| Objective:To explore whether the liraglutide has the therapeutic effect on the T2 DM and NAFLD rats,and to study the possible mechanism of it,in order to providing a new therapeutic method for patients with T2 DM and NAFLD in the clinic.Methods:Eight-week-old male Sprague-Dawley rats were randomly divided into control group and modeling group.The rats were fed with normal diet in the control group,and the other group’s rats were fed with high-sugar and high-fat diet.After one month,the mice in the modeling group were injected with 35mg/kg STZ intraperitoneally to establish the model of type 2 diabetes mellitus,72 hours later,blood glucose was measured to determine whether the model was formed or not.The control group were injected with the same amount of normal saline.Then the rat model of type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease was established by feeding with high sugar and high fat diet for one month.The T2 DM and NAFLD rats were randomly divided into three groups: model group,low dose liraglutide group and high dose liraglutide group.Then blood were collected of above four groups to measure blood lipid profile,alanine aminotransferase and aspartate aminotransferase.The drug intervention was then carried out for 8 weeks in the low dose group(100ug / Kg,subcutaneous injection,once a day)and in the high dose group(200ug / Kg,subcutaneous injection,once a day).Rats in the remaining two groups weresubcutaneously injected with 100 ug / Kg normal saline.Rats’ weight,fasting blood glucose and food and water intake were recorded every two weeks.Fasting blood glucose,fasting insulin,blood lipid profile,alanine aminotransferase and aspartate aminotransferase were measured at the end of the 8th week.Take out the whole liver tissue and weigh it.Paraffin sections were obtained from the same part of the liver of rats in each group and observed by electron microscope after HE staining.Western blot was used to detect the expression of endoplasmic reticulum stress index(GRP78)and negative feedback index of lipid synthesis(Insig-1)in each group.Results:1.General condition and changes of body weight and fasting blood glucoseThe rats in the control group had frequent nocturnal activities and had soft hair.Compared with it,the rats’ behavior was lazy,the reaction was slow,and the hair became dry and easy to fall off after injecting STZ.And their intake of food was increased,the mats needed to be cleaned up every day.But after liraglutide intervention the performance above has changed slightly,especially in high-dose group.The body weight of the rats fed with high-glucose and high-fat diet was significantly increased but lower after treated with liraglutide,the changes were more obvious in high-dose group(P<0.05).Compared with the control group,the fasting blood glucose of T2 DM and NAFLD group was increased,but this index was decreased after liraglutide intervention,and the high-dose group’s decline was even more pronounced(P<0.05).2.Blood lipid spectrum and liver function after mold makingCompared with the blank group,the levels of LDL-C,TC,TG,AST and ALT in the T2 DM and NAFLD group were significantly higher than those in the control group(P<0.05).And there was no significant difference between the other three groups after making mold(P>0.05).3.Blood lipid spectrum and liver function of rats after the intervention of liraglutideCompared with the model group,the indexes of LDL-C,TC,TG,AST and ALT decreased significantly in the two dose groups,and the high-dose group was more obvious(P<0.05),but it was still higher than that in the control group.4.The degree of liver injury under naked eyes and microscopeIn the normal group,the liver were rosy,tough and elastic,but in the model group were lighter in color,greasy on the surface,fragile in touch and larger in volume.The yellow-and-white area were observed on the liver surface of the rats after treated with liraglutide and the texture was slightly stronger,the volume of the liver was slightly lightened than that of the model group.And the above-mentioned changes were more obvious in the high-dose group.After HE staining,the hepatocytes of the normal liver were arranged neatly,and few lipid vacuoles were found.But the model group’s hepatocytes rehearsal disorder,and there are a large number of lipid droplets deposition.Compared with the model group,the liver cell arrangement returned to an orderly state and the number of lipid droplets decreased after injected liraglutide,and the improvement is more obvious in high-dose group.5.Expression of GRP78 and Insig-1 in liverCompared with the normal control group,the livers’ expression of GRP78 were increased and Insig-1 were decreased in the model groups(P<0.05).After injecting liraglutide the expression of GRP78 were significantly lower and Insig-1 higher than the model group(P<0.05),in the high dose group the expression of GRP78 were reduced further more(P<0.05),but there was no dose-dependent about the expression of Insig-1(P>0.05).Conclusion:1.liraglutide can reduce blood glucose,body weight but increase insulin sensitivity in rats with type 2 diabetes mellitus with non-alcoholic fatty liver disease,and the effect is correlated with the dose of liraglutide.2.Liraglutide can improve the blood lipid spectrum and liver function of type 2diabetic rats with non-alcoholic fatty liver disease,which is in a dose-dependent manner.3.Liraglutide may play a protective role in the liver of type 2 diabetic rats with non-alcoholic fatty liver disease by reducing endoplasmic reticulum stress and increasing Insig-1 expression. |
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