The Effect And Mechanism Of Sleeve Gastrectomy On Diabetic Cognitive Dysfunction In Rats

BackgroundGlobally,the number of people with diabetes mellitus(DM)has quadrupled in the past 30 years,making DM the ninth leading cause of death.DM and its complications pose a serious threat to global health and impose a great burden on global medical resources.Diabetic cognitive dysfunction(DCD)is increasingly recognized as a serious complication of DM,including mild cognitive impairment and dementia.Obesity and type 2 diabetes mellitus(T2DM)are rising rapidly in all age groups,leading to a significant increase in the prevalence of DCD.mild cognitive impairment(MCI)is the precursor stage of dementia,which is characterized by impairment of spatial learning,memory and other cognitive functions related to hippocampus.The main neuropathological features of DCD include neurofibrillary tangles caused by tau hyperphosphorylation,amyloid β-protein(Aβ)plaque formation,neuronal apoptosis,etc.Bariatric surgery(BS)was initially only used for the treatment of morbid obesity,but with the deepening of research,we found that it also plays a certain role in regulating DM and complications.Sleeve gastrectomy(SG)is currently the most popular type of surgery for weight loss.In previous studies,BS has been shown to be effective in improving DCD,but the underlying mechanism remains unclear.phosphatidylinositol 3-kinase(PI3K)insulin signaling pathway plays a key role in the development and development of diabetes-induced cognitive impairment by mediating growth factor signaling to maintain glucose homeostasis,cell proliferation and survival.AKT(Protein Kinase B,PKB)is a serine/threonine kinase activated through phosphorylation mediated by a PI3K-dependent mechanism.glycogen synthase kinase 3β(GSK3β),as a key enzyme in glycogen synthesis and one of the important kinases in tau phosphorylation,is regulated by p-AKT level.Study found that streptozotocin(STZ)induced diabetic rats and sugar to induce hippocampal neurons in the hippocampus,AKT phosphorylation levels decreased and GSK3β activity increased,this is the key factor in the production of insulin resistance.Previous studies have reported the close relationship between PI3K insulin signaling pathway and cognitive impairment.Therefore,we speculate that SG can effectively alleviate diabetes-induced neurodegeneration and ultimately improve cognitive function in diabetic rat models by activating PI3K signaling pathway.ObjectivesTo investigate the effect of SG on Diabetic cognitive dysfunction in DM rats and PI3K signaling pathway in rat hippocampus.Materials and MethodsSixty Wistar rats were randomly divided into control(CON)group,diabetes mellitus(DM)group,sham operation(SHAM)group and SG group.T2DM model was established by high-fat diet(HFD)combined with intraperitoneal injection of streptozocin(STZ).Behavioral evaluation was given using Morris water maze test and Y-maze.In addition,PET-CT,TUNEL assay,histological analysis,transmission electron microscopy(TEM),immunohistochemistry(IHC)and Western blot analysis were used to evaluate the alleviating effects and potential mechanisms of SG on DCD in DM rats.ResultsCompared with the sham group,SG induced significant improvement in the metabolic indices such as blood glucose and body weight.Besides,it could attenuate the insulin resistance compared with SHAM group.In addition,SG could improve the cognitive function of DM rats,which were featured by significant decrease in the escape latency,and significant increase in the time in target quadrant and platform crossings compared with the SHAM group.SG induced significant elevation in the spontaneous alternation compared with SHAM group.Moreover,SG triggered the inhibition of apoptosis of hippocampus neurons,and Western blot analysis showed SG induced significant increase in the ratios of Bcl-2/Bax and Caspase3/cleaved Caspase3.TEM demonstrated SG could significantly improve the microstructure of hippocampus neurons compared with the SHAM group.Western blot and IHC confirmed the significant decrease in the phosphorylation of tau at Ser404 and Ser396 sites in the SG group.Furthermore,SG activated the PI3K signaling pathway by elevating the phosphorylation of PI3K and Akt and GSK3β compared with the SHAM group.ConclusionThis study confirmed that SG can improve cognitive dysfunction caused by diabetes,and its effect is related to PI3K signaling pathway activation.This discovery provides a new therapeutic idea for the treatment of DCD.