Intensive insulin therapy protects the endothelium of critically ill patients

Abstract

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-κB 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.

Cardioprotective Effects of Insulin

“…98,99 Additionally, the suppression of inducible NO synthase, albeit not specifically in the myocardium, has been suggested as the mechanism responsible for the protection of the vascular endothelium in the Leuven study. 100 The analysis of liver and skeletal muscle biopsy samples from nonsurvivors revealed a significantly lower level of inducible NO synthase mRNA expression that concurred with lower levels of adhesion molecules, including intercellular adhesion module-1 and E-selectin, which facilitate leukocyte rolling in endothelium activation, in the IIT group. 100 …”

“…100 The analysis of liver and skeletal muscle biopsy samples from nonsurvivors revealed a significantly lower level of inducible NO synthase mRNA expression that concurred with lower levels of adhesion molecules, including intercellular adhesion module-1 and E-selectin, which facilitate leukocyte rolling in endothelium activation, in the IIT group. 100 …”

Serial plasma glucose changes in dogs suffering from severe dog bite wounds

“…A positive correlation has been found between the degree of hyperglycaemia and the risk of death in human trauma and cardiac patients 42 . In human critical care medicine, insulin resistance has been implicated as a major contributor to this phenomenon 1,25,26,42 . Aggressive control of even mildly elevated glucose concentrations, using insulin therapy, has shown a significant decline in death rates in human intensive care units, from 20.2 % to 10.6 % 42 .…”

“…Insulin has been shown to counteract the metabolic changes in sepsis. It is hypothesised that insulin protects the endothelium (thereby contributing to the prevention of organ failure), modulates inflammatory pathways, protects cells from direct glucose toxicity, preserves hepatic mitochondrial function, improves dyslipidaemia and shows an anabolic effect by suppressing proteolysis and activating protein synthesis 1,23,26,42 . Although benefits have been documented with insulin therapy in humans, the use of insulin in small animal patients cannot yet be recommended due to the lack of supporting evidence 23 .…”

Reduction of glucose and insulin concentrations during in vitro incubation of human whole blood at different temperatures

“…The two mentioned methodologies are principally different as several organs (liver [13], pancreas [14], muscles [15], endothelium [16] and adipose tissue [17]) as well as regulatory mechanisms (hypothalamicpituitary-adrenal axis [18]) influences the concentration of glucose and/or insulin in the human body, but not in isolated blood samples. Glucose and/or insulin concentration changes in aliquots during incubation might therefore be different from glucose and/or insulin homeostasis in vivo.…”