The effects of feeding a low protein diet on pancreatic insulin secretion early in life in genetically lean and obese Zucker rats were studied. Four-week-old lean (Fa/Fa) and obese (fa/fa) Zucker rats were fed either a 5% protein or a 20% protein diet for 3 wk. Rats were killed at 7 wk of age. Pancreatic islets were isolated and insulin response of islets was measured in a 60-min static incubation under one of the following conditions: 2.7 mmol/L glucose +/- 10 mmol/L arginine, 8.3 mmol/L glucose +/- 10 mmol/L arginine, and 16.7 mmol/L glucose. Serum insulin was significantly lower (P < or = 0.05) in lean, but not in obese rats fed low protein compared with those fed the normal protein diet. Interestingly, obese rats fed the low protein diet had the highest plasma glucose concentrations (P < or = 0.05) among the four groups. Feeding the low protein diet reduced insulin secretion of islets from lean rats by 70%, and from obese rats by 30 to 50% compared with rats fed the normal protein diet. Insulin content of islets was reduced significantly in lean rats fed the low protein diet (by 70%) and in obese rats (by 50%). A short-term protein deficiency early in life reduced in vitro insulin secretion of islets from both lean and obese rats. However, reductions in insulin content and insulin release from islets resulting from low protein feeding were not sufficient to alter hyperinsulinemia in genetically obese Zucker rats.