title: In Vitro and In Vivo Investigation of the Angiogenic Effects of Liraglutide during Islet Transplantation.
abstract: BACKGROUND
  This study investigated the angiogenic properties of liraglutide in vitro and in vivo and the mechanisms involved, with a focus on Hypoxia Inducible Factor-1α (HIF-1α) and mammalian target of rapamycin (mTOR).
  
  
  METHODS
  Rat pancreatic islets were incubated in vitro with 10 μmol/L of liraglutide (Lira) for 12, 24 and 48 h. Islet viability was studied by fluorescein diacetate/propidium iodide staining and their function was assessed by glucose stimulation. The angiogenic effect of liraglutide was determined in vitro by the measure of vascular endothelial growth factor (VEGF) secretion using enzyme-linked immunosorbent assay and by the evaluation of VEGF and platelet-derived growth factor-α (PDGFα) expression with quantitative polymerase chain reaction technic. Then, in vitro and in vivo, angiogenic property of Lira was evaluated using immunofluorescence staining targeting the cluster of differentiation 31 (CD31). To understand angiogenic mechanisms involved by Lira, HIF-1α and mTOR activation were studied using western blotting. In vivo, islets (1000/kg body-weight) were transplanted into diabetic (streptozotocin) Lewis rats. Metabolic control was assessed for 1 month by measuring body-weight gain and fasting blood glucose.
  
  
  RESULTS
  Islet viability and function were respectively preserved and enhanced (p<0.05) with Lira, versus control. Lira increased CD31-positive cells, expression of VEGF and PDGFα (p<0.05) after 24 h in culture. Increased VEGF secretion versus control was also observed at 48 h (p<0.05). Moreover, Lira activated mTOR (p<0.05) signalling pathway. In vivo, Lira improved vascular density (p<0.01), body-weight gain (p<0.01) and reduced fasting blood glucose in transplanted rats (p<0.001).
  
  
  CONCLUSIONS
  The beneficial effects of liraglutide on islets appeared to be linked to its angiogenic properties. These findings indicated that glucagon-like peptide-1 analogues could be used to improve transplanted islet revascularisation.
authors.affiliation: UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Bld René Leriche, 67200 Strasbourg, France.
authors.forename: Allan
authors.initials: A
authors.lastname: Langlois
authors.affiliation: UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Bld René Leriche, 67200 Strasbourg, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Mura
authors.affiliation: UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Bld René Leriche, 67200 Strasbourg, France.
authors.forename: William
authors.initials: W
authors.lastname: Bietiger
authors.affiliation: UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Bld René Leriche, 67200 Strasbourg, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Seyfritz
authors.affiliation: UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Bld René Leriche, 67200 Strasbourg, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Dollinger
authors.affiliation: UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Bld René Leriche, 67200 Strasbourg, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Peronet
authors.affiliation: UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Bld René Leriche, 67200 Strasbourg, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Maillard
authors.affiliation: UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Bld René Leriche, 67200 Strasbourg, France.|Service d'Endocrinologie, Diabète, Maladies Métaboliques, Pôle NUDE, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Pinget
authors.affiliation: UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Bld René Leriche, 67200 Strasbourg, France.|Service d'Endocrinologie, Diabète, Maladies Métaboliques, Pôle NUDE, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jeandidier
authors.affiliation: UMR DIATHEC, EA 7294, Centre Européen d'Etude du Diabète, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Bld René Leriche, 67200 Strasbourg, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Sigrist
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007515:Islets of Langerhans / Q000098:blood supply / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D000069450:Liraglutide / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D043925:Angiogenesis Inducing Agents; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; C075278:platelet-derived growth factor A; C467498:vascular endothelial growth factor A, rat; D000069450:Liraglutide; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases