title: Liraglutide protects Rin-m5f β cells by reducing procoagulant tissue factor activity and apoptosis prompted by microparticles under conditions mimicking Instant Blood-Mediated Inflammatory Reaction.
abstract: Instant Blood-Mediated Inflammatory Reaction (IBMIR) occurs at the vicinity of transplanted islets immediately after intraportal infusion and is characterized by cytokine secretion, tissue factor (TF) expression, and ß cell loss. Microparticles (MPs) are cellular effectors shed from the plasma membrane of apoptotic cells. Modulation of the properties of ß cell-derived MPs by liraglutide was assessed in a cellular model designed to mimic IBMIR oxidative and inflammatory conditions. Rin-m5f rat β cells were stimulated by H2 O2 or a combination of IL-1β and TNF-α. Cell-derived MPs were applied to naive Rin-m5f for 24 h. Apoptosis, MP release, TF activity, P-IκB expression, and MP-mediated apoptosis were measured in target cells. Direct protection by liraglutide was shown by a significant decrease in the oxidative stress-induced apoptosis (18.7% vs. 7.6%, P < 0.0001 at 1 μm liraglutide) and cellular TF activity (-40% at 100 nm liraglutide). Indirect cytoprotection led to 20% reduction in MP generation, thereby lowering MP-mediated apoptosis (6.3% vs. 3.7%, P = 0.022) and NF-κB activation (-50%) in target cells. New cytoprotective effects of liraglutide were evidenced, limiting the expression of TF activity by ß cells and the generation of noxious MPs. Altogether, these data suggest that liraglutide could target pro-apoptotic and pro-inflammatory MPs in transplanted islets.
authors.affiliation: EA 7293, Vascular and Tissular Stress in Transplantation, Federation of Translational Medicine of Strasbourg, Faculty of Medicine, University of Strasbourg, Strasbourg, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Gleizes
authors.forename: Andrei
authors.initials: A
authors.lastname: Constantinescu
authors.forename: Malak
authors.initials: M
authors.lastname: Abbas
authors.forename: Houda
authors.initials: H
authors.lastname: Bouhadja
authors.forename: Fatiha
authors.initials: F
authors.lastname: Zobairi
authors.forename: Laurence
authors.initials: L
authors.lastname: Kessler
authors.forename: Florence
authors.initials: F
authors.lastname: Toti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D055252:Cell-Derived Microparticles / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D016381:Islets of Langerhans Transplantation; D000069450:Liraglutide; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
chemical_list: D016328:NF-kappa B; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D013925:Thromboplastin
keywords: Instant Blood-Mediated Inflammatory Reaction; beta cell; liraglutide; membrane microparticles; tissue factor