The Antidiabetic Agent Sodium Tungstate Activates Glycogen Synthesis through an Insulin Receptor-independent Pathway

Jorge E. Domínguez, M. Carmen Muñoz, Delia Zafra, Isabel Sánchez-Pérez, Susanna Baqué, Martine Caron, Ciro Mercurio, Albert Barberà, Rosario Perona, Ramon Gomis, Joan J. Guinovart

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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 3β. 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.

Original languageEnglish
Pages (from-to)42785-42794
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number44
DOIs
Publication statusPublished - Oct 31 2003

ASJC Scopus subject areas

  • Biochemistry

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    Domínguez, J. E., Muñoz, M. C., Zafra, D., Sánchez-Pérez, I., Baqué, S., Caron, M., Mercurio, C., Barberà, A., Perona, R., Gomis, R., & Guinovart, J. J. (2003). The Antidiabetic Agent Sodium Tungstate Activates Glycogen Synthesis through an Insulin Receptor-independent Pathway. Journal of Biological Chemistry, 278(44), 42785-42794. https://doi.org/10.1074/jbc.M308334200