Effect Of Pterostilbene On Insulin Resistance Of Skeletal Muscle In Type 2 Diabetic Rats And Its Mechanism

ObjectivePterostilbene（PTE）,as a natural polyphenol compound,has been reported to have various biological functions,such as anti-inflammatory,anti-oxidant and anti-glycolipid disorders,but the specific mechanism is still unclear.This paper aims to explore the effect of PTE on skeletal muscle insulin resistance（IR）in type 2 diabetes mellitus（T2DM）rats.MethodsAfter feeding under optimal experimental conditions for one week,4-week-old Sprague-Dawley（SD）male rats（n=140）were randomly allocated into normal control group（NC group,n=20）and high-fat and high-sugar model group（n=120）.After 4weeks of high-fat and high-sugar feeding,the rats were intraperitoneally injected with1%Streptozotocin（STZ）solution（40 mg/kg）to construct a T2DM model.After 72h of STZ intraperitoneal injection,the fasting blood glucose（FBG）of the rat tail vein blood was greater than 11.1 mmol/L,accompanied by the symptoms of polydipsia,polyphagia,polyuria and weight loss,indicating the successful establishment of a T2DM model.A total of 103 rats successfully modeled were randomly divided into T2DM model control group（MC group,n=20）,low-dose pterostilbene intervention group（PTE-L group,n=20）,medium-dose pterostilbene intervention group（PTE-M group,n=20）,high-dose pterostilbene intervention group（PTE-H group,n=20）and rosiglitazone group（RSG group,n=20）.The NC group and MC group were given carboxymethyl cellulose sodium solution every day.PTE-L,PTE-M and PTE-H groups were given 20 mg/kg·d^-1,40 mg/kg·d^-1 and 80 mg/kg·d^-1 pterostilbene solution,respectively.RSG group were given 5 mg/kg·d^-1 rosiglitazone.After 6 and 12 weeks of intervention,the glucose metabolic characteristics,skeletal muscle glycogen level,oxidative stress level,and histopathological changes of pancreas and skeletal muscle were evaluated.Western blot was used to determine the protein expression of PPARγ,AMPKα,p-AMPKαand GLUT4 in rat skeletal muscle tissue.SPSS 22.0 and Graph Pad Prism 8.0 were used for data statistical analysis.Quantitative data that satisfied the normal distribution were represented by the mean±standard deviation（（?）±s）.Analysis of variance was performed to compare the means of multiple groups,and the least significant difference（LSD）test was conducted for multiple comparisons.An alpha level of 0.05 was considered as a significance criterion.Results（1）PTE could improve weight loss and glucose metabolism disorders in T2DM rats.Our results showed that the body weight of MC group was significantly lower than the NC group（P<0.05）;after 6 and 12 weeks of intervention,the body weight of PTE-L,PTE-M,PTE-H and RSG rats increased slowly,which was significantly higher than the MC group（P<0.05）.FBG and FINS in MC group were significantly higher than the NC group（P<0.05）;after PTE and RSG intervention,FBG and FINS were significantly lower than the MC group（P<0.05）.（2）PTE could improve the glycogen content of skeletal muscle in T2DM rats.The content of skeletal muscle in the MC group was significantly lower than the NC group（P<0.05）;after PTE and RSG intervention for 6 and 12 weeks,the skeletal muscle glycogen content increased,which was significantly higher than the MC group（P<0.05）.（3）PTE could improve the oxidative stress of skeletal muscle tissue in T2DM rats.Compared with the NC group,the Superoxide dismutase（SOD）activity decreased and the malondialdehyde（MDA）content increased in the MC group（P<0.05）;after PTE and RSG intervention for 6 and 12 weeks,the SOD activity increased and the MDA content decreased compared with the MC group,and the differences was statistically significant（P<0.05）.（4）Hematoxylin-eosin（HE）staining indicated that PTE had a protective effect on pancreas and skeletal muscle.PTE and RSG improved the morphology of skeletal muscle fibers and the arrangement of muscle cell nuclei and reduce inflammation;PTE and RSG could improve the morphology of pancreatic isletβcells and the inflammation infiltration of pancreatic tissue.（5）Western blot analysis showed that the expression levels of PPARγ,p-AMPKα/AMPKαand GLUT4 in the skeletal muscle of the MC group were significantly lower than the NC group（P<0.05）.After 6 and 12 weeks of PTE and RSG intervention,PPARγ,p-AMPKα/AMPKαand GLUT4 expressions were significantly higher than the MC group（P<0.05）.ConclusionPTE can not only improve glucose metabolism and increase skeletal muscle glycogen content,but also improve the histopathological damage of skeletal muscle and pancreas.In addition,PTE can also improve the oxidative stress of skeletal muscle tissue,activate the PPARγ/AMPKα/GLUT4 signaling pathway,and improve IR in diabetic rats.