title: Glucagon-like peptide-1 secreting cell function as well as production of inflammatory reactive oxygen species is differently regulated by glycated serum and high levels of glucose.
abstract: Glucagon-like peptide-1 (GLP-1), an intestinal hormone contributing to glucose homeostasis, is synthesized by proglucagon and secreted from intestinal neuroendocrine cells in response to nutrients. GLP-1 secretion is impaired in type 2 diabetes patients. Here, we aimed at investigating whether diabetic toxic products (glycated serum (GS) or high levels of glucose (HG)) may affect viability, function, and insulin sensitivity of the GLP-1 secreting cell line GLUTag. Cells were cultured for 5 days in presence or absence of different dilutions of GS or HG. GS and HG (alone or in combination) increased reactive oxygen species (ROS) production and upregulated proglucagon mRNA expression as compared to control medium. Only HG increased total production and release of active GLP-1, while GS alone abrogated secretion of active GLP-1. HG-mediated effects were associated with the increased cell content of the prohormone convertase 1/3 (PC 1/3), while GS alone downregulated this enzyme. HG upregulated Glucokinase (GK) and downregulated SYNTHAXIN-1. GS abrogated SYNTHAXIN-1 and SNAP-25. Finally, high doses of GS alone or in combination with HG reduced insulin-mediated IRS-1 phosphorylation. In conclusion, we showed that GS and HG might regulate different pathways of GLP-1 production in diabetes, directly altering the function of neuroendocrine cells secreting this hormone.
authors.affiliation: Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 6 Viale Benedetto XV, 16143 Genoa, Italy.
authors.forename: Alessandra
authors.identifier: 0000-0002-9084-2636
authors.initials: A
authors.lastname: Puddu
authors.affiliation: Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 6 Viale Benedetto XV, 16143 Genoa, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Sanguineti
authors.affiliation: Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 6 Viale Benedetto XV, 16143 Genoa, Italy ; Division of Cardiology, Department of Medicine, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, 64 Avenue de la Roseraie, 1211 Geneva, Switzerland ; Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland.
authors.forename: Fabrizio
authors.identifier: 0000-0003-0823-8729
authors.initials: F
authors.lastname: Montecucco
authors.affiliation: Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 6 Viale Benedetto XV, 16143 Genoa, Italy.
authors.forename: Giorgio L
authors.initials: GL
authors.lastname: Viviani
mesh_terms: D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D015536:Down-Regulation; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D005941:Glucokinase / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000097:blood*; D007328:Insulin / Q000378:metabolism; D052336:Proglucagon / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D050827:Syntaxin 1 / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C494208:SNAP25 protein, human; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D052336:Proglucagon; D052216:Glucagon-Like Peptide 1; D005941:Glucokinase