Insulin Mimetic Action of Vanadyl Chelates

Much emphasis has been given to the insulin mimetic properties of vanadium compounds. Of the organic VO²⁺-chelates, bis(acetylacetonato)oxidovanadium(IV) [VO(acac)₂], exhibits the greatest capacity to enhance insulin receptor kinase activity in cells compared to other organic VO²⁺-chelates and is associated with a dose-dependent capacity to lower plasma glucose in diabetic laboratory animals. We have identified the target enzyme of VO(acac)₂as protein tyrosine phosphatase-1B (PTP-1B). VO(acac)₂is the only VO²⁺-chelate that exhibits synergism with insulin, indicating that the two reagents influence the same signaling pathway. In contrast to tyrosine kinases, no inhibitor of PTP-1B has been developed for therapeutic purposes. A possible origin of this problem is that essentially all kinetic studies to identify a suitable inhibitor have been carried out with the non-specific, synthetic substrate p-nitrophenyl phosphate, showing only competitive inhibition. In contrast, in the presence of the physiologically relevant substrate, a phosphotyrosine-containing dodecapeptide analog of residues 988 – 999 of the epidermal growth factor receptor (EGFR), VO(acac)₂exhibits uncompetitive inhibition. In addition to its capacity to enhance glucose uptake in normal cells, VO(acac)₂is preferentially sequestered in malignant xenograft tumors and enhances the uptake of 2-(fluorine-18)-2-deoxy-glucose, the most frequently used reporter molecule for cancer detection by positron emission tomography (PET) imaging.