The present investigation was undertaken to characterize the direct inhibitory 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 (G-6-Pase) activity and on
glucagon stimulated
hyperglycemia in vivo. Both
bpV(phen) and
bpV(pic) were found to be potent competitive inhibitors of G-6-Pase with Ki values of 0.96 and 0.42 microM (intact microsomes) and 0.50 and 0.21 microM (
detergent-disrupted microsomes). The corresponding values for ortho-
vanadate were 20.3 and 20.0 microM. Administration of
bpV(phen) to postprandial rats did not affect the basal
glucose level although a modest and dose-dependent increase in plasma
lactate levels was seen. Injection of
glucagon raised the plasma
glucose level from 5.5 mM to about 7.5 mM in control animals and this increase could be prevented dose-dependently by
bpV(phen). The inhibition of the
glucagon-mediated
blood glucose increase was accompanied by a dose-dependent increase in plasma
lactate levels from 2 mM to about 11 mM. In conclusion, the finding that
vanadate and bpV compounds are potent inhibitors of G-6-Pase suggests that the
blood-glucose-lowering effect of these compounds which is seen in diabetic animals may be partly explained by a direct effect on this
enzyme rather than, as presently thought, being the result of inhibition of
phosphoprotein tyrosine phosphatases and thereby
insulin receptor dephosphorylation.