The antidiabetic agent sodium tungstate activates glycogen synthesis through an insulin receptor-independent pathway.
Sodium tungstate is a powerful antidiabetic agent when administered orally. In primary cultured hepatocytes, tungstate showed insulin-like actions, which led to an increase in glycogen synthesis and accumulation. However, this compound did not significantly alter the insulin receptor activation state or dephosphorylation rate in cultured cells (CHO-R) or in primary hepatocytes, in either short or long term treatments. In contrast, at low concentrations, tungstate induced a transient strong activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) after 5-10 min of treatment, in a similar way to insulin. Moreover, this compound did not significantly delay or inhibit the dephosphorylation of ERK1/2. ERK1/2 activation triggered a cascade of downstream events, which included the phosphorylation of p90rsk and glycogen synthase-kinase 3beta. Experiments with a specific inhibitor of ERK1/2 activation and kinase assays indicate that these proteins were directly involved in the stimulation of glycogen synthase and glycogen synthesis induced by tungstate without a direct involvement of protein kinase B (PKB/Akt). These results show a direct involvement of ERK1/2 in the mechanism of action of tungstate at the hepatic level.
Domínguez
Jorge E
JE
IRBB-Barcelona Science Park, Josep Samitier, 1-5, E-08028 Barcelona, Spain.
Muñoz
M Carmen
MC
Zafra
Delia
D
Sanchez-Perez
Isabel
I
Baqué
Susanna
S
Caron
Martine
M
Mercurio
Ciro
C
Barberà
Albert
A
Perona
Rosario
R
Gomis
Ramon
R
Guinovart
Joan J
JJ
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006003:Glycogen / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D017973:Tungsten Compounds / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007004:Hypoglycemic Agents; D007328:Insulin; D017973:Tungsten Compounds; D019000:Phosphotyrosine; C025399:sodium tungstate(VI); D006003:Glycogen; D011972:Receptor, Insulin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C045951:tungstate