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Horm Metab Res 2024; 56(04): 279-285
DOI: 10.1055/a-2190-2803
Original Article: Endocrine Research

Mechanistic Insights into Ferroptotic Cell Death in Pancreatic Islets

Florian Schepp
1   Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Undine Schubert
2   Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
3   Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
4   Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
,
Janine Schmid
2   Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
3   Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
4   Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
,
Susann Lehmann
2   Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
3   Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
4   Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
,
Gladys Oluyemisi Latunde-Dada
5   Division of Diabetes & Endocrinology, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, Kings College London, London, United Kingdom of Great Britain and Northern Ireland
,
Tugba Kose
5   Division of Diabetes & Endocrinology, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, Kings College London, London, United Kingdom of Great Britain and Northern Ireland
,
Charlotte Steenblock
2   Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
4   Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
,
Stefan R. Bornstein
2   Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
3   Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
4   Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
5   Division of Diabetes & Endocrinology, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, Kings College London, London, United Kingdom of Great Britain and Northern Ireland
6   CRTD, DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
7   Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
,
Andreas Linkermann
8   Division of Nephrology, Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
9   Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States
,
Barbara Ludwig
2   Department of Medicine III, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
3   Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
4   Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
6   CRTD, DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
› Author Affiliations
Funding Information Deutsche Forschungsgemeinschaft — http://dx.doi.org/10.13039/501100001659; IRTG 2251
› Further Information
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Abstract

Ferroptosis was recently identified as a non-apoptotic, iron-dependent cell death mechanism that is involved in various pathologic conditions. There is first evidence for its significance also in the context of islet isolation and transplantation. Transplantation of pancreatic human islets is a viable treatment strategy for patients with complicated diabetes mellitus type 1 (T1D) that suffer from severe hypoglycemia. A major determinant for functional outcome is the initial islet mass transplanted. Efficient islet isolation procedures and measures to minimize islet loss are therefore of high relevance. To this end, better understanding and subsequent targeted inhibition of cell death during islet isolation and transplantation is an effective approach. In this study, we aimed to elucidate the mechanism of ferroptosis in pancreatic islets. Using a rodent model, isolated islets were characterized relating to the effects of experimental induction (RSL3) and inhibition (Fer1) of ferroptotic pathways. Besides viability, survival, and function, the study focused on characteristic ferroptosis-associated intracellular changes such as MDA level, iron concentration and the expression of ACSL4. The study demonstrates that pharmaceutical induction of ferroptosis by RSL3 causes enhancement of oxidative stress and leads to an increase of intracellular iron, zinc and MDA concentration, as well as the expression of ACSL4 protein. Consequently, a massive reduction of islet function, viability, and survival was found. Fer1 has the potential to inhibit and attenuate these cellular changes and thereby protect the islets from cell death.

Key words

ferroptosis - islets - insulin secretion - diabetes - cell death - iron - ROS

Supplementary Material



Publication History

Received: 29 August 2023

Accepted after revision: 08 October 2023

Article published online:
13 November 2023

© 2023. Thieme. All rights reserved.

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