Barrett EJ, Wang H, Upchurch CT, Liu Z. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. Am J Physiol Endocrinol Metab 301: E252-E263, 2011. First published May 31, 2011 doi:10.1152/ajpendo.00186.2011Insulin, at physiological concentrations, regulates the volume of microvasculature perfused within skeletal and cardiac muscle. It can also, by relaxing the larger resistance vessels, increase total muscle blood flow. Both of these effects require endothelial cell nitric oxide generation and smooth muscle cell relaxation, and each could increase delivery of insulin and nutrients to muscle. The capillary microvasculature possesses the greatest endothelial surface area of the body. Yet, whether insulin acts on the capillary endothelial cell is not known. Here, we review insulin's actions at each of three levels of the arterial vasculature as well as recent data suggesting that insulin can regulate a vesicular transport system within the endothelial cell. This latter action, if it occurs at the capillary level, could enhance insulin delivery to muscle interstitium and thereby complement insulin's actions on arteriolar endothelium to increase insulin delivery. We also review work that suggests that this action of insulin on vesicle transport depends on endothelial cell nitric oxide generation and that insulin's ability to regulate this vesicular transport system is impaired by inflammatory cytokines that provoke insulin resistance.caveolae; endothelium; microvasculature; insulin transport SEVERAL RELATIVELY RECENT REVIEWS relate to insulin's vascular action. That by Muniyappa et al. (68) focuses particularly on pathways of insulin signaling in both endothelial and smooth muscle cells and how these molecular events explain insulin's vasodilatory action. A review by Clark (21) focuses on insulin as a regulator of nutritive vs. non-nutritive flow and the methodologies that have been developed and applied to skeletal muscle in order to address this role of insulin. We also recently summarized work relating to insulin's vascular action: in particular we focused on the temporal relationship between insulin delivery and insulin-mediated glucose disposal in skeletal muscle, arguing that insulin delivery to muscle is the rate limiting step for insulin action in that tissue (8). Readers are referred to those reviews for a comprehensive discussion of each topic. Here, we will focus first on insulin's vasodilatory effects as they relate to insulin's ability to regulate the delivery of both itself and nutrients to the tissue microvasculature where nutrient exchange occurs. We will then focus on transendothelial insulin movement, as this step appears to be rate limiting for insulin action in skeletal muscle. We will not deal with insulin's direct actions on vascular smooth muscle cells, as this has been well covered in a recent review (2). We will consider the relationship between insulin's effects on skeletal muscle microvascular perfusion and on transendothelial transport as potenti...

Findings to date do not support widespread screening for CAD in patients with T2DM. A future strategy identifying those at highest risk as screening candidates may ultimately be effective, but the optimal method for selecting those subjects or subsequent treatment is unknown.

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