PEROXOVANADIUM COMPOUNDS - BIOLOGICAL ACTIONS AND MECHANISM OF INSULIN-MIMESIS

When used alone, both vanadate and hydrogen peroxide (H2O2,) are weakl y insulin-mimetic, while in combination they are strongly synergistic due to the formation of aqueous peroxovanadium species pV((aq)). Admin istration of these pV((aq)), species leads to activation of the insuli n receptor tyrosine kinase (IRK), autophosphorylation at tyrosine resi dues and inhibition of phosphotyrosine phosphatases (PTPs). We therefo re undertook to synthesize a series of peroxovanadium (pV) compounds c ontaining one or two peroxo anions, an oxo anion and an ancillary liga nd in the inner co-ordination sphere of vanadium whose properties and insulin-mimetic potencies could be assessed. These pV compounds were s hown to be the most potent inhibitors of PTPs yet described. Their PTP inhibitory potency correlated with their capacity to stimulate IRK ac tivity. Some pV compounds showed much greater potency as inhibitors of insulin receptor (IR) dephosphorylation than epidermal growth factor receptor (EGFR) dephosphorylation, implying relative specificity as PT P inhibitors. Replacement of vanadium with either molybdenum or tungst en resulted in equally potent inhibition of IR dephosphorylation. Howe ver Wt activation was reduced by greater than 80% suggesting that thes e compounds did not access intracellular PTPs. The insulin-like activi ty of these pV compounds were demonstrable in vivo. Intra venous (i.v. ) administration of bpV(pic) and bpV(phen) resulted in the lowering of plasma glucose concentrations in normal rats in a dose dependent mann er. The greater potency of bpV(pic) compared to bpV(phen) was explicab le, in part, by the capacity of the former but not the latter to act o n skeletal muscle as well as liver. Finally administration of bpV(phen ) and insulin led to a synergism, where tyrosine phosphorylation of th e IR P-subunit increased by 20-fold and led to the appearance of four insulin-dependent in vivo substrates. The insulin-mimetic properties o f the pV compounds raises the possibility for their use as insulin rep lacements in the management of diabetes mellitus.