The Microvascular Control of Insulin Action and Insulin Resistance in Skeletal Muscle

Abstract

Skeletal muscle insulin resistance is a state of metabolic dysfunction that increases the risk of developing Type 2 diabetes and cardiovascular disease. Despite decades of research into potential myocellular defects, the mechanism of muscle insulin resistance remains unclear. One underappreciated aspect of muscle insulin action is the microvascular delivery of insulin to the surface of myocytes. Muscle insulin delivery is controlled by both perfusion and the rate at which insulin is transported across the continuous endothelium of muscle capillaries. While several studies have demonstrated that muscle perfusion is impaired in the setting of obesity and insulin resistance, the mechanism and regulation of trans-endothelial insulin transport is unclear. In this Dissertation, we developed a novel intravital microscopy technique to directly measure trans-endothelial insulin transport in skeletal muscle capillaries of live mice. Using this technique, we discovered that insulin moves across the endothelium by a fluid-phase transport mechanism that is not saturable and does not require the insulin receptor. Furthermore, we found that trans-endothelial insulin transport is impaired in a mouse model of obesity and insulin resistance. These findings demonstrate that the capillary endothelium contributes to muscle insulin resistance by restricting insulin’s access to myocytes. Surprisingly, we also found that reducing nitric oxide bioavailability through pharmacological inhibition of nitric oxide synthase accelerates trans-endothelial insulin transport. Finally, we were able to restore muscle insulin sensitivity in a mouse model of obesity-induced insulin resistance by treating mice with Angiotensin-(1-7), a peptide hormone which improves endothelial function. In summary, this Dissertation describes novel mechanisms by which the microvasculature controls insulin action and contributes to insulin resistance in skeletal muscle.