Semicarbazide-Sensitive Amine Oxidase/Vascular Adhesion Protein-1 Activity Exerts an Antidiabetic Action in Goto-Kakizaki Rats

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 4; pp. 1004 - 1013
• Main Authors: ABELLA, Anna, MARTI, Luc, TESTAR, Xavier, ZORZANO, Antonio, CAMPS, Marta, CLARET, Marc, FERNANDEZ-ALVAREZ, J, GOMIS, Ramon, GUMA, Anna, VIGUERIE, Nathalie, CARPENE, Christian, PALACIN, Manuel
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.04.2003
• Subjects: Adipocytes; Adipocytes - metabolism; Amine Oxidase (Copper-Containing) - administration & dosage; Amine Oxidase (Copper-Containing) - genetics; Amine Oxidase (Copper-Containing) - metabolism; Animals; Antidiabetics; Benzylamines - administration & dosage; Biological and medical sciences; Biological Transport - drug effects; Blood Glucose - analysis; Body fat; Cell Adhesion Molecules - metabolism; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - physiopathology; Diabetes therapy; Enzyme Inhibitors - metabolism; Fundamental and applied biological sciences. Psychology; Glucose; Glucose - metabolism; Hyperglycemia; Insulin - metabolism; Insulin - pharmacology; Insulin Resistance; Insulin Secretion; Islets of Langerhans - physiopathology; Kinases; Male; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Musculoskeletal system; Peroxides - metabolism; Phosphatase; Phosphorylation; Phosphotyrosine - metabolism; Physiological aspects; Plasma; Protein Tyrosine Phosphatases - antagonists & inhibitors; Proteins; Rats; Rats, Wistar; Recombinant Proteins - administration & dosage; Signal transduction; Type 2 diabetes; Vanadates - administration & dosage; France; Spain
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.4.1004

Semicarbazide-Sensitive Amine Oxidase/Vascular Adhesion Protein-1 Activity Exerts an Antidiabetic Action in Goto-Kakizaki Rats Anna Abella 1 , Luc Marti 1 , Marta Camps 1 , Marc Claret 2 , J. Fernández-Alvarez 2 , Ramon Gomis 2 , Anna Gumà 1 , Nathalie Viguerie 3 , Christian Carpéné 3 , Manuel Palacín 1 , Xavier Testar 1 and Antonio Zorzano 1 1 Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and Parc Científic de Barcelona, Barcelona, Spain 2 Endocrinology and Diabetes Unit, IDIBAPS, Hospital Clinic de Barcelona, Barcelona, Spain 3 Institut National de la Santé et de la Recherche Médicale (INSERM U 317), Toulouse, France 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. Footnotes Address correspondence and reprint requests to Antonio Zorzano, Department de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Av. Diagonal 645, 08028, Barcelona, Spain. E-mail: azorzano{at}porthos.bio.ub.es Received for publication 3 December 2002 and accepted in revised form 8 January 2003. A.A. and L.M. equally contributed to the study. IAPP, islet amyloid polypeptide; IRS, insulin receptor substrate; LAR, leukocyte antigen-related phosphatase; NMR, nuclear magnetic resonance; PTP1B, protein tyrosine phosphatase-1B; SHP2, src-homology phosphatase-2; SSAO, semicarbazide-sensitive amine oxidase; VAP-1, vascular adhesion protein-1. DIABETES