Blockade of the Renin-Angiotensin system improves insulin receptor signaling and insulin-stimulated skeletal muscle glucose transport in burn injury.
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.
Kasper
Sherry O
SO
Division of Trauma and Critical Care, Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee 37920, USA.
Phillips
Erin E
EE
Castle
Scott M
SM
Daley
Brian J
BJ
Enderson
Blaine L
BL
Karlstad
Michael D
MD
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D002056:Burns / Q000188:drug therapy / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D051275:Glucose Transporter Type 4; D007328:Insulin; C495694:Slc2a4 protein, rat; D058539:Phosphatidylinositol 3-Kinase; D011972:Receptor, Insulin; D005947:Glucose; D019808:Losartan