Independent signal-transduction pathways for vanadate and for insulin in the activation of glycogen synthase and glycogenesis in rat adipocytes

The activating effect of vanadate on glycogenesis and on glycogen synthase (uridine diphosphate-glucose-glycogen glucosyl transferase) activity was st udied in rat adipocytes and compared with that of insulin. Using several ap proaches and specific blockers, we found that vanadate and insulin resemble each other, in the activation of glycogen synthase, in several aspects: bo th require nonarrested protein phosphatase 1 activity; they are equally sup pressed by conditions that elevate cAMP-levels; and both depend on the acti vation of phosphatidylinositol-3 kinase. The basic differences between them are as follows: 1) vanadate promotes glycogenesis through the activation o f a cytosolic protein tyrosine kinase, in an insulin-receptor-independent m anner; 2) vanadate elevates glucose-6-phosphate (G-6-P) to a higher level t han insulin; 3) vanadate-activated glycogenesis is accompanied by an increa se in the cellular content of immunoreactive glycogen synthase, an effect l ess noticeable with insulin; 4) adipose glucose-6-phosphatase is inhibited by vanadate (dose for 50% inhibition, IC50 = 7 +/- 0.7 mu M) but not by ins ulin. We have concluded that insulin and vanadate activate glycogenesis through a phosphatidylinositol-3 kinase and dephosphorylation-dependent mechanism. V anadate, however, uses a receptor-independent pathway and is superior to in sulin in elevating the level of G-6-P, a key metabolite for activating glyc ogen synthase. This is attributed to the combined effect of vanadate in enh ancing glucose entry and in inhibiting dephosphorylation of endogenously fo rmed G-6-P. The latter effect is not exerted by insulin.