Correlation And Mechanism Between Bile Acids Metabolism And DJB Surgery In Type 2 Diabetes Mellitus

Objectives:To explore the correlation and possible mechanism of bile acids in the improvement of glucose metabolism in T2DM after duodenojejunal bypass surgery（DJB）.Methods:1.SD rat model was established by high-sugar and high-fat diet and low-dose injection of STZ.T2DM rats were divided into 4 groups with 10 rats in each group.Sham operation was performed in group A,and DJB surgery was performed in group B,C and D.weekly random blood glucose monitoring was used to verify the hypoglycemic effect of DJB surgery.2.At the second week after operation,group C and D were treated with cholestyramine intervention and antibiotic cocktail therapy respectively to remove inhibit bile acid reabsorption and intestinal bacteria.Random blood glucose and OGTT were used to observe the hypoglycemic effect on DJB surgery.3.ITT was performed before operation,2 weeks and 8 weeks after operation,and the levels of insulin and GLP-1 in peripheral blood were measured by ELISA method,then HOMA-IR was evaluated to analyze the possible hypoglycemic mechanism of DJB surgery.4.The concentrations of total bile acid in peripheral blood,portal vein blood and bile were measured before operation and 2 and 8 weeks after surgery.5.The samples were taken at the 8th week after surgery,and the expressions of key bile acid synthase（CYP7A1,CYP8B1,CYP27A1）,bile acid transporters in enterohepatic circulation（ABST,NTCP,BSEP,MRP2,MRP3,OSTα,OSTβ）and specific receptors and pathways（FXR-SHP,TGR5）in liver and ileum after DJB were compared by q PCR and WB methods.Results:1.After T2DM induction,SD rats were subjected to sham operation and DJB surgery,respectively.After operation,the rats survived well and were finally included in group A（n=10）,group B（n=8）,group C（n=7）and group D（n=9）.2.The preoperative blood glucose levels in group An and B were 20.98±0.98mmol/L and 22.03±4.78mmol/L,respectively.There was no significant difference between the two groups.After operation,the blood glucose levels were21.20±3.87mmol/L and 9.65±0.91mmol/L respectively,with statistical difference.After different intervention treatments,the random blood glucose of the four groups was 22.15±2.28mmol/L,8.80±1.65mmol/L,13.60±1.31mmol/L and 11.65±1.07mmol/L respectively.There was significant difference between group A and group B,C and D,and between group B and group C.The results of OGTT showed that there was significant difference in AUC_OGTT between group A and group B,C and D.after intervention,the AUC_OGTT in group B and group C were1257.25±26.84mmol/L·min and 1606.00±203.85mmol/L·min respectively,and there was significant difference between the two groups.It is suggested that DJB surgery can reduce blood glucose,while inhibition of bile acid reabsorption weakens the hypoglycemic effect of DJB surgery.3.There was no significant change in the concentration of insulin and GLP-1 in peripheral blood after DJB.The HOMA-IR in group A and B was 7.75±0.89 and4.17±0.46 respectively,which was statistically different,indicating that DJB surgery can reduce blood glucose in T2DM rats mainly by improving insulin resistance.4.After DJB surgery,the expression of key enzyme CYP7A1 in liver synthesis was down-regulated,the expression of bile acid uptake transporter NTCP in liver was down-regulated,and the expression of terminal ileal reabsorption transporter ASBT and OSTαwas up-regulated,while the concentration of TBA in bile decreased,portal vein blood had no significant change,and peripheral blood TBA concentration increased with statistical difference.It is suggested that the operation may play a hypoglycemic effect by increasing the reabsorption efficiency of bile acids.5.After DJB surgery,the expression of FXR-SHP in liver was up-regulated,and the expression of FXR and TGR5 in intestine was up-regulated.It is suggested that DJB may cause the change of bile acid metabolism and regulate blood glucose by relieving insulin resistance through FXR-SHP pathway and TGR5 receptor.Conclusions:After DJB,the synthesis and secretion of bile acid was inhibited,and the reabsorption of bile acid at the end of ileum was increased,thus increasing the bile acid entering portal vein and peripheral blood.By changing the distribution of bile acid in peripheral circulation and enterohepatic circulation,the expression of FXR and TGR5 receptors in enterohepatic circulation was further regulated,and finally insulin resistance played an important role in lowering blood glucose in T2DM.