Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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
_version_ 1784766085675876352
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
work_keys_str_mv AT giustilaura theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT tesimarta theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT ciregiafederica theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT marsellilorella theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT zalloccolorenzo theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT suleimanmara theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT delucacarmela theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT delguerrasilvia theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT zuccarinimariachiara theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT trerotolamarco theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT eizirikdeciol theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT cnopmiriam theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT mazzonimariar theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT marchettipiero theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT lucacchiniantonio theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT roncimaurizio theprotectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT giustilaura protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT tesimarta protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT ciregiafederica protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT marsellilorella protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT zalloccolorenzo protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT suleimanmara protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT delucacarmela protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT delguerrasilvia protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT zuccarinimariachiara protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT trerotolamarco protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT eizirikdeciol protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT cnopmiriam protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT mazzonimariar protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT marchettipiero protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT lucacchiniantonio protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved
AT roncimaurizio protectiveactionofmetforminagainstproinflammatorycytokineinducedhumanisletcelldamageandthemechanismsinvolved