Insulin regulates neurovascular coupling through astrocytes.

Abstract

Circulating insulin enters the brain through mechanisms incompletely characterized. We now report that mice lacking insulin receptors (IR) in astrocytes (GFAP-IR KO mice) show blunted brain responses to insulin, uncoupling of brain blood flow with glucose uptake with concomitant changes in brain vasculature and glucose transporter 1 levels. IR-deficient astrocytes show increased expression of HIF-1α/VEGF, promote growth of co-cultured endothelial cells, display increased reactive oxidant species (ROS) and disturbed mitochondrial activity. Treatment with the antioxidant N-acetylcysteine (NAC), ameliorated high ROS levels, normalized angiogenic signaling, and mitochondrial function including mitochondrial glucose and oxygen sensors. In vivo treatment with NAC also normalized brain perfusion. Thus, insulin receptors in astrocytes regulate neuro-vascular coupling.