| Research purposesType 2 diabetes can lead to cognitive dysfunction such as learning and memory impairement,but its underlying neurobiological mechanisms have not yet been fully elucidated.Hippocampal glucose metabolism is closely associated with cognitive.When type 2 diabetes occurs,what happens to the hippocampal glucose metabolism is not yet clear.Studies have shown that glucose metabolism is closely related to insulin signaling pathways and energy metabolism,and energy metabolism disorders are the key factors leading to inflammatory responses.Then,when type 2 diabetes occurs,what will happen to the insulin signaling pathway,energy metabolism and inflammatory signals in the hippocampus? Is this the cause of decreased expression of synaptic plasticity-related proteins in the hippocampus during diabetes? What does the relationship between aerobic exercise promoting hippocampal synaptic plasticity-related protein expression and the above signaling pathways? The series of issues still needs further discussion.In this study,a rat model of type 2 diabetes was established by high-fat diet combined with intraperitoneal injection of low-dose streptozotocin(STZ),and aerobic exercise interventions were performed to investigate changes in glucose metabolism,insulin signaling,energy metabolism,and inflammation-related signaling pathways in the hippocampus and the regulation of aerobic exercise through GC/MS metabolomics and Western blot,to explore the mechanisms of decreased expression of synaptic plasticity-related protein in hippocampus of diabetic rats and the regulatory mechanism of aerobic exercise.Research methods:A total of 102 male Sprague-Dawley(SD)rats weight were randomly divided into control group(C group,n=8)and high-fat diet group(HF group,n=94).The rats were fed with normal diet or high-fat diet,and after 8 weeks,obese rats were selected according to the standard that high-fat diet group rats had 20% higher body weight than control group rats.The obese rats were intraperitoneally injected with STZ(30mg/kg body weight).At 3th and 7th day of STZ injection,the rats with fasting blood glucose concentration higher than 11.1 mmol/l were taken as being diabetic.The diabetic rats were divided into diabetes group(DM group)and diabetic exercise group(TDM group).TDM rats were subjected to aerobic exercise for 4 weeks.24 hours after the end of exercise intervention,the blood sample and hippocampus were collected.Then,the fasting blood glucose,fasting insulin,HOMA-IR and lipid indexes were detected.The left hippocampus was used for GC/MS metabolomic analysis;and the right hippocampus was used for western blot to detect the expression of the glucose metabolism regulatory enzymes CS,OGDH,G-6-PD and AR,synapticplasticity-associated proteins NMDAR,SYN and Homer,PI3K/Akt/mTOR signaling proteins,p-PI3K/PI3 K,p-Akt/Akt,p-mTOR/mTOR,Raptor and Rictor,mTOR downstream signaling proteins p-p70s6k/p70s6 k and p-4EBP2/4EBP2,energy-sensing proteins p-AMPK/AMPK,Sirt1 and Ac-NF?B,and inflammatory signaling pathway protein NF?B,NLRP3 and IL-1?.Research Results1.Compared with group C,FBG,FINS and HOMA-IR were significantly increased in DM group(p<0.01),while FBG,FINS and HOMA-IR were significantly decreased in TDM group compared with DM group(p<0.01).2.Compared with group C,the levels of TC,TG and LDL in DM group were significantly increased(p<0.01).Compared with DM group,the levels of TC,TG and LDL in DM group were significantly decreased(p< 0.05,p<0.01,p<0.05).3.Compared with the group C,the lactic acid,sorbitol,fructose,ribose 5-phosphate,and xylulose 5-phosphate were significantly increased in the DM group,and the glycolytic pathway,the polyol pathway,and the pentose phosphate pathway were enhanced.Compared with group DM,the levels of lactic acid,sorbitol,myo-inositol,5-ribose 5-phosphate and xylose 5-phosphate in hippocampus of TDM rats were significantly decreased,and the glycolytic pathway,the polyol pathway and pentose phosphate pathway were inhibited;The level of citric acid increased significantly and TCA levels increased.4.Compared with group C,the levels of CS and OGDH in hippocampus of DM rats were significantly decreased(p<0.01),G-6-PD and AR levels were significantly increased(p<0.01,p<0.05).Compared with DM group,the level of CS in hippocampus of TDM group was significantly increased(p<0.01),and G-6-PD level was significantly decreased(p<0.05).5.In the Y maze,the number of actual alternations and the maximum number of alternations in the spontaneous alternation response of diabetic rats were significantly lower than control group(p< 0.01),and in the novel object recognition experiment,the number of new arm crossings and the total number of crossings were also significantly lower than control group(p < 0.01).Compared with diabetic group,there were no significant changes in the indicators of spontaneous alternation response and new foreign object recognition experiment However,the indicators showed a rising trend.6 Compared with group C,the levels of synaptic plasticity related proteins such as NMDAR,SYN and Homer in hippocampus of diabetic rats were significantly decreased(p< 0.01,p < 0.01,p < 0.01),whereas the levels of synaptic plasticity related proteins NMDAR,SYN and Homer in hippocampus of diabetic exercise ratswere significantly increased(p < 0.01,p < 0.01,p < 0.01).7.Compared with group C,the levels of p-PI3 K,p-Akt,p-mTOR,mTOR,Raptor,p-p70s6 k,and p-4EBP2 in hippocampus of DM rats were significantly decreased(p<0.01).Compared with group DM,the levels of p-PI3 K and p-Akt in hippocampus of TDM rats increased significantly(p<0.05,p<0.01),mTOR levels increased significantly(p <0.01),and p-p70s6 k and p-4EBP2 levels also increased significantly(p <0.05,p <0.01).8.Compared with group C,the levels of p-AMPK and Sirt1 in hippocampus of DM rats decreased significantly(p<0.05,p<0.01),while Ac-NF?B and NF?B levels increased significantly(p<0.01);Compared with the group DM,the levels of p-AMPK and Sirt1 in the hippocampus of TDM rats significantly increased(p<0.01,p<0.05),while Ac-NF?B and NF?B levels decreased significantly(p<0.05).9 Compared with group C,the levels of NLRP3 and IL-1? in hippocampus of DM rats were significantly increased(p< 0.01,p< 0.01);Compared with group DM,the levels of NLRP3 and IL-1? in hippocampus of TDM rats were decreased significantly(p< 0.01,p< 0.05).Research Conclusion1.High-fat diet combined with STZ induced diabetes,and the diabetic rats showed peripheral disorder of glucose and lipid metabolism and insulin resistance,while aerobic exercise can improve the above metabolic abnormalities.2.Diabetes caused alterations of hippocampal glucose metabolism,mainly manifested by decreased tricarboxylic acid cycle,excessive activation of the glycolytic pathway,the polyol pathway,and the pentose phosphate pathway;and 4-week aerobic exercise can improve diabetes induced abnormal hippocampal glucose metabolism.3.The expression of synaptic plasticity-associated protein was significantly decreased in diabetic rats,and which was accompanied by abnormal glucose metabolism in the hippocampus.Aerobic exercise improved the expression of synaptic plasticity-associated proteins in the hippocampus while improving glucose metabolism.4.Impaired glucose metabolism in the hippocampus of diabetic rats was accompanied by impaired insulin signaling pathway PI3K/Akt/mTOR in the hippocampal.When aerobic exercise improved insulin signaling pathway,glucose metabolism in the hippocampus became normal.5.Abnormal glucose metabolism in the hippocampus of diabetic rats was accompanied by impaired AMPK/Sirt1 signaling pathway and excessive activation of inflammatory signaling pathways NF?B/NLRP3/IL-1? in the hippocampus;aerobic exercise improved energy metabolism and inflammatory signaling pathways,at thesame time,glucose metabolism in the hippocampus also tended to be normal. |
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