Intensive insulin therapy protects the endothelium of critically ill patients

J Clin Invest. 2005 Aug;115(8):2277-86. doi: 10.1172/JCI25385.


The vascular endothelium controls vasomotor tone and microvascular flow and regulates trafficking of nutrients and biologically active molecules. When endothelial activation is excessive, compromised microcirculation and subsequent cellular hypoxia contribute to the risk of organ failure. We hypothesized that strict blood glucose control with insulin during critical illness protects the endothelium, mediating prevention of organ failure and death. In this preplanned subanalysis of a large, randomized controlled study, intensive insulin therapy lowered circulating levels of ICAM-1 and tended to reduce E-selectin levels in patients with prolonged critical illness, which reflects reduced endothelial activation. This effect was not brought about by altered levels of endothelial stimuli, such as cytokines or VEGF, or by upregulation of eNOS. In contrast, prevention of hyperglycemia by intensive insulin therapy suppressed iNOS gene expression in postmortem liver and skeletal muscle, possibly in part via reduced NF-kappaB activation, and lowered the elevated circulating NO levels in both survivors and nonsurvivors. These effects on the endothelium statistically explained a significant part of the improved patient outcome with intensive insulin therapy. In conclusion, maintaining normoglycemia with intensive insulin therapy during critical illness protects the endothelium, likely in part via inhibition of excessive iNOS-induced NO release, and thereby contributes to prevention of organ failure and death.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cell Hypoxia
  • Critical Illness
  • E-Selectin / blood
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / pathology
  • Female
  • Humans
  • Hyperglycemia / blood
  • Hyperglycemia / drug therapy
  • Hyperglycemia / pathology
  • Insulin / administration & dosage*
  • Intercellular Adhesion Molecule-1 / blood
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Middle Aged
  • Multiple Organ Failure / blood
  • Multiple Organ Failure / drug therapy*
  • Multiple Organ Failure / pathology
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • Up-Regulation
  • Vasomotor System / metabolism
  • Vasomotor System / pathology


  • E-Selectin
  • Insulin
  • Intercellular Adhesion Molecule-1
  • Nitric Oxide
  • NOS3 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III