Effect And Mechanism Of Exendin-4 On The Early Injury Of Pancreas In Severely Scalded Rats

Objective:Burn-induced hyperglycemia was strongly associated with clinical poor outcomes in major burns patients. Mounting evidences suggest that dysfunction of glycometabolism caused by burn is related to injury of pancreas. Exendin-4 is one of GLP-1 receptor agonist, which can significantly promote insulin secretion only when blood glucose higher than normal level, and effectively reduce fasting glucosewithout causing hypoglycemia. Accumulating evidence have demonstrated that Exendin-4 significantly suppress oxidative stress, inflammation and apoptosis.But the effect and mechanism of Exendin-4 on the injury of pancreas in severely scalded rats remain unknown. This sutdy aimed to explore the effect and mechanism of Exendin-4 on pancreas injury in severely scalded ratsMethods:Ninety-six Wistar rats were randomly divided into sham group^ sham+treatment group% scald group and scald+treatment group,with 24 rats in each group. Rats in scald group and scald+treatment group were inflicted with 50%TBSA full-thickness scald by a 12s immersion of the back and a 6s immersion of the abdomen in 94℃ hot water. Equal methods was used to scald rats in sham group and sham+treatment group with 37℃water. Equal amount of Exendin-4 (4ug/kg) were respectively infused into the rats in sham+treatment group and scald+treatment group by subcutaneous injection with twice a day. At post injury hour (PIH) 1d、3d、 5d, fasting blood-glucose(FBG) concentration was determined by cutting-tail method, serum insulin concentration was tested by radiomunoassay, water content of pancreatic tissue were calculated, the content Of MDA were tested by TBA method, histomorphology of pancreas was observed by HE staining, iNOS expression were measured with immunohistochemistry,3-NT, Cleaved caspase-3, and Bax expression were quantified by western blot.Results:At PIH 1d,3d and 5d, fasting blood-glucose(FBG) concentration were not obviously different between the sham group and sham+treatment group; At PIH 3d and 5d, FBG concentration in scald group were significantly higher than that in sham group and sham+treatment group; At PIH Id, FBG concentration in scald+treatment group were significantly lower than that in scald group, whereas significantly higher than that in sham group and sham+treatment group. At PIH Id, 3d and 5d, serum insulin concentration were not obviously different between the sham group and sham+treatment group; At PIH 1d,3d and 5d, serum insulin concentration in scald group were significantly higher than that in sham group and sham+treatment group; At PIH Id,3d and 5d, serum insulin concentration in scald+treatment group were significantly higher than that in scald group. At PIH 1d,3d and 5d, the water content of pancreatic tissue were not obviously different between the sham group and sham+treatment group; At PIH Id, the water content of pancreatic tissue in scald group was significantly higher than that in sham group and sham+treatment group; At PIH Id, the water content of pancreatic tissue in scald+treatment group was significantly higher than that in sham group and sham+treatment group; At PIH Id,3d and 5d, the water content of pancreatic tissue was not obviously different between the scald group and scald+treatment group. At PIH Id,3d and 5d, islets morphology were not obviously different between the sham group and sham+treatment group; At PIH Id,3d and 5d, the vacuolation of islets in scald group were significantly higher than that in sham group and sham+treatment group,the β-cell counts in scald group were significantly lower than that in sham group and sham+treatment group; At PIH Id, 3d and 5d, the β-cell counts in scald+treatment group were lower than that in scald group, and higher than that in sham group and sham+treatment group. At PIH Id,3d and 5d, the content of MDA of pancreatic tissue was not obviously different between the sham group and sham+treatment group; At PIH Id,3d and 5d, the content of MDA in pancreatic tissue in scald group was significantly higher than that in sham group and sham+treatment group; At PIH Id, and 3d, the content of MDA in pancreatic tissue in scald+treatment group was higher than that in sham group and sham+treatment group; At PIH 5d, the content of MDA in pancreatic tissue in scald+treatment group was significantly higher than that in scald group. Immunohistochemical staining showed that, at PIH Id,3d and 5d, the iNOS expression level in islets were not obviously different between the sham group and sham+treatment group; At PIH 1d,3d and 5d, the iNOS expression level in islets in scald group were higher than that in sham group and sham+treatment group; At PIH Id,3d and 5d, the iNOS expression level in islets in scald+treatment group were lower than that in scald group, and higher than that in sham group and sham+treatment group. The result of western blot showed that, at PIH Id,3d and 5d, the 3-NT protein expression level of pancreatic tissue were not obviously different between the sham group and sham+treatment group; At PIH 3d and 5d, the 3-NT protein expression level of pancreatic tissue in scald group were significantly higher than that in sham group and sham+treatment group; At PIH 3d and 5d, the 3-NT protein expression level of pancreatic tissue in scald+treatment group were significantly lower than that in scald group, and significantly higher than that in sham group and sham+treatment group. The result of western blot showed that, at PIH Id,3d and 5d, the Bax protein expression level of pancreatic tissue were not obviously different between the sham group and sham+treatment group; At PIH 3d and 5d, the Bax protein expression level of pancreatic tissue in scald group were significantly higher than that in sham group and sham+treatment group; At PIH 3d and 5d, the Bax protein expression level of pancreatic tissue in scald+treatment group were lower than that in scald group, and significantly higher than that in sham group and sham+treatment group. The result of western blot showed that, at PIH Id, 3d and 5d, the Cleaved caspase-3 protein expression level of pancreatic tissue were not obviously different between the sham group and sham+treatment group; At PIH Id,3d and 5d, the Cleaved caspase-3 protein expression level of pancreatic tissue in scald group were significantly higher than that in sham group and sham+treatment group; At PIH Id,3d and 5d, the Cleaved caspase-3 protein expression level of pancreatic tissue in scald+treatment group were lower than that in scald group, and higher than that in sham group and sham+treatment group.Conclusions:Subcutaneous Exendin-4 injection stimulates the release of insulin, reduces fasting blood glucose without causing hypoglycemia, decreases lipid and protein peroxidation injury, inhibits excessive inflammatory response and apoptotic cascade, increases the β cell count, improves the pancreas structure and function in severe scalded rats.