An insulin-mimetic compound (L-783,281) was used in an attempt to determine the role of the beta-cell insulin receptor (IR) on insulin release. Islets were isolated from C57Bl/6j mice and cultured for 1 to 4 days. Insulin release from individual islets perifused in the presence of 3 mmol/l glucose was 10.5 plus minus 1.4 pg/min. Addition of 10 micromol/l L-783,281 had no effect on the rate of insulin secretion. When L-783,281 was added to perifusion medium containing 11 mmol/l glucose, the insulin-mimetic compound significantly increased insulin release. Insulin release from the isolated islet is pulsatile. In the presence of 3 mmol/l glucose, addition of L-783,281 significantly decreased the frequency of the oscillations from 0.35 plus minus 0.03 to 0.22 plus minus 0.04 oscillations/min. Addition of L-783,281 to perifusion medium containing 11 mmol/l glucose had no effect on the frequency of the insulin pulses (0.30 plus minus 0.05 oscillations/min). These results indicate that activation of the beta-cell IR by L-783,281 augments insulin release in the presence of a stimulatory glucose concentration. At nonstimulatory glucose concentrations, activation of the beta-cell IR may affect mechanisms related to the frequency of the insulin pulses.