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

• Published in: Critical care medicine Vol. 29; no. 4; pp. 839 - 846
• Main Authors: McCowen, Karen C, Ling, Pei Ra, Ciccarone, Annamaria, Mao, Yilei, Chow, Jesse C, Bistrian, Bruce R, Smith, Robert J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD by the Society of Critical Care Medicine and Lippincott Williams & Wilkins 01-04-2001; Lippincott
• Subjects: Analysis of Variance; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Down-Regulation; Eating; Emergency and intensive care: infection, septic shock; Endotoxemia - metabolism; Escherichia coli; Insulin - metabolism; Insulin Receptor Substrate Proteins; Intensive care medicine; Lipopolysaccharides; Liver - metabolism; Male; Medical sciences; Muscle, Skeletal - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction; Pathophysiology; Rat; Critically ill; Rodentia; Experimental study; Insulin; Infection; Resistance; In vivo; Metabolic disorder; Vertebrata; Mammalia; Animal; Bacteriosis; Endotoxemia
• ISSN: 0090-3493; 1530-0293
• DOI: 10.1097/00003246-200104000-00032

OBJECTIVESTo 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.
DESIGNProspective, controlled animal study.
SETTINGUniversity research laboratory.
SUBJECTSMale Sprague-Dawley rats24 in the 3-day endotoxin study, 22 in each acute endotoxin study.
INTERVENTIONSIn prolonged endotoxemia studies, endotoxin (1 mg·kg·24 hrs) 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.
CONCLUSIONSProlonged 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.