Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death
Pancreatic β-cells depend on the well-balanced regulation of cytosolic zinc concentrations, providing sufficient zinc ions for the processing and storage of insulin, but avoiding toxic effects. The zinc transporter ZnT8, encoded by SLC30A8,is a key player regarding islet cell zinc homeostasis, and p...
| Main Authors: | , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2022
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| Online Access: | https://hdl.handle.net/10356/162958 |
| _version_ | 1826119488627539968 |
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| author | Karsai, Maria Zuellig, Richard A. Lehmann, Roger Cuozzo, Federica Nasteska, Daniela Luca, Edlira Hantel, Constanze Hodson, David J. Spinas, Giatgen A. Rutter, Guy A. Gerber, Philipp A. |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Karsai, Maria Zuellig, Richard A. Lehmann, Roger Cuozzo, Federica Nasteska, Daniela Luca, Edlira Hantel, Constanze Hodson, David J. Spinas, Giatgen A. Rutter, Guy A. Gerber, Philipp A. |
| author_sort | Karsai, Maria |
| collection | NTU |
| description | Pancreatic β-cells depend on the well-balanced regulation of cytosolic zinc concentrations, providing sufficient zinc ions for the processing and storage of insulin, but avoiding toxic effects. The zinc transporter ZnT8, encoded by SLC30A8,is a key player regarding islet cell zinc homeostasis, and polymorphisms in this gene are associated with altered type 2 diabetes susceptibility in man. The objective of this study was to investigate the role of ZnT8 and zinc in situations of cellular stress as hypoxia or inflammation. Isolated islets of WT and global ZnT8-/- mice were exposed to hypoxia or cytokines and cell death was measured. To explore the role of changing intracellular Zn2+ concentrations, WT islets were exposed to different zinc concentrations using zinc chloride or the zinc chelator N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN). Hypoxia or cytokine (TNF-α, IFN-γ, IL1-β) treatment induced islet cell death, but to a lesser extent in islets from ZnT8-/- mice, which were shown to have a reduced zinc content. Similarly, chelation of zinc with TPEN reduced cell death in WT islets treated with hypoxia or cytokines, whereas increased zinc concentrations aggravated the effects of these stressors. This study demonstrates a reduced rate of cell death in islets from ZnT8-/- mice as compared to WT islets when exposed to two distinct cellular stressors, hypoxia or cytotoxic cytokines. This protection from cell death is, in part, mediated by a reduced zinc content in islet cells of ZnT8-/- mice. These findings may be relevant for altered diabetes burden in carriers of risk SLC30A8 alleles in man. |
| first_indexed | 2024-10-01T05:01:09Z |
| format | Journal Article |
| id | ntu-10356/162958 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:01:09Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1629582023-03-05T16:44:56Z Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death Karsai, Maria Zuellig, Richard A. Lehmann, Roger Cuozzo, Federica Nasteska, Daniela Luca, Edlira Hantel, Constanze Hodson, David J. Spinas, Giatgen A. Rutter, Guy A. Gerber, Philipp A. Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Beta Cell Hypoxia Pancreatic β-cells depend on the well-balanced regulation of cytosolic zinc concentrations, providing sufficient zinc ions for the processing and storage of insulin, but avoiding toxic effects. The zinc transporter ZnT8, encoded by SLC30A8,is a key player regarding islet cell zinc homeostasis, and polymorphisms in this gene are associated with altered type 2 diabetes susceptibility in man. The objective of this study was to investigate the role of ZnT8 and zinc in situations of cellular stress as hypoxia or inflammation. Isolated islets of WT and global ZnT8-/- mice were exposed to hypoxia or cytokines and cell death was measured. To explore the role of changing intracellular Zn2+ concentrations, WT islets were exposed to different zinc concentrations using zinc chloride or the zinc chelator N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN). Hypoxia or cytokine (TNF-α, IFN-γ, IL1-β) treatment induced islet cell death, but to a lesser extent in islets from ZnT8-/- mice, which were shown to have a reduced zinc content. Similarly, chelation of zinc with TPEN reduced cell death in WT islets treated with hypoxia or cytokines, whereas increased zinc concentrations aggravated the effects of these stressors. This study demonstrates a reduced rate of cell death in islets from ZnT8-/- mice as compared to WT islets when exposed to two distinct cellular stressors, hypoxia or cytotoxic cytokines. This protection from cell death is, in part, mediated by a reduced zinc content in islet cells of ZnT8-/- mice. These findings may be relevant for altered diabetes burden in carriers of risk SLC30A8 alleles in man. Published version D J H was supported by MRC (MR/N00275X/1 and MR/S025618/1) and Diabetes UK (17/0005681) Project Grants. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D J H). G A R was supported by a Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1) and by Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) project grants. This project has received funding from the European Union’s Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115881 (RHAPSODY) to G A R. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. P A G received funding for this project from the Theiler-Haag and the Philhuman foundation. 2022-11-14T01:16:47Z 2022-11-14T01:16:47Z 2022 Journal Article Karsai, M., Zuellig, R. A., Lehmann, R., Cuozzo, F., Nasteska, D., Luca, E., Hantel, C., Hodson, D. J., Spinas, G. A., Rutter, G. A. & Gerber, P. A. (2022). Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death. Journal of Endocrinology, 253(1), 1-11. https://dx.doi.org/10.1530/JOE-21-0271 0022-0795 https://hdl.handle.net/10356/162958 10.1530/JOE-21-0271 35017316 2-s2.0-85124576415 1 253 1 11 en Journal of Endocrinology © 2022 The authors. Published by Bioscientifica Ltd. This work is licensed under a Creative Commons Attribution 4.0 International License. application/pdf |
| spellingShingle | Science::Medicine Beta Cell Hypoxia Karsai, Maria Zuellig, Richard A. Lehmann, Roger Cuozzo, Federica Nasteska, Daniela Luca, Edlira Hantel, Constanze Hodson, David J. Spinas, Giatgen A. Rutter, Guy A. Gerber, Philipp A. Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death |
| title | Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death |
| title_full | Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death |
| title_fullStr | Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death |
| title_full_unstemmed | Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death |
| title_short | Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death |
| title_sort | lack of znt8 protects pancreatic islets from hypoxia and cytokine induced cell death |
| topic | Science::Medicine Beta Cell Hypoxia |
| url | https://hdl.handle.net/10356/162958 |
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