title: Glucagon-like peptide-1 triggers protective pathways in pancreatic beta-cells exposed to glycated serum.
abstract: Advanced glycation end products (AGEs) might play a pathophysiological role in the development of diabetes and its complications. AGEs negatively affect pancreatic beta-cell function and the expression of transcriptional factors regulating insulin gene. Glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates glucose homeostasis, might counteract the harmful effects of AGEs on the beta cells in culture. The aim of this study was to identify the intracellular mechanisms underlying GLP-1-mediated protection from AGE-induced detrimental activities in pancreatic beta cells. HIT-T15 cells were cultured for 5 days with glycated serum (GS, consisting in a pool of AGEs), in the presence or absence of 10 nmol/L GLP-1. After evaluation of oxidative stress, we determined the expression and subcellular localization of proteins involved in maintaining redox balance and insulin gene expression, such as nuclear factor erythroid-derived 2 (Nrf2), glutathione reductase, PDX-1, and MafA. Then, we investigated proinsulin production. The results showed that GS increased oxidative stress, reduced protein expression of all investigated factors through proteasome activation, and decreased proinsulin content. Furthermore, GS reduced ability of PDX-1 and MafA to bind DNA. Coincubation with GLP-1 reversed these GS-mediated detrimental effects. In conclusion, GLP-1, protecting cells against oxidants, triggers protective intercellular pathways in HIT-T15 cells exposed to GS.
authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Genova, 6 Viale Benedetto XV, 16132 Genova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Puddu
authors.forename: Roberta
authors.initials: R
authors.lastname: Sanguineti
authors.forename: Arianna
authors.initials: A
authors.lastname: Durante
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.forename: Giorgio L
authors.initials: GL
authors.lastname: Viviani
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000378:metabolism; D015151:Immunoblotting; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D052216:Glucagon-Like Peptide 1