Effects And Mechanism Of Ellagic Acid And Its Metabolite On Liver Insulin Resistance In Diabetic Mice

Objective: To study the effects and mechanisms of ellagic acid(EA)and metabolite urolithin A(UA/UroA)on liver insulin resistance(IR)in diabetic mice.Methods:(1)C57BL/6 mice were randomly divided into normal group,model group,EA group and UroA group according to body weight.After 6 weeks of high-fat diet,streptozotocin(STZ)was injected intraperitoneally to establish diabetic model.After 6 weeks of administration,oral glucose tolerance test and insulin tolerance test was conducted;after 8 weeks,body weight,liver weight,blood lipid,liver function,fasting blood glucose(FBG),and fasting insulin(FINS)levels were measured;liver index,insulin resistance index(HOMA-IR)and Insulin Sensitivity Index(ISI)were calculated;HE staining observe pathological changes in mouse liver;immunoblotting to detect mouse liver phosphorylated protein kinase B(p-AKT)and glucose transporter 2(Glut2),Microtubule-associated protein light chain 3(LC3II/I),selective autophagy linker protein(p62)expression levels.(2)C57BL/6 mice were randomly divided into control group,model group,UA group,UA combined with chloroquine(CQ)group,and STZ was injected intraperitoneally 6 weeks later to establish a diabetic mouse model.After 7 weeks of administration,the detection index were the same as the method(1).Results:(1)Both EA and UA can reduce FBG,FINS,HOMA-IR,increase ISI in diabetic mice(P<0.05);reduce plasma triglycerides(TG),low-density lipoprotein cholesterol(LDL-C),Alanine aminotransferase(ALT),aspartate aminotransferase(AST),increase high-density lipoprotein cholesterol(HDL-C)(P<0.01);improve liver pathological structural damage;up-regulate liver p-AKT,Glut2 protein expression(P<0.01);down-regulate LC3II/I,p62 protein expression(P<0.01).(2)After UA combined with CQ intervention,the intervention of CQ significantly reversed the effect of UA on diabetic mice(P<0.05),showed that the autophagy inhibitor CQ significantly weakened the effect of UA.Conclusions: Both EA and UA can improve insulin resistance(IR)in diabetic mice,correct abnormal liver signal transduction and abnormal autophagy,and the autophagy inhibitor CQ significantly weakens the role of UA.It is further proved that the effect of UA in improving IR may be through activation of liver autophagy.