cytokines; label-free shotgun analysis; metformin; proteomics; β-cell; Cytokines; Insulin; Metformin; Caspase 3; Glucose; Caspase 3/metabolism; Cytokines/metabolism; Glucose/metabolism; Glucose/toxicity; Humans; Insulin/metabolism; Diabetes Mellitus, Type 1/metabolism; Diabetes Mellitus, Type 2/drug therapy; Diabetes Mellitus, Type 2/metabolism; Islets of Langerhans/metabolism; Metformin/pharmacology; Diabetes Mellitus, Type 1; Islets of Langerhans; Biochemistry, Genetics and Molecular Biology (all); General Medicine
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Giusti, Laura ; School of Pharmacy, University of Camerino, 62032 Camerino, Italy
Tesi, Marta; Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
Ciregia, Federica ; Université de Liège - ULiège > GIGA > GIGA I3 - Rheumatology ; Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
Marselli, Lorella ; Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
Zallocco, Lorenzo ; Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Suleiman, Mara; Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
De Luca, Carmela; Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
Del Guerra, Silvia; Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
Zuccarini, Mariachiara; Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, 66100 Chieti, Italy ; Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" of Chieti-Pescara, 66100 Chieti, Italy
Trerotola, Marco ; Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, 66100 Chieti, Italy ; Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" of Chieti-Pescara, 66100 Chieti, Italy
Eizirik, Decio L; ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium
Cnop, Miriam; ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium
Mazzoni, Maria R; Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Marchetti, Piero; Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
Lucacchini, Antonio ; Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
Ronci, Maurizio ; Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, 66100 Chieti, Italy ; Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, 66100 Chieti, Italy
D.L.E., M.C., P.M. and L.M. receive support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreements No 115,797 (INNODIA) and 945,268 (INNODIA HARVEST). These Joint Undertakings receive support from the Union’s Horizon 2020 research and innovation program and “EFPIA”, “JDRF”, and “The Leona M. and Harry B. Helmsley Charitable Trust”. P.M. and L.M. are supported by the Italian Ministry of University and Research, PRIN 2017 (2017KAM2R5_005).
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