How does blood glucose control with insulin save lives in intensive care?
Greet Van den Berghe
Greet Van den Berghe
Published November 1, 2004
Citation Information: J Clin Invest. 2004;114(9):1187-1195. https://doi.org/10.1172/JCI23506.
View: Text | PDF
Science in Medicine

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.

Authors

Greet Van den Berghe

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Simplified model of insulin signaling. Insulin binding to the extracellu...
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.