Blockade of the Renin-Angiotensin system improves insulin receptor signaling and insulin-stimulated skeletal muscle glucose transport in burn injury

Shock. 2011 Jan;35(1):80-5. doi: 10.1097/SHK.0b013e3181e762da.

Abstract

Burn injury is associated with a decline in glucose utilization and insulin sensitivity due to alterations in postreceptor insulin signaling pathways. We have reported that blockade of the renin-angiotensin system with losartan, an angiotensin II type 1 (AT1) receptor blocker, improves whole body insulin sensitivity and glucose metabolism after burn injury. This study examines whether losartan improves insulin signaling pathways and insulin-stimulated glucose transport in skeletal muscle in burn-injured rats. Rats were injured by a 30% full-skin-thickness scalding burn and treated with losartan or placebo for 3 days after burn. Insulin signaling pathways were investigated in rectus abdominus muscle taken before and 90 s after intraportal insulin injection (10 U·kg). Insulin-stimulated insulin receptor substrate 1-associated phosphatidylinositol 3-kinase and plasma membrane-associated GLUT4 transporter were substantially increased with losartan treatment in burn-injured animals (59% above sham). Serine phosphorylated AKT/PKB was decreased with burn injury, and this decrease was attenuated with losartan treatment. In a separate group of rats, the effect of insulin on 2-deoxyglucose transport was significantly impaired in burned as compared with sham soleus muscles, in vitro; however, treatment of burned rats with losartan completely abolished the reduction of insulin-stimulated 2-deoxyglucose transport. These findings demonstrate a cross talk between the AT1 and insulin receptor that negatively modulates insulin receptor signaling and suggest a potential role of renin-angiotensin system blockade as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle and improving whole-body glucose homeostasis in burn injury.

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Biological Transport / drug effects
  • Blotting, Western
  • Burns / drug therapy
  • Burns / metabolism*
  • Glucose / metabolism*
  • Glucose Transporter Type 4 / metabolism
  • Insulin / pharmacology*
  • Losartan / pharmacology*
  • Losartan / therapeutic use
  • Male
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Phosphatidylinositol 3-Kinase / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Insulin / metabolism*
  • Renin-Angiotensin System / drug effects*
  • Signal Transduction / drug effects

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Glucose Transporter Type 4
  • Insulin
  • Slc2a4 protein, rat
  • Phosphatidylinositol 3-Kinase
  • Receptor, Insulin
  • Glucose
  • Losartan