Regulation of Insulin Transcytosis Across Endothelium in Metabolic Health and Disease

The delivery of insulin to the skeletal muscle has a major influence on glucose disposal in muscle, where 80% of total body glucose disposal occurs. The skeletal muscle microvascular endothelial cells play a critical role in peripheral insulin sensitivity through their regulation of insulin delivery. Recent advancements in methodologies have provided in-depth views of the molecular mechanisms by which the endothelial cells regulate the delivery process. However, how the cellular machinery is modulated under physiological or pathological conditions remains largely unexplored. Conditions with estrogen deficiency and obesity are 2 situations that are closely associated with peripheral insulin resistance and type 2 diabetes in humans. It is of great interest to determine whether and how endothelial control of insulin delivery impacts the development of metabolic dysregulation under these and other conditions. This review aims to provide an overview of the molecular mechanisms governing insulin delivery to the skeletal muscle. The available evidence will be presented that the transcytosis of insulin across the endothelial cell monolayer in skeletal muscle plays a critical role in muscle insulin delivery, thereby having a major impact on overall glucose homeostasis. In vivo investigations with manipulation of mechanisms in endothelial cells will be summarized, and the current knowledge gaps will be presented. Interrogation of the role of the endothelium in insulin transport provides a paradigm in which insights are being gained about cellular actions of insulin, molecular transport by endothelial cells, and the intricacies of glucose homeostasis.