Vanadate (VO-3), an essential trace element with insulin-mimetic actions, produces systemic hyperglycemia following central administration in mice. The hyperglycemic effect is due to specific action of vanadate or its reduced form, vanadyl (VO2+); other ions of similar atomic weight (Cr, Mn) or structure (phosphate) have no effect. The effect of central vanadate to raise circulating glucose is blocked by coadministration of 3-O-methylglucose or polymyxin B, which prevent insulin- and vanadate-stimulated glucose transport. Finally, the central hyperglycemic effect is prevented by treatments which block sympathetic outflow from the CNS or diminish the levels of circulating epinephrine. These results show that vanadate is able to influence peripheral glucoregulation by increasing sympathetic outflow from the CNS. Moreover, they suggest that this effect is linked to action of VO-3 or its reduced form, VO2+, to stimulate glucose transport into neuronal cells.