Endocytosis of insulin at the blood-brain barrier.

For insulin to act within the brain, it is primarily transported from the blood across the blood-brain barrier (BBB). However, the endocytic machinery necessary for delivering insulin to the brain remains unknown. Additionally, there are processes within the brain endothelial cell that are designed to respond to insulin binding and elicit intracellular signaling. Using pharmacological inhibitors of different types of endocytosis (clathrin-vs. caveolin-mediated), we investigated molecular mediators of both insulin BBB binding in isolated mouse brain microvessels and BBB insulin transport in mice studied by brain perfusion. We found clathrin-mediated mechanisms responsible for insulin surface binding in isolated brain microvessels while caveolin-mediated endocytosis may mediate BBB insulin transport specifically in the hypothalamus. These results further define the molecular machinery necessary for transporting insulin into the CNS and highlight the distinction between insulin internalization for transendothelial transport vs. intracellular signaling.

The impact of acute rosiglitazone on insulin pharmacokinetics at the blood-brain barrier.

INTRODUCTION: CNS insulin levels are decreased and insulin receptor signalling is dampened in Alzheimer's disease (AD). Increasing CNS insulin levels through a variety of methods has been shown to improve memory. Indeed, medications routinely used to improve insulin resistance in type 2 diabetes are now being repurposed for memory enhancement. CNS insulin is primarily derived from the circulation, by an active transport system at the blood-brain barrier (BBB). The goal of this study was to determine whether rosiglitazone (RSG), a drug used to improve insulin sensitivity in type 2 diabetes, could enhance insulin transport at the BBB, as a potential therapeutic for improving memory. METHODS: Using radioactively labelled insulin and the multiple-time regression analysis technique, we measured the rate of insulin BBB transport and level of vascular binding in mice pretreated with vehicle or 10 µg RSG in the presence or absence of an insulin receptor inhibitor. RESULTS: Although we found acute RSG administration does not affect insulin transport at the BBB, it does restore BBB vascular binding of insulin in an insulin receptor-resistant state. CONCLUSIONS: Acute RSG treatment does not alter insulin BBB transport in healthy mice but can restore insulin receptor binding at the BBB in an insulin-resistant state.