Clonidine is a hypotensive drug acting as an alpha-mimetic agent in the central nervous system and causing cardiovascular depression. Clonidine administration in animals and man causes slight hyperglycemia and lipid mobilization, as well as an increase in growth hormone levels. We have studied the effect of a 3-day oral treatment (78 microgram three times daily) upon glucose (5 g i.v.)- and tolbutamide (1 g i.v.)-induced insulin release in subjects without metabolic alterations. Acute insulin response (3 min after IVGTT) and insulin release (area between 0 and 10 min) were significantly reduced after clonidine treatment. Blood glucose levels were not affected by clonidine treatment; the insulinogenic index 3 min after the glucose load was significantly reduced by clonidine administration. There was neither an evident effect on tolbutamide-induced insulin release nor a modification of the hypoglycemic effect of tolbutamide. Clonidine did not affect basal lipolysis, evaluated in vitro as glycerol release from human subcutaneous adipose tissue fragments, while norepinephrine-induced lipolysis was slightly reduced. The results presented are compatible with an alpha-mimetic effect of clonidine on pancreatic and adipose tissue.