Central nervous system insulin signaling can influence the rate of insulin influx into brain

BACKGROUND: Insulin transport across the blood-brain barrier (BBB) is a highly regulated, saturable process, known to be affected by many peripheral substrates including insulin itself and triglycerides. This is in contrast to insulin leakage into peripheral tissues. Whether the central nervous system (CNS) can control the rate of insulin uptake by brain remains to be determined. Insulin BBB interactions are impaired in Alzheimer’s disease (AD) and CNS insulin resistance is widely prevalent in AD. Therefore, if CNS insulin controls the rate of insulin transport across the BBB, then the defective transport of insulin seen in AD could be one manifestation of the resistance to CNS insulin observed in AD. METHODS: We investigated whether enhancing CNS insulin levels or induction of CNS insulin resistance using an inhibitor of the insulin receptor altered the blood-to-brain transport of radioactively labeled insulin in young, healthy mice. RESULTS: We found that insulin injected directly into the brain decreased insulin transport across the BBB for whole brain and the olfactory bulb in male mice, whereas insulin receptor blockade decreased transport in female mice for whole brain and hypothalamus. Intranasal insulin, currently being investigated as a treatment in AD patients, decreased transport across the BBB of the hypothalamus. CONCLUSIONS: These results suggest CNS insulin can control the rate of insulin brain uptake, connecting CNS insulin resistance to the rate of insulin transport across the BBB.