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The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved
Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human β-cells exposed to gluco- and/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human β-cell stress induced by pro-inflammatory cytokines (which mediate...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9368307/ https://www.ncbi.nlm.nih.gov/pubmed/35954309 http://dx.doi.org/10.3390/cells11152465 |
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author | Giusti, Laura Tesi, Marta Ciregia, Federica Marselli, Lorella Zallocco, Lorenzo Suleiman, Mara De Luca, Carmela Del Guerra, Silvia Zuccarini, Mariachiara Trerotola, Marco Eizirik, Decio L. Cnop, Miriam Mazzoni, Maria R. Marchetti, Piero Lucacchini, Antonio Ronci, Maurizio |
author_facet | Giusti, Laura Tesi, Marta Ciregia, Federica Marselli, Lorella Zallocco, Lorenzo Suleiman, Mara De Luca, Carmela Del Guerra, Silvia Zuccarini, Mariachiara Trerotola, Marco Eizirik, Decio L. Cnop, Miriam Mazzoni, Maria R. Marchetti, Piero Lucacchini, Antonio Ronci, Maurizio |
author_sort | Giusti, Laura |
collection | PubMed |
description | Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human β-cells exposed to gluco- and/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human β-cell stress induced by pro-inflammatory cytokines (which mediate β-cells damage in type 1 diabetes, T1D) and investigated the underlying mechanisms using shotgun proteomics. Human islets were exposed to 50 U/mL interleukin-1β plus 1000 U/mL interferon-γ for 48 h, with or without 2.4 µg/mL metformin. Glucose-stimulated insulin secretion (GSIS) and caspase 3/7 activity were studied, and a shotgun label free proteomics analysis was performed. Metformin prevented the reduction of GSIS and the activation of caspase 3/7 induced by cytokines. Proteomics analysis identified more than 3000 proteins in human islets. Cytokines alone altered the expression of 244 proteins (145 up- and 99 down-regulated), while, in the presence of metformin, cytokine-exposure modified the expression of 231 proteins (128 up- and 103 downregulated). Among the proteins inversely regulated in the two conditions, we found proteins involved in vesicle motility, defense against oxidative stress (including peroxiredoxins), metabolism, protein synthesis, glycolysis and its regulation, and cytoskeletal proteins. Metformin inhibited pathways linked to inflammation, immune reactions, mammalian target of rapamycin (mTOR) signaling, and cell senescence. Some of the changes were confirmed by Western blot. Therefore, metformin prevented part of the deleterious actions of pro-inflammatory cytokines in human β-cells, which was accompanied by islet proteome modifications. This suggests that metformin, besides use in T2D, might be considered for β-cell protection in other types of diabetes, possibly including early T1D. |
format | Online Article Text |
id | pubmed-9368307 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-93683072022-08-12 The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved Giusti, Laura Tesi, Marta Ciregia, Federica Marselli, Lorella Zallocco, Lorenzo Suleiman, Mara De Luca, Carmela Del Guerra, Silvia Zuccarini, Mariachiara Trerotola, Marco Eizirik, Decio L. Cnop, Miriam Mazzoni, Maria R. Marchetti, Piero Lucacchini, Antonio Ronci, Maurizio Cells Article Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human β-cells exposed to gluco- and/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human β-cell stress induced by pro-inflammatory cytokines (which mediate β-cells damage in type 1 diabetes, T1D) and investigated the underlying mechanisms using shotgun proteomics. Human islets were exposed to 50 U/mL interleukin-1β plus 1000 U/mL interferon-γ for 48 h, with or without 2.4 µg/mL metformin. Glucose-stimulated insulin secretion (GSIS) and caspase 3/7 activity were studied, and a shotgun label free proteomics analysis was performed. Metformin prevented the reduction of GSIS and the activation of caspase 3/7 induced by cytokines. Proteomics analysis identified more than 3000 proteins in human islets. Cytokines alone altered the expression of 244 proteins (145 up- and 99 down-regulated), while, in the presence of metformin, cytokine-exposure modified the expression of 231 proteins (128 up- and 103 downregulated). Among the proteins inversely regulated in the two conditions, we found proteins involved in vesicle motility, defense against oxidative stress (including peroxiredoxins), metabolism, protein synthesis, glycolysis and its regulation, and cytoskeletal proteins. Metformin inhibited pathways linked to inflammation, immune reactions, mammalian target of rapamycin (mTOR) signaling, and cell senescence. Some of the changes were confirmed by Western blot. Therefore, metformin prevented part of the deleterious actions of pro-inflammatory cytokines in human β-cells, which was accompanied by islet proteome modifications. This suggests that metformin, besides use in T2D, might be considered for β-cell protection in other types of diabetes, possibly including early T1D. MDPI 2022-08-08 /pmc/articles/PMC9368307/ /pubmed/35954309 http://dx.doi.org/10.3390/cells11152465 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Giusti, Laura Tesi, Marta Ciregia, Federica Marselli, Lorella Zallocco, Lorenzo Suleiman, Mara De Luca, Carmela Del Guerra, Silvia Zuccarini, Mariachiara Trerotola, Marco Eizirik, Decio L. Cnop, Miriam Mazzoni, Maria R. Marchetti, Piero Lucacchini, Antonio Ronci, Maurizio The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved |
title | The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved |
title_full | The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved |
title_fullStr | The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved |
title_full_unstemmed | The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved |
title_short | The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved |
title_sort | protective action of metformin against pro-inflammatory cytokine-induced human islet cell damage and the mechanisms involved |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9368307/ https://www.ncbi.nlm.nih.gov/pubmed/35954309 http://dx.doi.org/10.3390/cells11152465 |
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