L-glutamic acid gamma-monohydroxamate - A potentiator of vanadium-evoked glucose metabolism in vitro and in vivo

We report that the vanadium ligand L-Glu(gamma)HXM potentiates the capacity of free vanadium ions to activate glucose uptake and glucose metabolism in rat adipocytes in vitro (by 4-5-fold) and to lower blood glucose levels in hyperglycemic rats in vivo (by 5-7-fold). A molar ratio of two L-Glu(gamma )HXM molecules to one vanadium ion was most effective. Unlike other vanadiu m ligands that potentiate the insulinomimetic actions of vanadium, L-Glu(ga mma)HXM partially activated lipogenesis in rat adipocytes in the absence of exogenous vanadium, This effect was not manifested by D-Glu(gamma)HMM, At 10-20 mu M L-Glu(gamma)HXM, lipogenesis was activated 9-21%, This effect wa s approximately g-fold higher (140 +/- 15% of maximal insulin response) in adipocytes derived from rats that had been treated with vanadium for severa l days. Titration of vanadium(lV) with L-Glu(gamma)HXM led to a rapid decre ase in the absorbance of vanadium(IV) at 765 nm, and V-51 NMR spectroscopy revealed that the chemical shift of vanadium(IV) at -490 ppm disappeared wi th the appearance of a signal characteristic to vanadium(V) (-530 ppm) upon adding one equivalent of L-Glu(gamma)HXM. In summary, L-Glu(gamma)HXM is h ighly active in potentiating vanadium-activated glucose metabolism in vitro and in vivo and facilitating glucose metabolism in rat adipocytes in the a bsence of exogenous vanadium probably through conversion of trace intracell ular vanadium into an active insulinomimetic compound. We propose that the active species is either a 1:1 or 2:1 L-Glu(gamma)HXM vanadium complex in w hich the endogenous vanadium(IV) has been altered to vanadium(V), Finally w e demonstrate that L-Glu(gamma)HXM- and L-Glu(gamma)HXM vanadium-evoked lip ogenesis is arrested by wortmannin and that activation of glucose uptake in rat adipocytes is because of enhanced translocation of GLUT4 from low dens ity microsomes to the plasma membrane.