title: Oral insulin-mimetic compounds that act independently of insulin.
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.
authors.affiliation: Institute for Research in Biomedicine, Josep Samitier 1-5, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: García-Vicente
authors.forename: Francesc
authors.initials: F
authors.lastname: Yraola
authors.forename: Luc
authors.initials: L
authors.lastname: Marti
authors.forename: Elena
authors.initials: E
authors.lastname: González-Muñoz
authors.forename: María José
authors.initials: MJ
authors.lastname: García-Barrado
authors.forename: Carles
authors.initials: C
authors.lastname: Cantó
authors.forename: Anna
authors.initials: A
authors.lastname: Abella
authors.forename: Sandy
authors.initials: S
authors.lastname: Bour
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
authors.forename: Cristina
authors.initials: C
authors.lastname: Sierra
authors.forename: Nuria
authors.initials: N
authors.lastname: Brandi
authors.forename: Christian
authors.initials: C
authors.lastname: Carpéné
authors.forename: Julio
authors.initials: J
authors.lastname: Moratinos
authors.forename: Marta
authors.initials: M
authors.lastname: Camps
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacín
authors.forename: Xavier
authors.initials: X
authors.lastname: Testar
authors.forename: Anna
authors.initials: A
authors.lastname: Gumà
authors.forename: Fernando
authors.initials: F
authors.lastname: Albericio
authors.forename: Miriam
authors.initials: M
authors.lastname: Royo
authors.forename: Alec
authors.initials: A
authors.lastname: Mian
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D001596:Benzylamines / Q000737:chemistry / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D055504:Insulin Receptor Substrate Proteins; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D017968:Vanadium Compounds / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D001596:Benzylamines; D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D017968:Vanadium Compounds; D013311:Streptozocin; C030796:benzylamine; D005947:Glucose