Sustained endotoxemia leads to marked down-regulation of early steps in the insulin-signaling cascade

Crit Care Med. 2001 Apr;29(4):839-46. doi: 10.1097/00003246-200104000-00032.


Objectives: To determine the effects of sustained, 3-day endotoxin infusion on early steps of the insulin-signaling pathway in rat liver and skeletal muscle in vivo; to examine insulin signaling in well-established acute endotoxin models of insulin resistance.

Design: Prospective, controlled animal study.

Setting: University research laboratory.

Subjects: Male Sprague-Dawley rats: 24 in the 3-day endotoxin study, 22 in each acute endotoxin study.

Interventions: In prolonged endotoxemia studies, endotoxin (1 hrs-1) was administered via jugular venous catheter for 74 hrs. Insulin was then injected, and liver and skeletal muscle were removed after 5 mins. In acute endotoxemia studies, an endotoxin bolus (1 mg/kg) was administered, and insulin-signaling responses were studied after 4 hrs.

Measurements and main results: In liver of rats with sustained endotoxemia, there were significant decreases in insulin-stimulated tyrosine phosphorylation of insulin receptors (74%), insulin receptor substrate (IRS)-1 (74%), and IRS2 (53%); binding of the p85 subunit of phosphatidylinositide 3-kinase to IRS1 (80%); and IRS1-precipitable phosphatidylinositide 3-kinase activity (>90%). These findings were associated with significant reductions in abundance of insulin receptors (37%), IRS1 (60%), and IRS2 (23%). Signaling in skeletal muscle was similarly affected, with reduced IRS1 phosphorylation (49%), IRS1 abundance (50%), and binding of p85 to IRS1 (57%). Insulin signaling 4 hrs after endotoxin administration was not different from controls.

Conclusions: Prolonged endotoxemia is associated with marked deficits in early steps of the insulin-signaling pathway, which are at least partly explained by reduced abundance of the insulin receptor and IRS proteins. Signaling defects were not evident 4 hrs after endotoxin administration under conditions of adequate nutrition, indicating that insulin resistance develops gradually, may require concomitant malnutrition, and is not reversed by the development of endotoxin tolerance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Down-Regulation
  • Eating
  • Endotoxemia / metabolism*
  • Escherichia coli*
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins
  • Lipopolysaccharides*
  • Liver / metabolism*
  • Male
  • Muscle, Skeletal / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction*


  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Lipopolysaccharides
  • Phosphoproteins
  • Phosphatidylinositol 3-Kinases