The selective alpha-2 adrenoceptor agonist UK 14.304 induced in the mouse a dose-dependent hyperglycemic response which was accompanied by a concomitant inhibition of insulin secretion. Similar effects were observed with the preferential alpha-2 receptor agonists clonidine and guanabenz whereas less pronounced effects were found with (-)-epinephrine. No significant effects on blood glucose levels were observed with the alpha-1 adrenoceptor agonist methoxamine. Adrenalectomy or depletion of catecholamine stores by reserpine, alpha-methylparatyrosine or DSP4 failed to modify the hyperglycemic response to UK 14.304. However, streptozotocin diabetic mice did not respond to UK 14.304. The hyperglycemia induced by submaximal doses of UK 14.304 was antagonized by the centrally and peripherally acting alpha-2 adrenoceptor antagonists rauwolscine, yohimbine, idazoxan and phentolamine, by the peripheral antagonist benextramine but not by prazosin (alpha-1 selective) or propranolol (beta adrenergic). Thus, it may be suggested that the alpha agonist-induced hyperglycemia is mediated via postsynaptic alpha-2 adrenoceptors located on pancreatic beta cells and that it is mediated through the inhibition of insulin secretion.