Peroxyvanadium compounds inhibit glucose-6-phosphatase activity and glucagon-stimulated hepatic glucose output in the rat in vivo

The present investigation was undertaken to characterize the direct inhibit ory action of the peroxyvanadium compounds oxodiperoxo(1,10-phenanthroline) vanadate(V) (bpV(phen)) and oxodiperoxo(pyridine-2-carboxylate) vanadate(V ) (bpV(pic)) on pig microsomal glucose-6-phosphatase (Gr-6-Pase) activity a nd on glucagon stimulated hyperglycemia in vivo. Both bpV(phen) and bpV(pic ) were found to be potent competitive inhibitors of Gr-6-Pase with Ki value s of 0.96 and 0.42 mu M (intact microsomes) and 0.50 and 0.21 mu M (deterge nt-disrupted microsomes). The corresponding values for ortho-vanadate were 20.3 and 20.0 mu M. Administration of bpV(phen) to postprandial rats did no t affect the basal glucose level although a modest and dose-dependent incre ase in plasma lactate levels was seen. Injection of glucagon raised the pla sma glucose level from 5.5 mM to about 7.5 mM in control animals and this i ncrease could be prevented dose-dependently by bpV(phen). The inhibition of the glucagon-mediated blood glucose increase was accompanied by a dose-dep endent increase in plasma lactate levels from 2 mM to about 11 mM. In concl usion, the finding that vanadate and bpV compounds are potent inhibitors of G-6-Pase suggests that the blood-glucose-lowering effect of these compound s which is seen in diabetic animals may be partly explained by a direct eff ect on this enzyme rather than, as presently thought, being the result of i nhibition of phosphoprotein tyrosine phosphatases and thereby insulin recep tor dephosphorylation. (C) 1999 Academic Press.