U ltradian "oscillations" or "pulses" of insulin secretion with periods around 120 min occur in man. It is not known whether glucose plays an active role in generating these oscillations, or if an intrapancreatic pacemaker generates oscillations in insulin secretion that entrain glucose passively. To determine if the frequency of pulses of insulin secretion could be modified by oscillatory glucose infusion, seven normal men were studied on three separate occasions. The first study involved a constant glucose infusion administered at a rate of 6 mg/kg per min for 28 h. During the two subsequent studies, the subjects received an oscillatory glucose infusion for 28 h with the same mean rate, an amplitude of 33% above and below the mean infusion rate, a sinusoidal waveshape and a period either 20% longer ("slow oscillatory infusion") or 20% shorter ("rapid oscillatory infusion") than the periodicity observed during constant glucose infusion. Samples for insulin, C-peptide, and glucose were drawn at 10-min intervals during the last 24 h of each study. Insulin secretion rates were calculated by deconvolution of C-peptide levels. During constant glucose infusion, the respective periods of oscillation of glucose and insulin secretion averaged 126 +/- 5 min and 118 +/- 3 min (mean +/- SEM). During the slow oscillatory infusion, the period of infusion was 155 +/- 7 min and the periods of insulin secretion and glucose were, respectively, 155 +/- 7 min and 150 +/- 5 min. During rapid oscillatory infusion, the period of infusion was 103 +/- 5 min and the period of both insulin secretion and glucose was 105 +/- 5 min. Thus the periodicity of both insulin secretion and plasma glucose changed in parallel with the exogenous periodicity, indicating complete entrainment of the secretory oscillations. These results suggest that the ultradian oscillations of insulin secretion are caused by the feedback loop linking glucose and insulin.