Defining the ferroptotic phenotype of beta cells in type 1 diabetes and its inhibition as a potential antidiabetic strategy
2023
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Authors:
Markelić, MilicaStančić, Ana
Saksida, Tamara
Grigorov, Ilijana
Mićanović, Dragica
Veličković, Ksenija
Martinović, Vesna
Savić, Nevena
Gudelj, Anđelija
Otašević, Vesna
Document Type:
Article (Published version)
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© 2023 Markelic, Stancic, Saksida, Grigorov, Micanovic, Velickovic, Martinovic, Savic, Gudelj and Otasevic.
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Show full item recordAbstract:
Introduction: 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.
Methods: 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.
Results: 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.
Discussion: 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
Keywords:
ferroptosis; β-cell death; diabetes; ferroptosis inhibitor; ferrostatin-1Source:
Frontiers in Endocrinology, 2023, 14, 1227498-Funding / projects:
- 6525651‚Program saradnje srpske nauke sa dijasporom: Vaučeri za razmenu znanja, Fond za nauku Republike Srbije
- Signaling molecules in diabetes: search for potential targets in intrinsic pathways for prediction and intervention in diabetes (RS-MESTD-Basic Research (BR or ON)-173020)
DOI: 10.3389/fendo.2023.1227498
ISSN: 1664-2392
PubMed: 37600723