Reduced endothelial caveolin-1 underlies deficits in brain insulin signalling in type 2 diabetes.

Patients with type 2 diabetes exhibit severe impairments in insulin signaling in the brain and are 5-times more likely to develop Alzheimer's disease. However, what leads to these impairments is not fully understood. Here, we show reduced expression of endothelial cell caveolin-1 (Cav-1) in the db/db (Leprdb) mouse model of type-2 diabetes. This reduction correlated with alterations in insulin receptor expression and signaling in brain microvessels as well as brain parenchyma. These findings were recapitulated in the brains of endothelial cell-specific Cav-1 knock-out (Tie2Cre; Cav-1fl/fl) mice. Lack of Cav-1 in endothelial cells led to reduced response to insulin as well as reduced insulin uptake. Furthermore, we observed that Cav-1 was necessary for the stabilization of insulin receptors in lipid rafts. Interactome analysis revealed the insulin receptor interacts with Cav-1 and caveolae-associated proteins, insulin degrading enzyme, and the tight junction protein Zonula Occludence-1 in brain endothelial cells. Restoration of Cav-1 in Cav-1 knockout brain endothelial cells rescued insulin receptor expression and localization. Overall, these results suggest that Cav-1 regulates insulin signaling and uptake by brain endothelial cells by regulating IR-a and IR-b localization and function in lipid rafts. Furthermore, depletion of endothelial cell specific Cav-1 and the resulting impairment in insulin transport leads to alteration in insulin signaling in the brain parenchyma of type 2 diabetes.