1. The effects of various stimuli, including changes in glucose concentration, arginine, tyramine and noradrenaline, on insulin and glucagon secretion were investigated using isolated perfused pancreata of obese and lean male Zucker rats at 12 months of age. 2. In Zucker fatty rats, the insulin secretion rate was significantly (P < 0.01) higher than that of lean rats at all glucose concentrations tested (8.3, 16.7 and 1.4 mmol/l). However, the integrated insulin secretory response to raising the glucose concentration from 8.3 to 16.7 mmol/l was almost absent in these rats. The glucagon secretion rates were significantly lower at 8.3 and 1.4 mmol/l glucose (P < 0.001 for both), and in responses to 10 micrograms/ml tyramine and 0.1 mumol/l noradrenaline (P < 0.05 for both), in Zucker fatty rats. Integrated insulin and glucagon responses to 10 mmol/l arginine were identical in the two groups. 3. Histopathological and immunochemical studies revealed hyperplasia of beta-cells and scattered alpha-cells in the enlarged islets of Zucker fatty rats. 4. These results suggest that, in Zucker fatty rats, the decreased glucagon secretion in the isolated perfused pancreas is attributable to changes in the environment of alpha-cells and/or the inhibitory effects of hypersecreted insulin.