Oral Insulin-Mimetic Compounds That Act Independently of Insulin

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 2; pp. 486 - 493
• Main Authors: GARCIA-VICENTE, Silvia, YRAOLA, Francesc, BRANDI, Nuria, CARPENE, Christian, MORATINOS, Julio, CAMPS, Marta, PALACIN, Manuel, TESTAR, Xavier, GUMA, Anna, ALBERICIO, Fernando, ROYO, Miriam, MIAN, Alec, MARTI, Luc, ZORZANO, Antonio, GONZALEZ-MUNOZ, Elena, GARCIA-BARRADO, Maria José, CANTO, Caries, ABELLA, Anna, BOUR, Sandy, ARTUCH, Rafael, SIERRA, Cristina
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.2007
• Subjects: Adipocytes; Adipocytes - drug effects; Administration, Oral; Animals; Antidiabetics; Benzylamines - chemistry; Benzylamines - therapeutic use; Biological and medical sciences; Care and treatment; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes research; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Epidermal growth factor; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genetic aspects; Glucose - metabolism; Health aspects; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Injections, Subcutaneous; Insulin; Insulin Receptor Substrate Proteins; Insulin resistance; Ketamine; Kinases; Lipid Metabolism - drug effects; Male; Medical sciences; Mice; Mice, Inbred C57BL; Muscle, Skeletal - drug effects; Oxidative Stress - drug effects; Phosphoproteins - metabolism; Phosphorylation - drug effects; Polyclonal antibodies; Proteins; Rats; Rats, Wistar; Streptozocin; Vanadium Compounds - chemistry; Vanadium Compounds - therapeutic use; Spain; France; Endocrinopathy; Pancreatic hormone; Insulin; Diabetes mellitus
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-0269

Oral Insulin-Mimetic Compounds That Act Independently of Insulin Silvia García-Vicente 1 2 , Francesc Yraola 3 , Luc Marti 1 4 , Elena González-Muñoz 1 2 , María José García-Barrado 5 , Carles Cantó 2 , Anna Abella 1 , Sandy Bour 6 , Rafael Artuch 7 , Cristina Sierra 7 , Nuria Brandi 7 , Christian Carpéné 6 , Julio Moratinos 5 , Marta Camps 1 2 , Manuel Palacín 1 2 , Xavier Testar 1 2 , Anna Gumà 2 , Fernando Albericio 1 3 , Miriam Royo 3 , Alec Mian 4 and Antonio Zorzano 1 2 1 Institute for Research in Biomedicine, Barcelona, Spain 2 Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain 3 Unitat de Química Combinatòria, Parc Científic de Barcelona, Barcelona, Spain 4 Genmedica Therapeutics, Barcelona, Spain 5 Department of Physiology and Pharmacology, School of Medicine, University of Salamanca, Salamanca, Spain 6 Institut National de la Santé et de la Recherche Médicale (INSERM U586), Toulouse, France 7 Servei de Bioquímica, Hospital de Sant Joan de Deu, Esplugues, Barcelona, Spain Address correspondence and reprint requests to Antonio Zorzano, Institute for Research in Biomedicine, Josep Samitier 1-5, Barcelona, Spain. E-mail: azorzano{at}pcb.ub.es Abstract The hallmarks of insulin action are the stimulation and suppression of anabolic and catabolic responses, respectively. These responses are orchestrated by the insulin pathway and are initiated by the binding of insulin to the insulin receptor, which leads to activation of the receptor’s intrinsic tyrosine kinase. Severe defects in the insulin pathway, such as in types A and B and advanced type 1 and 2 diabetes lead to severe insulin resistance, resulting in a partial or complete absence of response to exogenous insulin and other known classes of antidiabetes therapies. We have characterized a novel class of arylalkylamine vanadium salts that exert potent insulin-mimetic effects downstream of the insulin receptor in adipocytes. These compounds trigger insulin signaling, which is characterized by rapid activation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3 independent of insulin receptor phosphorylation. Administration of these compounds to animal models of diabetes lowered glycemia and normalized the plasma lipid profile. Arylalkylamine vanadium compounds also showed antidiabetic effects in severely diabetic rats with undetectable circulating insulin. These results demonstrate the feasibility of insulin-like regulation in the complete absence of insulin and downstream of the insulin receptor. This represents a novel therapeutic approach for diabetic patients with severe insulin resistance. B4V10, tetraquis(benzylammonium) decavanadate B5V10, pentaquis(benzylammonium) decavanadate B6V10, hexaquis(benzylammonium) decavanadate DMEM, Dulbecco’s modified Eagle’s medium EGF, epidermal growth factor GH, growth hormone GSK, glycogen synthase kinase IRS, insulin receptor substrate SCZ, semicarbazide SSAO, SCZ-sensitive amine oxidase V10, sodium decavanadate salt VAP-1, vascular adhesion protein-1 Footnotes S.G.-V., F.Y., and L.M. contributed equally to this work. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-0269 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted October 26, 2006. Received February 27, 2006. DIABETES