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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−1). 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.

Insulin resistance after burn is associated with alterations in postreceptor insulin signaling and abnormal glucose homeostasis. The renin-angiotensin system (RAS) exerts a largely inhibitory role on insulin action and is activated after burn injury. We hypothesized that upregulation of RAS is involved in the development of insulin resistance in burned rats. We examined the possibility that an angiotensin II type 1 (AT1) receptor blocker, losartan, enhances insulin sensitivity and thereby increases glucose tolerance in thermally injured rats. A 30% body surface area burn was induced by immersion of the dorsum into water with a temperature level of 95 degrees C for 15 s. Sham-burned rats were immersed in water with a temperature level of 23 degrees C. Losartan (30 mg/kg per day) or placebo (water) was given by gavage immediately after the burn injury and daily for 3 days postburn injury, resulting in sham-burned, burn placebo, and burn losartan groups. Plasma angiotensin II levels between burn placebo and sham-burned groups were not different 3 days after burn injury. However, losartan significantly increased plasma angiotensin II levels (P0.05), suggesting blockade of the AT1 receptor. An oral glucose tolerance test was performed 3 days postburn injury. There was an increase in the area under the curve for insulin and the glucose insulin index in burn placebo group as compared with sham-burned group, indicating insulin resistance. Losartan treatment abolished the insulin resistance in burn as evidenced by an area under the curve for insulin and glucose insulin index lower than that in the burn placebo group and similar to that in the sham-burned group. This suggests that insulin resistance and glucose intolerance associated with burn injury is, in part, caused by RAS.