From oversight to insight: the curious case of the endothelial insulin receptor

Insulin is produced in the pancreas and regulates blood glucose levels by binding to the insulin receptor (IR) thereby stimulating glucose uptake into cells. Inadequate insulin production or dysregulated IR signaling leads to diabetes. Most research, to date, has focused on enhancing insulin production or correcting impaired IR signaling in tissues of nutrient exchange, for example, muscle or fat. However, the transendothelial trafficking of insulin to target tissues is also crucial in regulating organismal responses to insulin. In fact, this process has been established as the rate-limiting step for glucose disposal. Initially, it was believed that the transendothelial trafficking of insulin was dependent on endothelial IR. Unfortunately, subsequent studies have demonstrated that mice lacking endothelial IR possess minimal changes in insulin sensitivity. These studies have contributed to the widespread belief that endothelial IR does not regulate insulin trafficking and insulin sensitivity. However, recent genetic studies from our laboratory, and others, have shown that enhancing endothelial IR activity improves insulin sensitivity. These studies underscore the crucial role of endothelial IR in regulating insulin trafficking and metabolism. Now that researchers have conclusively demonstrated the presence and function of IR on endothelial cells (ECs) in vivo, it is essential to clarify why this receptor has been so controversial. Additionally, this timely review aims to encourage vascular biology researchers to explore how endothelial IR is regulated and identify new roles for this receptor on ECs.