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-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.

Figure 1

Simplified concept and rationale of the study. Low concentrations of NO, normally generated by eNOS, are likely to be beneficial for the endothelium and organ function, whereas high concentrations of NO, generated via iNOS induction, may contribute to endothelium dysfunction, excessive vasodilation, extravasation, and tissue injury. Insulin-titrated prevention of hyperglycemia during critical illness may theoretically protect the endothelium via its effects on eNOS and iNOS expression and activity.

Figure 2

Blood glucose control, insulin doses, and CRP serum levels. White bars represent patients who received conventional insulin therapy (n = 224), gray bars patients who received intensive insulin therapy (n = 181). Data are expressed as mean ± SEM. Adm, admission day. *P ≤ 0.05; **P ≤ 0.01.

Figure 3

Serum ICAM-1 and E-selectin levels. Data are presented as box plots; the central line indicates the median, the box the IQR, and the whiskers the 10th and 90th percentiles. White boxes represent the patients in the conventional insulin therapy group (n = 222), gray boxes patients in the intensive insulin therapy group (n = 181). For 2 patients, serum samples were not available. **P – 0.01; ^§P ≤ 0.1.

Figure 4

Relationship between serum levels of IL-6 and IL-10 and mortality. Day 5 IL-6 and IL-10 levels of the whole group of patients (n = 405) were stratified and, in each class, the percentage of survivors relative to the number of patients was determined. Indicated ranges are expressed in picograms/milliliter.

Figure 5

NOS gene expression and NF-κB activation in postmortem biopsies. Transcript levels of eNOS and iNOS were measured in postmortem liver and skeletal muscle biopsies. NF-κB activation was evaluated in these tissues by analysis of the levels of phosphorylated IκB. Data are presented as box plots; the central line indicates the median, the box the IQR, and the whiskers the 10th and 90th percentiles. iNOS gene expression data were normally distributed. White boxes represent the patients in the conventional insulin therapy group (n = 49), gray boxes patients in the intensive insulin therapy group (n = 27). *P ≤ 0.05; **P ≤ 0.01; ^§P ≤ 0.1.

Figure 6

Serum NO levels. Data are presented as box plots; the central line indicates the median, the box the IQR, and the whiskers the 10th and 90th percentiles. Patients were compared with healthy volunteers (dark gray box; n = 30). White boxes represent the patients in the conventional insulin therapy group (n = 50 on admission, n = 222 on day 7), light gray boxes patients in the intensive insulin therapy group (n = 50 on admission, n = 180 on day 7). *P ≤ 0.05 versus conventional insulin therapy; ^†P ≤ 0.05 day 7 versus admission day; ^#P ≤ 0.05 versus healthy volunteers; ^##P ≤ 0.01 versus healthy volunteers.