We examined the effect of the infusion of a vasoactive intestinal peptide (VIP) antisense oligodeoxynucleotide into the third cerebral ventricle above the hypothalamic suprachiasmatic nucleus (SCN) using osmotic minipump for 3 days (0.2 nmol/ml per h) on the hyperglycemic response to intracerebroventricular injection of 2-deoxy-D-glucose (2DG) (80 micromol) in rats. After the infusion of the VIP antisense the inhibition of VIP expression in the SCN was observed in association with suppressions of the hyperglycemia, hyperglucagonemia and relative hypoinsulinemia due to the 2DG injection. Furthermore, additional intracranial injection of VIP (4 nmol) restored these responses to the 2DG injection in rats treated with the VIP antisense. These findings suggest that VIP neurons in the SCN are involved in the regulation of glucose metabolism.