title: Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 activity exerts an antidiabetic action in Goto-Kakizaki rats.
abstract: In this study we have explored whether the bifunctional protein semicarbazide-sensitive amine oxidase (SSAO)/vascular adhesion protein-1 (VAP-1) represents a novel target for type 2 diabetes. To this end, Goto-Kakizaki (GK) diabetic rats were treated with the SSAO substrate benzylamine and with low ineffective doses of vanadate previously shown to have antidiabetic effects in streptozotocin-induced diabetic rats. The administration of benzylamine in combination with vanadate in type 2 diabetic rats acutely stimulated glucose tolerance, and the chronic treatment normalized hyperglycemia, stimulated glucose transport in adipocytes, and reversed muscle insulin resistance. Acute in vivo administration of benzylamine and vanadate stimulated skeletal muscle glucose transport, an effect that was also observed in incubated muscle preparations coincubated with adipose tissue explants or with human recombinant SSAO. Acute administration of benzylamine/vanadate also ameliorated insulin secretion in diabetic GK rats, and this effect was also observed in incubated pancreatic islets. In keeping with these observations, we also demonstrate that pancreatic islets express SSAO/VAP-1. As far as mechanisms of action, we have found that benzylamine/vanadate causes enhanced tyrosine phosphorylation of proteins and reduced protein tyrosine phosphatase activity in adipocytes. In addition, incubation of human recombinant SSAO, benzylamine, and vanadate generates peroxovanadium compounds in vitro. Based on these data, we propose that benzylamine/vanadate administration generates peroxovanadium locally in pancreatic islets, which stimulates insulin secretion and also produces peroxovanadium in adipose tissue, activating glucose metabolism in adipocytes and in neighboring muscle. This opens the possibility of using the SSAO/VAP-1 activity as a local generator of protein tyrosine phosphatase inhibitors in antidiabetic therapy.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Abella
authors.forename: Luc
authors.initials: L
authors.lastname: Marti
authors.forename: Marta
authors.initials: M
authors.lastname: Camps
authors.forename: Marc
authors.initials: M
authors.lastname: Claret
authors.forename: J
authors.initials: J
authors.lastname: Fernández-Alvarez
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
authors.forename: Anna
authors.initials: A
authors.lastname: Gumà
authors.forename: Nathalie
authors.initials: N
authors.lastname: Viguerie
authors.forename: Christian
authors.initials: C
authors.lastname: Carpéné
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacín
authors.forename: Xavier
authors.initials: X
authors.lastname: Testar
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D006631:Amine Oxidase (Copper-Containing) / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000503:physiopathology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage; D014638:Vanadates / Q000008:administration & dosage
chemical_list: D001596:Benzylamines; D001786:Blood Glucose; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D007328:Insulin; D010545:Peroxides; D011994:Recombinant Proteins; D019000:Phosphotyrosine; D014638:Vanadates; C030796:benzylamine; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); D017027:Protein Tyrosine Phosphatases; D005947:Glucose