We hypothesized that plasma insulin crosses the blood-cerebrospinal fluid (CSF) barrier and, as people gain weight, provides a physiological feedback signal to the central nervous system to inhibit food intake and further weight gain. However, it has not been demonstrated in man that insulin can enter the CSF from peripheral blood. To test whether increases in plasma insulin result in elevated CSF immunoreactive insulin (IRI) levels, we infused insulin iv in varying amounts approximating postprandial levels in eight normal subjects for 4.5 h. Euglycemia was maintained [88 +/- 3 (+/- SEM) mg/dl] by means of a variable glucose infusion. Samples were obtained every 30 min for measurements of insulin in peripheral plasma and insulin in lumbar CSF. Plasma IRI increased from a mean basal level of 12 +/- 1.2 microU/ml to a mean (during the 180- to 270-minute period) of 268 +/- 35 microU/ml. CSF IRI increased in all subjects during the infusion from a mean basal level of 0.9 +/- 0.1 microU/ml to a mean (during the 180- to 270-min period) of 2.8 +/- 0.4 microU/ml (P less than 0.006). By contrast, CSF IRI in two subjects who received an infusion of 0.9% saline did not increase. In summary, CSF insulin concentrations increased during peripheral infusions of insulin. This is the first demonstration in man that plasma insulin gains access to CSF and indicates a mechanism whereby peripheral insulin could provide a feedback signal to the central nervous system.