Constant infusion of glucose (10 mg . kg-1 . min-1) into conscious, intact dogs induced oscillations in the plasma concentrations of glucose and insulin. Glucose rose from basal (98 +/- 1 mg/dl) and, after 3 h, entered oscillations that persisted until the end of the 9-h glucose infusion. Between 240 and 540 min, glucose fluctuated by +/- 17 mg/dl about a mean value of 143 +/- 2 mg/dl; frequency of the glucose oscillation was 0.54 +/- 0.03 cycles/h. During the same time interval, insulin increased from basal 13 +/- 2 mu U/ml to mean 46 +/- 4 mu U/ml. Insulin oscillated at an amplitude (peak-to-peak) of 48 mu U/ml, with frequency not different from that of glucose (0.60 +/- 0.09 cycles/h). The oscillation in glucose "led" the insulin oscillation by 22 +/- 5 min. In three animals, [2-3H]glucose was infused along with unlabeled glucose during oscillations, and it was determined that almost all (98%) of the glucose appearance was from the exogenous infusion. Thus varying endogenous glucose production was ruled out as a contributory factor to the glucose oscillation. Total glucose uptake (Rd) fluctuated periodically at the same frequency as glucose and insulin (0.56 +/- 0.05 cycles/h) and with a large amplitude (Rd mean = 248 mg/min; peak-to-peak amplitude = 85 mg/min). Direct splanchnic balance measurements were made in the interval 240-540 min to determine the specific contributions of splanchnic (Rds) and peripheral glucose uptake (Rdp) to the oscillation in total Rd. Peripheral uptake oscillated in phase with plasma insulin and accounted for 80% (57.5 g) of total Rd. The splanchnic bed (presumably liver) sequestered 20% (14.1 g) of infused glucose, and Rds varied in phase with plasma glucose. The liver extracted 5.6 +/- 0.3% of the total amount of glucose presented to it in the 5-h interval of observation. It is concluded that a) large fluctuations in peripheral glucose utilization are responsible for the observed periodicities in glucose concentration; b) peripheral uptake fluctuations result from periodic bursts in insulin secretion; c) during glucose infusion, glucose is the primary moment-to-moment regulator of hepatic glucose uptake, whereas insulin is the principal regulator of peripheral glucose utilization.