The effects of glucagon and epinephrine on adenylate cyclase activity in homogenates of isolated islets and insulin release were studied in rats fed on either a control or a high fat diet for 12 weeks. Rats were divided into non-stress group and stress group. Rats in stress groups received electrical shocks (1 hr/day) for the last 3 weeks of the experimental period. Islet adenylate cyclase activity was measured by the conversion of [2-3H]ATP to cyclic [3H]AMP. While the basal activity of adenylate cyclase was increased by stress, it was reduced by the high fat diet. In the presence of a low glucose concentration, the adenylate cyclase activity was higher in non-stress groups rather than in stress groups. However, the adenylate cyclase activity was not altered by an increase in glucose concentration. Characteristically, the adenylate cyclase activity in fat diet-stress group was reduced by 16.7 mM glucose and glucose-stimulated insulin release was low. Stress enhanced glucagon-stimulated adenylate cyclase activity, which was reduced by the high fat diet. The effect of glucagon on adenylate cyclase activity was similar to that on insulin release. Epinephrine (10-6M) did not after the adenylate cyclase activity in all four groups. It is concluded that a decrease of glucose-stimulated insulin release produced by the combined actions of a high fat diet and electric stress may involve at least partly the inhibition of adenylate cyclase-cyclic AMP system activated by glucose itself.