The Vascular Endothelium, a Benign Restrictive Barrier? NO! Role of Nitric Oxide in Regulating Insulin Action

  1. Joyce M. Richey
  1. Diabetes and Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, California
  1. Corresponding author: Joyce M. Richey, jrichey{at}

Insulin resistance is the primary abnormality associated with obesity, type 2 diabetes, and hypertension (1,2). Interestingly, these disease processes also share a common underlying impairment of vascular endothelial function. For many years the endothelium was thought of as nothing more than a benign barrier between blood and extracellular space. But intensive investigations demonstrate a myriad of actions by the endothelium, including regulation of blood flow (3,4), vascular tone (5), vascular permeability (6), and the immune response (7). The capillary endothelium regulates blood flow via the release of several vasoactive agents, in particular nitric oxide (NO) (8). Baron (4) first demonstrated that insulin can stimulate the release of endothelial NO, thereby regulating blood flow and its own delivery. Insulin has multiple hemodynamic actions to enhance its ability to increase glucose uptake in skeletal muscle (4, 911). The three major methods include: 1) increasing blood flow to the tissue by modulation of endothelial factors; 2) increasing the number of capillaries that dilate within the tissue (increasing microvascular volume), which allows for an increase in total permeable surface area for insulin and glucose to enter the space that bathes the active myocytes (i.e., the interstitial space); and 3) increasing permeability of the capillaries, thus allowing more glucose and insulin to pass from the blood to the interstitial space. In insulin-resistant states, these hemodynamic actions of insulin are impaired, presumably due to reduced NO bioavailability (12).

The seminal study by Bergman and colleagues …

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