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.MethodsAnimals 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.ResultsDiabetes 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.DiscussionOverall, 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

【 授权许可】

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Copyright © 2023 Markelic, Stancic, Saksida, Grigorov, Micanovic, Velickovic, Martinovic, Savic, Gudelj and Otasevic