Blood-borne insulin is known to cross the blood-brain barrier (BBB) where it can act as a satiety peptide. We examined in mice the pharmacokinetics and characteristics of such passage by multiple-time regression analysis. The unidirectional influx constant (Ki) of human insulin radioactively labeled with iodine (I-Ins) ranged from 0.87 to 1.7 microliters/g-min. The transport of I-Ins was inhibited almost 50% by 0.1 micrograms/mouse of unlabeled human insulin, a dose that had no effect on serum glucose. Similar results were found with rat insulin. The results with self-inhibition suggest that any hemoencephalic signal transmitted by the blood to brain transport of insulin is independent of the effects of insulin on glucose. The transport of I-Ins was altered by aluminum but not by administration of tyrosine, verapamil, or leptin, indicating independence from amino acid transport, the p-glycoprotein system, a slow calcium channel, or leptin transport. By contrast with insulin, enzyme degradation limited the uptake and accumulation by brain of intravenously injected, radioactively labeled glucagon and glucagon-like peptide. In conclusion, these results are consistent with the view that insulin can affect satiety and related behaviors independently of its peripheral effects by crossing the BBB to act within the brain.