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Oral Insulin-Mimetic Compounds That Act Independently of Insulin

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

Abbreviations: 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

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.

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