Open Accessβ cell membrane remodelling and procoagulant events occur in inflammation‐driven insulin impairment: a GLP ‐1 receptor dependent and independent control
Author(s) -
Gleizes Céline,
Kreutter Guillaume,
Abbas Malak,
Kassem Mohamad,
Constantinescu Andrei Alexandru,
BoisraméHelms Julie,
Yver Blandine,
Toti Florence,
Kessler Laurence
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12683
Subject(s) - liraglutide , insulin , endocrinology , receptor , lipid raft , secretion , medicine , glucagon like peptide 1 receptor , exocytosis , microbiology and biotechnology , chemistry , biology , type 2 diabetes , diabetes mellitus , agonist
Inflammation and hyperglycaemia are associated with a prothrombotic state. Cell‐derived microparticles ( MP s) 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 MP s 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.