Therapeutic Effects and Mechanism of Liraglutide in Rats with Type 2 Diabetes and Metabolic-associated Fatty Liver Disease

Background: SREBP-1c/Insig/SCAP acts as a lipid de novo synthesis pathway, and its factors are highly expressed in the endoplasmic reticulum. At present, this pathway has become a research hotspot in the development of metabolic-associated fatty liver disease. However, there are few studies on how various factors in this pathway change after endoplasmic reticulum stress; in particular, the role of the insulin-inducing gene-1 (Insig-1) has not been elucidated in detail. Objective: The aim of the study was to investigate whether liraglutide has a therapeutic effect on rats with T2DM and MAFLD, and to further study its possible mechanism. Methods: Rats in the control group and modeling group were fed with normal diet and high-sugar and high-fat diet, respectively. 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. T2DM and MAFLD rats were randomly divided into three groups: model group, low-dose liraglutide group, and high-dose liraglutide group. Fasting blood glucose, fasting insulin, blood lipid profile, alanine aminotransferase, and aspartate aminotransferase were measured at the end of 8^th week. 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: Liver tissue from the drug intervention groups demonstrated a decrease in lipid droplet vacuoles, and the hepatocytes were arranged neatly again. While the expression of GRP78 rose, that of Insig-1 declined. There were differences observed with different doses of liraglutide; the higher the dose was, the more obvious the effect. No such changes were observed in T2DM and MAFLD rats after injection of saline. Conclusion: In this study, we show that liraglutide may have a therapeutic effect on rats with T2DM and MAFLD by reducing endoplasmic reticulum stress in the liver and increasing the expression of Insig-1.