Oral insulin-mimetic compounds that act independently of insulin.
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.
García-Vicente
Silvia
S
Institute for Research in Biomedicine, Josep Samitier 1-5, Barcelona, Spain.
Yraola
Francesc
F
Marti
Luc
L
González-Muñoz
Elena
E
García-Barrado
María José
MJ
Cantó
Carles
C
Abella
Anna
A
Bour
Sandy
S
Artuch
Rafael
R
Sierra
Cristina
C
Brandi
Nuria
N
Carpéné
Christian
C
Moratinos
Julio
J
Camps
Marta
M
Palacín
Manuel
M
Testar
Xavier
X
Gumà
Anna
A
Albericio
Fernando
F
Royo
Miriam
M
Mian
Alec
A
Zorzano
Antonio
A
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*
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