title: The antidiabetic agent sodium tungstate activates glycogen synthesis through an insulin receptor-independent pathway.
abstract: 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.
authors.affiliation: IRBB-Barcelona Science Park, Josep Samitier, 1-5, E-08028 Barcelona, Spain.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Domínguez
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Muñoz
authors.forename: Delia
authors.initials: D
authors.lastname: Zafra
authors.forename: Isabel
authors.initials: I
authors.lastname: Sanchez-Perez
authors.forename: Susanna
authors.initials: S
authors.lastname: Baqué
authors.forename: Martine
authors.initials: M
authors.lastname: Caron
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
authors.forename: Albert
authors.initials: A
authors.lastname: Barberà
authors.forename: Rosario
authors.initials: R
authors.lastname: Perona
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
authors.forename: Joan J
authors.initials: JJ
authors.lastname: Guinovart
mesh_terms: 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*
chemical_list: 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