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Abstract: Mammalian target of rapamycin (mTOR) is an important mediator for cross talk between nutritional signals and metabolic signals of insulin by downregulating insulin receptor substrate proteins. Therefore, mTOR inhibition could become a therapeutic strategy in insulin-resistant states, including insulin resistance induced by burn. We tested this hypothesis in the rat model of 30% TBSA full thickness burn, using the mTOR inhibitor rapamycin. Rapamycin (0.4mg/kg, i.p.) was injected 2h before euglycemic–hyperinsulinemic glucose clamps at 4 days after burn. IRS-1, phospho-serine307, phospho-tyrosine of IRS-1 and phospho-mTOR in muscle tissue were determined by immunoprecipitation and Western blot analysis or immunohistochemistry. Plasma TNF-α, insulin and C-peptide were determined before and after euglycemic–hyperinsulinemic glucose clamps. Our data showed that TNF-α, insulin and C-peptide significantly increased in the early stage after burn (P <0.01). The infused rates of total 10% glucose (GIR, mg/kgmin) significantly decreased at 4 days after burn. The level of IRS-1 serine307 phosphorylation in muscle in vivo significantly increased after burn (P <0.01), while insulin-induced tyrosine phosphorylation of IRS-1 significantly decreased (P <0.01). Inhibition of mTOR by rapamycin inhibited the phosphorylation of mTOR, reduced serine307 phosphorylation, elevated tyrosine phosphorylation and partly prevented the decrease of GIR after burn. However, TNF-α, insulin and C-peptide were not decreased by rapamycin treatment postburn. Taken together, these results indicate that the mTOR pathway is an important modulator of the signals involved in the acute regulation of insulin-stimulated glucose metabolism, and at least, partly contributes to burn-induced insulin resistance. mTOR inhibition may become a therapeutic strategy in insulin-resistant states after burn. [Copyright &y& Elsevier]

Burn wound excision and grafting is a common clinical practice that decreases patient morbidity and mortality. It is not known, however, if the salutary effects of this procedure are related to effects on interleukin 6 (IL-6) and tumor necrosis factor (TNF-) α, and to reducing insulin resistance after burn. Sprague–Dawley rats were randomly divided into three groups: control, burn, burn±excision groups. Rats in burn group were given a third-degree scald burn covering 30% total body surface area (TBSA) and no wound excision. Rats in burn±excision group were subjected to a 30% third-degree burn followed by complete excision and allografting of the injury site within 15min after burn. The rats in control group were treated in the same manner as the burn group, except that they were immersed in a room-temperature water. Glucose tolerance tests (GTT) were observed at 3 days after burn, euglycemic–hyperinsulinemic glucose clamps were performed at 4 days after burn and interleukin 6 (IL-6) and tumor necrosis factor (TNF-) α were determined after euglycemic–hyperinsulinemic glucose clamps. The levels of IL-6 and TNF-α increased after burn. Significant differences in GTT were observed between control and burn groups, and the rate of glucose infused measured in burned rats was significantly decreased compared with that in control at 4 days after burn. Early excision and grafting significantly decreased levels of IL-6 and TNF-α, and further reduced insulin resistance following thermal injury compared with burn group. Conclusion: Early excision and grafting appeared to have an effect on inflammatory mediators and further reduced insulin resistance induced by major burns. [Copyright &y& Elsevier]

Abstract: The aim of this study was to investigate the changes of glucose tolerance, insulin sensitivity, and euglycemic–hyperinsulinemic glucose clamps following a 30% TBSA full thickness third degree burn in rats. Sprague–Dawley rats weighing 160–170g received 30% TBSA full thickness third degree burn by immersing the back of trunk for 12s in a boiling water bath under anesthesia. Weight- and time-matched sham burn group (control) was treated in the same manner as the trauma group, except that they were immersed in a room-temperature water bath. After 12h overnight fasting, plasma insulin concentration was determined by ELISA using rat-insulin enzyme immunoassay kit (SPI-BIO) and blood glucose was assayed by glucose analyzer at 3 days after burn. Insulin sensitivity index was calculated by using slightly modified formula. The rat was injected with 5% glucose (2g/kg body weight, intraperitoneally) to observe the change of glucose tolerance at 3 days after burn. Euglycemic–hyperinsulinemic glucose clamps were performed at 4 days after burn. Insulin sensitivity index of burn group was significantly reduced compared with control group at 3 days after burn (0.58±0.23 versus 1.23±0.16, P <0.01). The significant difference of glucose tolerance was observed between the two groups and the glucose infused rate measured in burned rats was significantly decreased compared with that in control at 4 days after injury (7.23±1.35 versus 12.31±0.54, P <0.01). Conclusion: Burn causes the significant change of glucose metabolism and results in insulin resistance in rats. [Copyright &y& Elsevier]