{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:31:22Z","timestamp":1787499082846,"version":"build-2736575974"},"reference-count":106,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T00:00:00Z","timestamp":1659916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Innovative Medicines Initiative 2 Joint Undertaking","award":["115,797"],"award-info":[{"award-number":["115,797"]}]},{"name":"Innovative Medicines Initiative 2 Joint Undertaking","award":["945,268"],"award-info":[{"award-number":["945,268"]}]},{"name":"Innovative Medicines Initiative 2 Joint Undertaking","award":["2017KAM2R5_005"],"award-info":[{"award-number":["2017KAM2R5_005"]}]},{"name":"Union\u2019s Horizon 2020 research and innovation program","award":["115,797"],"award-info":[{"award-number":["115,797"]}]},{"name":"Union\u2019s Horizon 2020 research and innovation program","award":["945,268"],"award-info":[{"award-number":["945,268"]}]},{"name":"Union\u2019s Horizon 2020 research and innovation program","award":["2017KAM2R5_005"],"award-info":[{"award-number":["2017KAM2R5_005"]}]},{"name":"\u201cEFPIA\u201d, \u201cJDRF\u201d, and \u201cThe Leona M. and Harry B. Helmsley Charitable Trust\u201d","award":["115,797"],"award-info":[{"award-number":["115,797"]}]},{"name":"\u201cEFPIA\u201d, \u201cJDRF\u201d, and \u201cThe Leona M. and Harry B. Helmsley Charitable Trust\u201d","award":["945,268"],"award-info":[{"award-number":["945,268"]}]},{"name":"\u201cEFPIA\u201d, \u201cJDRF\u201d, and \u201cThe Leona M. and Harry B. Helmsley Charitable Trust\u201d","award":["2017KAM2R5_005"],"award-info":[{"award-number":["2017KAM2R5_005"]}]},{"name":"Italian Ministry of University and Research","award":["115,797"],"award-info":[{"award-number":["115,797"]}]},{"name":"Italian Ministry of University and Research","award":["945,268"],"award-info":[{"award-number":["945,268"]}]},{"name":"Italian Ministry of University and Research","award":["2017KAM2R5_005"],"award-info":[{"award-number":["2017KAM2R5_005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Metformin, a drug widely used in type 2 diabetes (T2D), has been shown to protect human \u03b2-cells exposed to gluco- and\/or lipotoxic conditions and those in islets from T2D donors. We assessed whether metformin could relieve the human \u03b2-cell stress induced by pro-inflammatory cytokines (which mediate \u03b2-cells damage in type 1 diabetes, T1D) and investigated the underlying mechanisms using shotgun proteomics. Human islets were exposed to 50 U\/mL interleukin-1\u03b2 plus 1000 U\/mL interferon-\u03b3 for 48 h, with or without 2.4 \u00b5g\/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 \u03b2-cells, which was accompanied by islet proteome modifications. This suggests that metformin, besides use in T2D, might be considered for \u03b2-cell protection in other types of diabetes, possibly including early T1D.<\/jats:p>","DOI":"10.3390\/cells11152465","type":"journal-article","created":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T21:09:18Z","timestamp":1659992958000},"page":"2465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7366-1932","authenticated-orcid":false,"given":"Laura","family":"Giusti","sequence":"first","affiliation":[{"name":"School of Pharmacy, University of Camerino, 62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Tesi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Ciregia","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"},{"name":"Laboratory of Rheumatology, GIGA Research, CHU de Li\u00e8ge, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6698-2962","authenticated-orcid":false,"given":"Lorella","family":"Marselli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6385-4116","authenticated-orcid":false,"given":"Lorenzo","family":"Zallocco","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Suleiman","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Del Guerra","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariachiara","family":"Zuccarini","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Medical, Oral and Biotechnological Sciences, University \u201cG. d\u2019Annunzio\u201d of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1855-7002","authenticated-orcid":false,"given":"Marco","family":"Trerotola","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Medical, Oral and Biotechnological Sciences, University \u201cG. d\u2019Annunzio\u201d of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Decio L.","family":"Eizirik","sequence":"additional","affiliation":[{"name":"ULB Center for Diabetes Research, Universit\u00e9 Libre de Bruxelles, 1070 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Cnop","sequence":"additional","affiliation":[{"name":"ULB Center for Diabetes Research, Universit\u00e9 Libre de Bruxelles, 1070 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria R.","family":"Mazzoni","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0917-4491","authenticated-orcid":false,"given":"Antonio","family":"Lucacchini","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0797-6087","authenticated-orcid":false,"given":"Maurizio","family":"Ronci","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Pharmacy, University \u201cG. d\u2019Annunzio\u201d of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American Diabetes Association (2021). 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