Effects Of Urolithin A On Pancreas Of Diabetic Mice And It's Underlying Mechanism

Objective: To study the effects and underlying mechanism of urolithin A(UroA)on pancreas of diabetic mice.Methods:(1)45 male mice were randomly pick 10 as normal control group,another 35 mice were injected with low dose(50 mg/kg,5 times)streptozotocin(STZ)intraperitoneally to induce type1 diabetic model.After successful modeling,diabetic mice were randomly divided into the diabetes model group(M),UroA treated group,and the urolithin A and autophagy inhibitor chloroquine co-treated group(CQ group)according to blood glucose.Urolithin A was treated for 8 weeks.The water intake volume,body weight,fasting blood glucose and oral glucose tolerance were measured during the experimental period.After the experiment,serum glycated serum protein(GSP),insulin(INS),interleukin-1?(IL-1?),interleukin-6(IL-6)and tumor necrosis factor alpha(TNF-?)levels were measured in serum,The pathological structure of pancreatic tissue observed under the optical microscope.(2)50 male c57BL/6 mice were randomly divided into normal control group(Ctrl),diabetes model group(Model),urolithin A treatment group(UroA group),urolithin A and autophagy inhibitor chloroquine co-treated group(UroA+CQ group),the normal group was fed with normal diet,and the other mice were fed with high fat diet for 6 weeks.The model of type II diabetes was established by intraperitoneal injection of streptozotocin(STZ 50 mg/kg,2times).Water intake volume,body weight,fasting blood glucose(FBG),oral glucose tolerance and insulin tolerance were measured during the experimental period.Plasma C-peptide,IL-1?,IL-10,and malondialdehyde(MDA),glutathione(GSH)levels were measured by ELISA after the experiment.The pathological structure of pancreatic tissue was observed under the optical microscope.The ultrastructure of pancreatic cells was observed under the Transmission electron microscope.The relative expression levels of LC3II/I,p62,beclin1,PI3Kp85,AKT,p-AKT,mTOR and p-mTOR in pancreatic tissue were detected by western blot.Results:(1)urolithin A reduced water intake volume(P<0.05),fasting blood glucose(P<0.05),glycated serum protein(P<0.05),insulin and inflammation levels(P<0.05)in diabetic mice,and oral Glucose tolerance were improved as well,HE staining results showed that urolithin A can repair the pathological structure of islets and make the islet morphology more regular.After the combination of the autophagy inhibitor chloroquine the anti-diabetic effects of urolithin A was severely impaired.(2)UroA treatment significantly reduced FBG,C-peptide,MDA,IL-1?(P all<0.05),and significantly increased GSH and IL-10(P both<0.05),improved glucose Tolerance and islet function in diabetic mice.It improves the pathological and the ultrastructure damages of pancreas.The autophagy-related protein LC3II/I and BECLIN1 was significantly increased(P<0.05),while p62 was significantly decreased(P<0.05).P-AKT and p-mTOR were significantly elevated(P<0.05).However,when combine UroA with chloroquine(autophagy inhibitor),the efficacy of UroA was severely impaired.Conclusion:(1)urolithin A has anti-diabetic effects on type I diabetic mice,including hypoglycemic,anti-inflammatory and improving pancreatic tissue structure,and its mechanism may be related to activation of autophagy.(2)Urolithin A may regulate autophagy through the PI3K/AKT/mTOR signaling pathway,thereby protecting pancreatic tissue damage under diabetic stress.