title: β cell membrane remodelling and procoagulant events occur in inflammation-driven insulin impairment: a GLP-1 receptor dependent and independent control.
abstract: Inflammation and hyperglycaemia are associated with a prothrombotic state. Cell-derived microparticles (MPs) are the conveyors of active procoagulant tissue factor (TF) and circulate at high concentration in diabetic patients. Liraglutide, a glucagon-like peptide (GLP)-1 analogue, is known to promote insulin secretion and β-cell preservation. In this in vitro study, we examined the link between insulin impairment, procoagulant activity and plasma membrane remodelling, under inflammatory conditions. Rin-m5f β-cell function, TF activity mediated by MPs and their modulation by 1 μM liraglutide were examined in a cell cross-talk model. Methyl-β-cyclodextrine (MCD), a cholesterol depletor, was used to evaluate the involvement of raft on TF activity, MP shedding and insulin secretion as well as Soluble N-éthylmaleimide-sensitive-factor Attachment protein Receptor (SNARE)-dependent exocytosis. Cytokines induced a two-fold increase in TF activity at MP surface that was counteracted by liraglutide. Microparticles prompted TF activity on the target cells and a two-fold decrease in insulin secretion via protein kinase A (PKA) and p38 signalling, that was also abolished by liraglutide. Large lipid raft clusters were formed in response to cytokines and liraglutide or MCD-treated cells showed similar patterns. Cells pre-treated by saturating concentration of the GLP-1r antagonist exendin (9-39), showed a partial abolishment of the liraglutide-driven insulin secretion and liraglutide-decreased TF activity. Measurement of caspase 3 cleavage and MP shedding confirmed the contribution of GLP-1r-dependent and -independent pathways. Our results confirm an integrative β-cell response to GLP-1 that targets receptor-mediated signalling and membrane remodelling pointing at the coupling of insulin secretion and inflammation-driven procoagulant events.
authors.affiliation: EA7293, Vascular and Tissular Stress in Transplantation, Faculty of Medicine, University of Strasbourg, Illkirch, France.|Federation of Translational Medicine of Strasbourg, Faculty of Medicine, University of Strasbourg, Strasbourg, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Gleizes
authors.affiliation: EA7293, Vascular and Tissular Stress in Transplantation, Faculty of Medicine, University of Strasbourg, Illkirch, France.|Federation of Translational Medicine of Strasbourg, Faculty of Medicine, University of Strasbourg, Strasbourg, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Kreutter
authors.affiliation: EA7293, Vascular and Tissular Stress in Transplantation, Faculty of Medicine, University of Strasbourg, Illkirch, France.|Doctoral School of Sciences and Technologies, Lebanese University, Beiruth-Hadath, Lebanon.
authors.forename: Malak
authors.initials: M
authors.lastname: Abbas
authors.affiliation: EA7293, Vascular and Tissular Stress in Transplantation, Faculty of Medicine, University of Strasbourg, Illkirch, France.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Kassem
authors.affiliation: EA7293, Vascular and Tissular Stress in Transplantation, Faculty of Medicine, University of Strasbourg, Illkirch, France.|Department of Parasitology and Parasitic Diseases and Animal Biology, Faculty of Veterinary Medicine, University of Agronomical Sciences and Veterinary Medicine, Bucharest, Romania.
authors.forename: Andrei Alexandru
authors.initials: AA
authors.lastname: Constantinescu
authors.affiliation: Department of Reanimation, Nouvel hopital civil, Strasbourg CEDEX, France.|Federation of Translational Medicine of Strasbourg, Faculty of Medicine, University of Strasbourg, Strasbourg, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Boisramé-Helms
authors.affiliation: EA7293, Vascular and Tissular Stress in Transplantation, Faculty of Medicine, University of Strasbourg, Illkirch, France.
authors.forename: Blandine
authors.initials: B
authors.lastname: Yver
authors.affiliation: UMR7213 CNRS, Laboratory of Biophotonics and Pharmacology, Faculty of Pharmacy, University of Strasbourg, Illkirch, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Toti
authors.affiliation: EA7293, Vascular and Tissular Stress in Transplantation, Faculty of Medicine, University of Strasbourg, Illkirch, France.|Federation of Translational Medicine of Strasbourg, Faculty of Medicine, University of Strasbourg, Strasbourg, France.|Department of Diabetology, University Hospital, Strasbourg Cedex, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Kessler
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D055252:Cell-Derived Microparticles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D000069450:Liraglutide / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D050600:SNARE Proteins / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010446:Peptide Fragments; D050600:SNARE Proteins; C083773:exendin (9-39); D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D013925:Thromboplastin; D017868:Cyclic AMP-Dependent Protein Kinases; D053148:Caspase 3
keywords: GLP-1 receptor; exocytosis; insulin; ion channels; lipid raft; microparticles; tissue factor; β cell