Peroxyvanadium Compounds Inhibit Glucose-6-phosphatase Activity and Glucagon-Stimulated Hepatic Glucose Output in the Ratin Vivo

Abstract

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 withKivalues of 0.96 and 0.42 μM (intact microsomes) and 0.50 and 0.21 μM (detergent-disrupted microsomes). The corresponding values forortho-vanadate were 20.3 and 20.0 μM. 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.