Effect Of GLP-1 RAs On Serum MCP-1 And TGF-β In T2DM Patients With NAFLD

Objective: With the increasing incidence rate of non-alcoholic fatty liver disease(NAFLD)in type 2 diabetes(T2DM),the exploration of its potential drug intervention targets and mechanisms has become a hot focus.However,both monocyte chemotactic protein-1(MCP-1)and transforming growth factor-β(TGF-β)as key cytokines,which involved in liver inflammatory injury and NAFLD progression,have been gradually recognized in recent years.At the same time,more and more evidence shows that glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are thought to benefit T2 D patients with NAFLD due to their combined effects of weight loss,improving insulin resistance and liver oxidative stress relief.Our study aims to establish a prospective longitudinal cohort of type 2 diabetes patients with NAFLD treated with GLP-1 RAs,and explore the changes in serum MCP-1 and TGF-β after 12 weeks of treatment as well as their correlation with indicators related to glycolipid metabolism and liver fat content,in order to clarify the effect of GLP-1 RAs treatment on liver inflammation,and lay a foundation for exploring the mechanism of GLP-1 RAs inhibiting liver inflammation and improving insulin resistance in the future.Method: This study is a longitudinal cohort study.Among the type 2 diabetes patients treated with GLP-1 RAs in the Affiliated Hospital of Qingdao University from September 2020 to December 2022,40 T2 DM patients with fatty liver who met the admission and discharge criteria,40 normal people and 40 nonalcoholic fatty liver patients who visited the hospital at the same time were included as experimental group(DM group)、normal control group(NC group)and fatty liver group(FL group)respectively.The basic data of the three groups of subjects were collected,and the baseline serum MCP-1 and TGF-β,fasting blood sugar,liver function,renal function,blood lipids and other indicators of the three groups of subjects were measured at the same time.The DM group received lifestyle interventions and treatment with GLP-1 RAs combined with oral hypoglycemic drugs.Before treatment,subjects of DM group also need to measure liver fat content,fasting C-peptide,2-hour postprandial C-peptide,Glycated hemoglobin and other indicators,calculate HOMA-IR,and recheck the above indicators 12 weeks after treatment.The quantitative comparison of experimental data was conducted using T-test,while the comparison of counting data was conducted using χ2-test,using one-way ANOVA and rank sum tests to compare the differences between multiple groups of variables,.The statistical results were statistically significant with P<0.05 as the difference.Results: 1.Comparison of MCP-1 and TGF-β levels between NC group,FL group and DM group Compared to the DM group before GLP-1 RAs treatment,the concentrations of serum MCP-1 and TGF-β were significantly higher than those of the NC group(P<0.05).The level decreased significantly compared with that before treatment(P<0.05).Compared with the FL group,TGF-β in the post-treatment group can be seen.The level was significantly lower than that of FL group(P<0.05).The level of MCP-1 decreased with the FL group,but the difference was not significant.2.Comparison of basic data in each groupThe BMI,ALT,GGT,FBG,UA and TC of the DM group,were significantly higher than those in NC group(P<0.05),while HDL were significantly lower(P<0.05).BMI,GGT and TC in FL group were significantly higher than those in NC group(P<0.05).Compared with the FL group,the BMI and FBG of the subjects in the DM group increased significantly(P<0.05),while HDL decreased significantly(P<0.05).3.Comparison of clinical data in DM group after treatmentAfter treatment,the body weight,BMI,FBG,HbA1 c,LDL,C-peptide 60 minutes after meal,liver fat content and HOMA-IR of the subjects were significantly lower than those before treatment(P<0.05).After grouping and comparison,there were no significant differences in the changes of weight,MCP-1,TGF-β,liver fat content in patients with concomitant medication.4.Subgroup analysis1)There were no significant differences in clinical indicators such as HbA1 c compliance,weight loss,MCP-1,TGF-β,and liver fat content among subjects receiving different GLP-1 RA formulations(P>0.05).2)After grouping and comparison,there were no significant differences in body weight,MCP-1,TGF-β,liver fat content,and other changes among the subjects receiving the combined medication(P<0.05).3)The degree of weight loss and TGF-β reduction in subjects who achieved HbA1 c control was significantly higher than those who did not achieve HbA1 c control(P<0.05).The degree of MCP-1 reduction in subjects with significantly reduced liver fat content(a decrease of ≥ 4%)was significantly higher than that in subjects with increased,unchanged,or no significant decrease in liver fat content(P<0.05);Compared to subjects with serum LDL levels lower than the median(0.33 mmol/L),subjects with significantly lower LDL levels showed a more significant decrease in MCP-1 levels after treatment(P<0.05).Conclusion: 1.Compared with the NC group,subjects in the FL group and patients with T2 DM complicated with NAFLD have serum MCP-1 and TGF-β significant increasing in level2.After treatment with GLP-1 RAs,the serum levels of MCP-1 and TGF-β in type 2 diabetes patients with NAFLD decreased significantly,which indicates that GLP-1 RAs have the effect of inhibiting intrahepatic inflammation and delaying hepatic fibrosis,and this effect may be related to the mechanism of improving the disorder of glucose and lipid metabolism and reducing the content of intrahepatic fat in patients with type 2 diabetes.