Chronic treatment with bovine pancreatic polypeptide (bPP) is reported to decrease body weight and reduce fasting glucose and insulin concentrations in congenitally obese mice. The present study examines the effects of acute and chronic bPP treatment on insulin release and glucose clearance in lean and obese rodents. After single injections of 0, 5, 50, or 500 μg of bPP/kg of body weight, the insulin response to an intragastric glucose meal (5 g/kg of body weight) was substantially inhibited by the two higher doses of bPP. The change in glucose concentration over time was similar among all animals except those receiving the highest dose of bPP (500 μg/kg of body weight); in this group, glucose rose to higher levels and was slower to return to basal levels. Chronic treatment of rats with 200 μg of bPP/day/kg of body weight for 5 days did not modify glucose or insulin responses to the glucose meal, but did increase the activity of hepatic glycogen synthase. In contrast, basal glucose levels were lower in obese mice (ob/ob) treated with bPP and glucose clearance was improved in the treated group after injection of exogenous insulin. Islet hormone concentrations in pancreatic extracts were compared in lean and obese mice treated with and without 200 u-g of bPP/day/kg of body weight for 5 days. The pancreases of obese mice had higher concentrations of insulin and PP, and treatment with exogenous bPP increased endogenous PP in the pancreases of both phenotypes. Treatment with exogenous bPP also increased the insulin content of obese pancreases, but was without effect in pancreases of lean mice. Somatostatin content did not differ between lean and obese mice, and treatment with bPP produced no change in pancreatic somatostatin in either phenotype. The present results suggest that acute administration of PP inhibits insulin release. Chronic PP treatment of congenitally obese rodents but not lean animals produces a selective beneficial effect on basal glucose levels and improves peripheral sensitivity to insulin.