Earlier experiments with the microsphere technique suggested that a heightened serum glucose concentration consistently leads to an increase in islet blood flow (IBF). Several lines of evidence suggest that this glucose-sensitive control mechanism is located at an extrapancreatic site. The purpose of this study was to define the possible role of the central nervous system in such a mechanism. D-glucose, L-glucose, 3-O-methylglucose, or saline were therefore infused into the carotid artery, each at a dose of 1 mg X kg body wt-1 X min-1 for 3 min, and the pancreatic and islet blood flows were measured. None of these substances affected the systemic serum glucose level. The intracarotid infusion of D-glucose, however, caused a rapid increase in both the serum insulin concentration and IBF. The blood flow to the whole pancreas nevertheless remained unchanged, indicating a redistribution of flow within the gland. Carotid infusion of the other test substances or a similar amount of D-glucose given in a femoral vein did not affect these parameters. Both the increase in serum insulin concentration and the increase in IBF caused by D-glucose could be abolished by vagotomy or administration of atropine. When the systemic blood glucose concentration was increased by intraperitoneal glucose administration (2 g/kg body wt), vagotomy blocked the increase in islet blood flow but not the concomitant insulin release. These observations suggest that the glucose-induced increase in IBF is mediated by vagal cholinergic influences.