How does blood glucose control with insulin save lives in intensive care?

Abstract

Patients requiring prolonged intensive care are at high risk for multiple organ failure and death. Insulin resistance and hyperglycemia accompany critical illness, and the severity of this "diabetes of stress" reflects the risk of death. Recently it was shown that preventing hyperglycemia with insulin substantially improves outcome of critical illness. This article examines some potential mechanisms underlying prevention of glucose toxicity as well as the effects of insulin independent of glucose control. Unraveling the molecular mechanisms will provide new insights into the pathogenesis of multiple organ failure and open avenues for novel therapeutic strategies.

Figure 1

Simplified model of insulin signaling. Insulin binding to the extracellular domain of the insulin receptor elicits a conformational change, which in turn leads to receptor autophosphorylation (P) and tyrosine phosphorylation of intracellular protein substrates. Two main branching pathways are activated by insulin: (a) One is the MAPK signaling cascade, in which the Grb2/Sos pathway leads to activation of Ras signaling, affecting cell proliferation and apoptosis. In view of their mitogenic nature, these can be characterized as “growth signal” effects. (b) The other is the IRS pathway, which leads to activation of kinases dependent upon the heterodimeric (p85/p110) PI3K, such as Akt, also referred to as protein kinase B (PKB); Akt modulates enzyme activities that, besides affecting NO generation and apoptosis, control glucose, lipid, and protein metabolism. This PI3K-branching pathway is termed the “metabolic signal.” PI(4, 5)P2, phosphoinositide 4,5 di-phosphate; PI(3, 4, 5)P3, phosphoinositide 3,4,5 tri-phosphate; PDK1 phosphoinositide–dependent kinase–1; MEK, MAPK kinase.

Figure 2

Intensive insulin therapy saves lives in the intensive care unit. Kaplan-Meier curves show cumulative survival of 1,548 patients from the Leuven study who received intensive insulin treatment (blood glucose maintained below 110 mg/dl; yellow) or conventional insulin treatment (insulin only given when blood glucose exceeded 200 mg/dl, resulting in mean blood glucose levels of 150–160 mg/dl; green) during their ICU or hospital stay. The upper panels display results from all patients; the lower panels display results for long-stay (>5 days) ICU patients only. P values were determined with the use of the Mantel-Cox log-rank test. Adapted with permission from the New England Journal of Medicine (10).

Figure 3

A diagrammatic representation of energy production in mitochondria and the mechanism of peroxynitrite generation. Excessive glycolysis and oxidative phosphorylation may result in more peroxynitrite generation in the critically ill. The ensuing nitration of mitochondrial complexes I and IV, MnSOD, GAPDH, and VDAC may suppress the activity of the mitochondrial electron transfer chain, impair detoxification of superoxide, shuttle glucose into toxic pathways, and increase apoptosis, respectively. These toxic effects may explain organ and cellular system failure related to adverse outcome in the critically ill. Proteins that are nitrated are indicated by the letter N in a yellow circle. Figure adapted with permission from American journal of physiology. Heart and circulatory physiology (44). TCA, tricarboxylic acid cycle; CoQ, coenzyme Q; Cyt c, cytochrome c; mtNOS, mitochondrial NO synthase; ANT, adenine nucleotide translocase; SCOT, succinyl-CoA:3-oxoacid CoA-transferase, ONOO^–, peroxynitrite; F0, the portion of the mitochondrial ATP synthase that channels protons through the membrane.

Figure 4

Venn diagram modeling the effect of the interaction between glucose toxicity and lack of insulin on the vulnerable state of critical illness. Complications of type 1 and type 2 diabetes are explained by hyperglycemia and/or lack of insulin effect. Critical illness is also characterized by hyperglycemia and lack of insulin effect, but additional risk factors render both of these effects more acutely toxic, as indicated by the blue shading. These risk factors include the post-hypoxia reperfused state, iNOS-activated NO generation, increased expression of GLUT-1 and GLUT-3 transporters, and cytokine-, neurological-, and hormone-induced alterations in cellular processes. Hence, improved outcome of critical illness with insulin-titrated maintenance of normoglycemia is likely to be explained by the prevention of both direct glucose toxicity and insulin-induced effects that are independent of glucose control.