Study On The Mechanism Of Disorder Of Glucose Metabolism In Spontaneous Hyperuricemia Mice

Objective:1?To investigate the effect of high uric acid on the expression of peroxisome proliferator-activated receptor ?(PPAR-?),phosphoenolpyruvate carboxy kinase(Pck1)and rapamycin target protein(m TOR)in C57BL/6 mice and the role of PPAR-?,Pck1,m TOR in islet ? cell apoptosis in C57BL/6 mice.2?The role of GLUT2 and GLUT4 in high uric acid induced insulin resistance.Methods: 1?One group were mice that developed spontaneous hyperuricemia(knockout urate oxidase)(SCD-KO);the other group were control wild type mice(SCD-WT).After the end of the experiment,the serum were detected by ELISA kit for fasting insulin(FINS),uric acid(UA)and fasting blood glucose(FBG).Apoptotic rate of pancreatic islet cells was measured by TUNEL kit in pancreatic tissue.Morphology and structure of pancreas were observed by HE staining.Part of the pancreas tissue was homogenized,RNA was extracted,and the relative expression levels of PPAR-?,Pck1,m TOR genes in each group were detected by RT-PCR.The pancreatic tissue proteins were extracted and the relative expression of each group of proteins were detected by Western blot.2?High fat diet fed spontaneous hyperuricemia mice(HFD-KO)and control wild-type mice of similar age and weight(HFD-WT),After spontaneously hyperuricemia mice were successfully modeled,half of the mice were randomly selected and treated with allopurinol(100 mg/kg)(ULT)for 1 week.Repeated testing of insulin tolerance test(ITT),glucose tolerance test(GTT),FINS,FBG.After the end of the experiment,serum UA,FINS,triglycerides(TG)and free fatty acids(FFA)were detected using an ELISA kit.Liver and muscle tissue were homogenized to extract protein and Western blot was used to detect the relative expression of GLUT2 and GLUT4 protein.Results: 1?The UA level in KO mice remained stable during the experiment(483.9±24.3)?mol/L and was significantly higher than that in WT mice(143.8±23.2)?mol/L;No difference in fasting blood glucose,fasting insulin,insulin sensitivity between SCD-KO mice and SCD-WT mice;Compared with SCD-WT group,the glucose tolerance of SCDKO group was decreased,and the apoptosis rate of islet cell in SCD-KO group was significantly increased(P<0.05).The degree of damage of pancreas cells in SCD-KO mice was more severe(P<0.05).The relative expressions of m RNA and protein of PPAR-?,Pck1 and m TOR in SCD-KO group were all increased(all P<0.05).2?There was no significant difference in fasting blood glucose in mice fed with high fat diet;The level of FINS in HFD-KO mice was higher than that in HFD-WT mice((0.636±0.07)ng/ml vs.(0.456±0.03)ng/ml)(P<0.01).Significant decrease in insulin sensitivity and significant disorder of glucose metabolism in HFD-KO group;Although high-fat diet increased uric acid,the uric acid in HFD-KO mice was still significantly higher than that in HFD-WT mice((216.61±27.5)?mol/L vs.(549.68±48.7)?mol/L)(P <0.05);Compared with HFD-WT group,the expression of Slc2a4/GLUT4 in gastrocnemius muscle of HFD-KO mice was decreased and the expression of Slc2a2/GLTU2 in liver of HFD-KO group mice was increased,Allopurinol gavage treatment decreased the uric acid level by approximately 200 ?mol/L.HFD-KO mice had improved glucose metabolism and increased insulin sensitivity.The expression of Slc2a4/GLUT4 in the gastrocnemius muscle was increased and the expression of Slc2a2/GLTU2 in liver was decreased in HFD-KO group.Conclusions:1?Uric acid may participate in the apoptosis of islet cells through the PPAR-?-Pck1-m TOR signaling pathway.2 ? Uric acid may induce insulin resistance by decreasing the expression of Slc2a4/GLUT4 in the gastrocnemius muscle and increasing the expression of Slc2a2/GLUT2 in the liver.