Regulation of insulin entry into the brain

Abstract

AbstractBackgroundCentral nervous system (CNS) insulin has repeatedly been shown to play a role in cognition. Little, if any, insulin is synthesized in the brain and therefore requires navigation of the blood‐brain barrier (BBB) to act. The BBB is a unique structure in the brain that regulates the entry of serum substrates and can act as both a barrier and signaling structure. We hypothesize the BBB is a critical structure involved in the regulation of CNS insulin signaling and CNS insulin availability. We have investigated the regulation of insulin BBB transport and interactions under various conditions including exercise, brain insulin resistance, and have begun to explore the mechanisms for insulin transport across the BBB.MethodFor exercise, male and female mice were habituated to locked voluntary running wheels. After habituation, wheels were unlocked in some cages (exercise) for 24 hours while remaining locked (sedentary) in the others. For brain insulin resistance, mice were treated with an intracerebroventricular delivery of the insulin receptor antagonist, S961. For mechanisms involved in insulin BBB transport and interactions, endocytosis inhibitors were used to differentiate between clathrin and caveolin endocytosis. Following manipulation, insulin BBB pharmacokinetics were assessed with the quantitative multiple‐time regression analysis using radioactively labeled insulin and albumin, a marker for vascular space. Mice were injected intravenously or perfused in situ with the radiolabeled substrates and at timepoints up to 10 min, blood and brains collected and radioactivity measured. 125I‐insulin entry and binding to the BBB was assessed.ResultExercise enhanced 125I‐insulin interactions at the BBB. Specifically, exercise increased insulin BBB transport by two‐fold in males and increased insulin binding at the BBB in females. Brain insulin resistance impaired 125I‐insulin transport across the BBB, particularly in females. Lastly, caveolin‐mediated endocytosis may be involved in hypothalamic 125I‐insulin BBB transport.ConclusionWe have shown insulin BBB transport is highly regulated and can be impacted by exercise, brain insulin resistance, and may involve various endocytic pathways in a regional‐dependent manner. Continued investigation on the pathways involved in insulin BBB transport is warranted to aid in treating or preventing brain insulin resistance as occurs in Alzheimer’s disease.