The Effectiveness And Mechanism Of Metabolic Surgery On Daibetic Cardiac Dysfunction In Diabetic Rats

[Background]Diabetic cardiac dysfunction is a severe complication of diabetes,with no effective treatment.Currently,bariatric surgery is more and more widely used to attenuate diabetes-associated diseases.The effect of bariatric surgery on alleviating diabetic cardiomyopathy(DCM)is gaining more and more people's attention,but its mechanism is unclear.It is generally believed that the endoplasmic reticulum(ER)stress-mediated apoptosis participated in the pathological process of DCM.In the condition of diabetes,cell glucolipid metabolic disorders,ER working environment disturbed,ER stress initiates maintaining cell normal function,if the interference power is larger,ER stress unable to restore the normal function of cells,and then triggers cell apoptosis to maintain the normal operation of the body.Therefore,this study based on DCM rat model,to observe the metabolic surgeries' effect on diabetic rat myocardial dysfunction and the effect of ER stress.[Methods]This study based on a diabetic rat model induced by high-fat diet in combination with low dose of STZ,performed by duodenum jejunum bypass(DJB),sleeve gastrectomy(SG),and SHAM respectively.Each observation indexes include:(1)measure systemic blood sugar and lipid levels at a specific time point before and after surgery;(2)perform Oral glucose tolerance test(OGTT)and Insulin tolerance test(ITT),and compare the effect of metabolic surgery on diabetic rats' sugar metabolism;(3)after 8 weeks,perform echocardiography,and compare the effect of metabolic surgery on diabetic rats' cardiac function;(4)perform HE staining,Masson staining,oil red 0 staining and Tunel staining;measure myocardial morphology and cell apoptosis;(5)perform immunohistochemical experiment,western blot and qRT-PCR detection of ER stress signaling molecules GRP78,PERK,p-PERK,IRE1?,p-IRE1?,ATF6,CHOP and caspasel2 expression.[Results]1.In DJB group,SG group and SHAM group,rats were successfully completed surgery.2.Preoperative,there was no difference in the three groups of rats'weight;postoperative 1 week,three groups of rats weight loss was to the lowest point,and then gradually rising,DJB group and SHAM group rats weight increase in the whole experimental period,no statistical difference between two groups of rats weight;SG group rats weight gain rate is relatively slow,at 6 weeks postoperatively,in comparison to DJB group and SHAM group rats,SG group rats weight' difference reached statistical significance.3.AUCOGTI and AUCITI:,according to the results of preoperative,there was no difference in the three groups;postoperative 2 weeks and 8 weeks,the values of AUCOGTT and AUCITT in DJB and SG groups were significantly lower than the SHAM group(P<0.01),no difference between DJB and SG groups.4.8 weeks postoperatively,compared with the SHAM group,in DJB and SG groups diabetic rats cardiac function improved significantly,characterized by echocardiography results:LVPWd and LVEDd significantly reduced(LVEDd:P<0.01;LVPWd:P<0.001),while LVEF,FS and E/A significantly elevated(LVEF:P<0.01;FS:P<0.05;E/A:P<0.001);no statistical differences between DJB and SG groups.5.HE and Masson staining results show that after metabolic surgery,myocardial cell hypertrophy and myocardial fibrosis alleviate in the DJB and SG groups;Oil red 0 staining results suggest no change of myocardial cell lipid after metabolic surgery.6.8 weeks postoperatively,compared with the SHAM group,myocardial cell apoptosis ratesin the DJB and SG groups were significantly lower(P<0.001);no difference between DJB and SG groups.7.Immunohistochemistry,western blot and qRT-PCR results suggest that after metabolic surgery,GRP78,CHOP,caspasel2 and PERK,p-PERK were significantly lower than that of SHAM group,and there was no statistically significant difference between DJB and SG groups;among the three groups,the expression of IRE1 ?,p-IRE1 ? and ATF6 had no statistical differences.[Conclusion]1.DJB and SG both can effectively improve the glucose tolerance and insulin resistance in diabetic rats.2.DJB and SG both can improve myocardial function in diabetic rats.3.DJB and SG can significantly reduce the myocardial cell apoptosis of diabetic rats.4.DJB and SG improve myocardial function by inhibiting PERK-mediated ERS in diabetic rat model.