AbstractAims/hypothesis. Hypothalamic neuropeptide Y is implicated in the aetiology of obesity and insulin resistance because of its hyperinsulinaemic, hyperphagic effects. We investigated the interaction of adrenal glucocorticoids and the parasympathetic nervous system in the hyperinsulinaemia caused by neuropeptide Y infusion in rats.Methods. Neuropeptide Y was intracerebroventricularly given to normal or adrenalectomised rats for 36 days with pair-feeding, with or without subcutaneous dexamethasone infusion. We measured basal and intravenous glucose-induced insulinaemia and the effect of prior atropine injection.Results. Neuropeptide Y increased basal plasma insulin and C-peptide concentrations (380 90 and 1000 60 pmol/l, vs 190 20 and 590 50 pmol/l in controls, p 0.05). Neuropeptide Y also increased the plasma concentrations of these hormones as early as 60 s after glucose injection (1630 170 and 3200 170 pmol/l for insulin and C peptide, respectively, vs 1080 80 and 1860 130 pmol/l in controls, p 0.05). Atropine reversed the effect of neuropeptide Y on basal plasma insulin and C-peptide concentrations but had no effect on post-glucose plasma concentrations. The hyperinsulinaemic effects of neuropeptide Y were prevented by adrenalectomy, but were restored by dexamethasone infusion. Dexamethasone in itself did not statistically significantly increase insulinaemia in adrenalectomised rats. As in intact rats, atropine attenuated the basal hyperinsulinaemia of adrenalectomised rats that had been infused with neuropeptide Y and dexamethasone but had no effect on post-glucose hyperinsulinaemia.Conclusion/interpretation. These data suggest firstly that neuropeptide Y infused centrally induces basal hyperinsulinaemia in rats through glucocorticoid-dependant parasympathetic activation to the pancreas. Secondly, neuropeptide Y potentiates glucose-induced insulinaemia through a pathway dependant on adrenal glucocorticoids that cannot be reversed by short-term blockade of the increased parasympathetic tonus. [Diabetologia (2000) 43: 859865]