Insulin-mimetic action of vanadate - Role of intracellular magnesium

The insulin-mimetic effect of vanadate is well established, and vanadate has been shown to improve insulin sensitivity in diabetic rats and humans. Although the exact mechanism(s) remain undefined, we have previously demonstrated a direct relation of intracellular free magnesium (Mg) levels to glucose disposal, to insulinemic responses following glucose loading, and to insulin-induced ionic effects. To investigate whether the insulin-mimetic effects of vanadate could similarly be mediated by Mg-i, we utilized P-31-nuclear magnetic resonance spectroscopy to measure Mgi in erythrocytes from normal (NL, n= 10) and hypertensive (HTN, n= 12) subjects, before and after incubation with insulin and with different doses of sodium vanadate. In NL, vanadate elevated Mg, levels, with maximum efficacy at 50 mu mol/L (186 +/-6 to 222 +/-6 mu mol/L, P >0.01), as did physiologically maximal doses of insulin, 200 muU/mL (185 +/-6 to 222 +/-8 mu mol/L, P <0.01). In HTN, only vanadate, but not insulin, increased Mg, (insulin: 173 +/-7 to 180 +/-9 mu mol/L, P=NS; vanadate: 170 +/-7 to 208 +/- 10 mu mol/L, P <0.01). Mg-i responses to insulin (r=0.637, P <0.001), but not to vanadate (r=0.15, P=NS), were closely and directly related to basal Mgi levels. We conclude that (1) both vanadate and insulin stimulate erythrocyte Mg, levels; (2) cellular Mgi responses to insulin, but not to vanadate, depend on basal Mgi content-the lower the basal Mg,, the less the Mgi response to insulin. As such, (3) Mgi responses to vanadate were equivalent among HTN and NL, whereas HTN cells exhibited blunted Mg-i responses to insulin, and (4) the ability of vanadate to improve insulin sensitivity clinically may be mediated, at least in part, by its ability to increase Mg-i levels, which in turn, helps to determine cellular insulin action.