(207a) Insulin Exits Skeletal Muscle Capillaries By Fluid-Phase Transport

Before insulin can stimulate myocytes to take up glucose, it must first move from the circulation to the interstitial space. The continuous endothelium of skeletal muscle (SkM) capillaries restricts insulin's access to myocytes. The mechanism by which insulin crosses this continuous endothelium is critical to understand insulin action and insulin resistance; however, methodological obstacles have limited understanding of endothelial insulin transport in vivo. Therefore, we developed a fully bioactive, fluorescent insulin probe and intravital microscopy platform to enable direct visualization of insulin efflux from SkM capillaries in vivo. Mathematical modeling of insulin efflux kinetics was applied to identify fluid-phase transport as the major mode of transendothelial insulin efflux in mice. Model-independent experiments demonstrating that insulin movement is neither saturable nor affected by insulin receptor antagonism confirmed the modeling results. Our finding that insulin enters the SkM interstitium by fluid-phase transport may have implications in the pathophysiology of SkM insulin resistance as well as in the treatment of diabetes with various insulin analogs.