The Regulatory Mechanism Of Glucagonlike Peptide-1 Analogs On Fat Distribution In Type 2 Diabetes

Objectives:Compared with fat content,body fat distribution plays a more important role on the occurrence and development of metabolic diseases.For some type 2 diabetes mellitus(T2DM)patients with normal body mass index(BMI)but with central obesity,their blood glucose levels remain difficult to be controled after administration of multiple drugs,but GLP-1 analogs could significantly improve their blood glucose.Thus,whether GLP-1 analogs have the effect on changing body fat distribution remains unknown.The aim of this study is to firstly analyze the distribution characteristics of body fat in T2DM patients and to explore the correlation between body fat distribution and diabetes in the population of East China.Secondly,we use the isotope tracing techniques and molecular biology to investigate the regulatory mechanism of liraglutide,a GLP-1 analog,on body fat distribution in animal models.Methods:Based on SPECT-China study,a cross-sectional survey on the prevalence of metabolic diseases and risk factors in East China from 2014 to 2015,a total of 8368participants were included for this study.Compare the differences of various obesity indicators between the three groups at different blood glucose levels.Linear regression and logistic regression analyses were conducted to explore the relationship between various obesity indicators and diabetes.ROC analysis was conducted to predict the effectiveness of various obesity indicators on diabetes.In the animal experiment,after establishing simple obese and obese T2DM rat models,the rats were randomly divided into five groups:the simple obese control group,the obese T2DM control group,the obese T2DM+low-dose liraglutide intervention group,the obese T2DM+high-dose liraglutide intervention group and the obese T2DM+diet-control group.After intervention for 12 weeks,Changes in metabolic parameters about glucose and lipid metabolism,body fat content and body fat distribution were detected.In vivo,isotope tracers of 6,6-D2-glucose and U-¹³C-glycerol were infused and in vitro 9,10-³H-palmitic acid was used to culture skeletal muscle to determine the Ra_glu,GNG,Ra_gly,fat deposition and synthesis rates in different fat depots and the?oxidation rate of fatty acid.The expression levels of adipose-related genes were also evaluated in different tissues.Results:1.The proportion of central obesity patients in the diabetic group was higher than that in the normal blood glucose group(P<0.05).After adjusting for influcing factors,both systemic obesity and central obesity increased the risk of diabetes.Among them,higher CVAI(OR1.88,95%CI 1.64-2.16)and LAP(OR1.99,95%CI 1.67-2.37)had higher risk for diabetes.ROC analysis showed that CVAI and LAP with the largest area under the curve were more powerful than BMI with the smallest area under the curve to predict the occurrence of diabetes;2.After being fed with a high fat diet for 8 weeks,both Wistar and GK rats had more than20%body weights compared with their corresponding control groups.In addition,GK rats had significantly higher blood glucose levels than Wistar rats,indicating that simple obese and obese type 2 diabetic rat models were established successfully;3.Compared with obese T2DM group,liraglutide improved the metabolic indeces of glucose and lipid metabolsim significantly.After liraglutide treatment,visceral fat accumulation were significantly reduced and subcutaneous fat were relatively mildly increased;however,in the diet control group,the reduction of visceral fat was not obvious,but subcutaneous fat was reduced;4.Compared with obese T2DM group,liraglutide decreased the Ra_glu,GNG,Ra_gly and visceral fat synthesis rates,but increased subcutaneous fat synthesis rates and fatty acid?oxidation rates in the skeletal muscle.Compared with the mesenteric fat depot,the fat deposition in both inguinal and cluneal subcutaneous fat depots were increased;5.Liraglutide down-regulated the expression levels of the lipogensis-and lipolysis-related key enzymes in the visceral fat tissues,but up-regulated their expression leves of fatty ascid oxidation-related key enzymes.The expression levels of the lipogensis-related key enzymes in inguinal and cluneal subcutaneous white adipose tissues(WAT)were up-regulated,but the expression levels of the lipolysis-related key enzyme were up-regulated in the inguinal WAT,but dowe-regulated in the cluneal WAT.However,the key enzyme of fatty acid oxidation showed the opposite expression trend.In addition,the uncoupling protein 1 was up-regulated in the subcutaneous WAT.Conclusions:1.In eastern China,the body fat distribution of patients with T2DM concentrated more in the trunk center.Central obesity had a greater risk for the occurrence of diabetes.Therefore,it is of great importance to a type of drug with the efficacy of decreasing the blood glucose and body weight and redistributing the body fat when treating obese type 2diabetes.2.Liraglutide can decrease the visceral fat distribution and relatively increase the subcutaneous fat distribution by differentially regulating the lipid metabolism and expression of adipose-related genes in different depots and promoting browning remodeling in subcutaneous WAT to increase insulin sensitivity,which provides a new theoretical basis for the prevention and treatment of obesity type 2 diabetes mellitus and its complications.