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Independent Signal-Transduction Pathways for Vanadate and for Insulin in the Activation of Glycogen Synthase and Glycogenesis in Rat Adipocytes¹

Department of Biological Chemistry (N.S., J.L., Z.H., Y.S.), The Weizmann Institute of Science, Rehovot 76100, Israel; and Department of Medicine-C (D.G.), Barzilai Medical Center, Ashkelon 78306, Israel

Address all correspondence and requests for reprints to: Yoram Shechter, Department of Biological Chemistry, Weizmann Institute of Science, Rehovot-76100, Israel.

The activating effect of vanadate on glycogenesis and on glycogen synthase (uridine diphosphate-glucose-glycogen glucosyl transferase) activity was studied in rat adipocytes and compared with that of insulin. Using several approaches and specific blockers, we found that vanadate and insulin resemble each other, in the activation of glycogen synthase, in several aspects: both require nonarrested protein phosphatase 1 activity; they are equally suppressed by conditions that elevate cAMP-levels; and both depend on the activation of phosphatidylinositol-3 kinase. The basic differences between them are as follows: 1) vanadate promotes glycogenesis through the activation of a cytosolic protein tyrosine kinase, in an insulin-receptor-independent manner; 2) vanadate elevates glucose-6-phosphate (G-6-P) to a higher level than insulin; 3) vanadate-activated glycogenesis is accompanied by an increase in the cellular content of immunoreactive glycogen synthase, an effect less noticeable with insulin; 4) adipose glucose-6-phosphatase is inhibited by vanadate (dose for 50% inhibition, IC₅₀ = 7 ± 0.7 µM) but not by insulin.

We have concluded that insulin and vanadate activate glycogenesis through a phosphatidylinositol-3 kinase and dephosphorylation-dependent mechanism. Vanadate, however, uses a receptor-independent pathway and is superior to insulin in elevating the level of G-6-P, a key metabolite for activating glycogen synthase. This is attributed to the combined effect of vanadate in enhancing glucose entry and in inhibiting dephosphorylation of endogenously formed G-6-P. The latter effect is not exerted by insulin.

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