Mechanism Of Bile Acid Signal Regulating Hepatic And Intestinal Gluconeogenesis After Modified Jejunoileal Bypass

Objective:In the previous study,we found that modified jejunoileal bypass(the side-to-side jejuno ileal bypass plus normal loop ligation SSJIBL)had significant weight loss and hypoglycemic effect.Based on our previous research,we speculate that bile acids may improve glucose metabolism by regulating hepatointestinal gluconeogenesis during SSJIBL.In order to solve the above problems and confirm the above conjecture,this study took GK rats as the research objects,and took SSJIBL and bile ileum diversion(BID)established by our team as the operation models to carry out the experimental study.We hope that this study can provide a theoretical basis for the clinical application of SSJIBL in the treatment of T2 DM.Methods:We used 30 SPF(specific pathogen free)GK rats(goto Kakizaki,diabetic rat model)aged from 10 to 12 weeks,weighing 350 to 450 g.after adaptive feeding(high-fat diet),postprandial blood glucose was detected at 9:00-10:00 a.m.every day.Blood glucose value ≥ 16.7 mmol / l was included in the experiment.Urine and fecal samples were collected before operation to detect the body weight,food intake and fed blood OGTT(oral glucose tolerance test)was performed.Twenty four model rats were randomly divided into sham group,SSJIBL group and BID group.Body weight,food intake,FEG,OGT,urine and fecal samples were collected at specific time points.The rats were killed 16 days after operation,and the relevant samples were collected to detect the levels of serum liver function,blood lipid and glycosylated serum protein in each group.The morphological changes of liver in each group were observed by HE staining,and the composition and content of serum and fecal bile acid in each group were detected by LM precise targeting bile acid.The genes related to bile acid metabolism and gluconeogenesis were detected by fluorescence quantitative PCR.Results:1.Survival rate of rats in each group: the survival rate of sham group and SSJIBL group were significantly higher than that of BID group.One rat died 4 days after operation in Sham group,one rat died 1 week after operation in SSJIBL group,and one rat died 3 days,5 days and 7 days after operation in BID group.All other rats survived to the end of the experiment.2.Body weight and 24-hour food intake: the preoperative food intake of each operation group had no change compared with sham group(P > 0.05).The 24-hour food intake of SSJIBL and BID groups was lower than that of sham group 0-2 weeks after operation(P < 0.05),but there was no significant difference between BID group and SSJIBL group(P > 0.05);the ratio of postoperative body weight to preoperative body weight of BID group and SSJIBL group were lower than that of sham group 0-2weeks after operation(P < 0.01),but there was no significant difference between BID group and SSJIBL group(P > 0.05).3.FBG levels in SSJIBL and BID groups were lower than those in sham group0-2 weeks after operation(P < 0.01),but there was no significant difference between SSJIBL and BID groups(P > 0.05);4.OGTT: before operation,there was no significant difference among SSJIBL,BID and Sham groups(P > 0.05).At 7 days after operation,there was no significant difference between BID group and sham group(P > 0.05).The blood glucose of BID group and sham group was higher than that of SSJIBL group at any time point after intragastric administration of glucose(P<0.01).15 days after operation,BID and SSJIBL were significantly lower than sham group(P<0.01),and there was no significant difference between BID group and SSJIBL group(P > 0.05).5.Changes of serum biochemical level: transaminase and γ-GT in BID group were significantly higher than those in the other two groups on the 16 th day after operation(P < 0.05)There was no significant difference in the levels of bilirubin,glycosylated serum protein,alkaline phosphatase,albumin,total cholesterol,triglyceride,high density lipoprotein and low density lipoprotein among the three groups(P > 0.05);the levels of total bile acid in SSJIBIL and BID were higher than those in sham group(P < 0.05).6.Liver HE staining: 16 days after operation,microscopic observation in SSJIBIL group and Sham group showed that the liver tissue was relatively intact,without obvious cellular degeneration,steatosis and inflammatory changes;BID group: liver structure necrosis,cell degeneration,inflammatory cell infiltration.7.Fluorescent quantitative PCR: the relative expression of CYP7A1 gene: ssjibl,BID were increased compared with Sham group,there was no statistical difference(P > 0.05).CYP27A1: bid and SSJIBIL were higher than those in Sham group(P <0.05),but there was no significant difference between BID and SSJIBIL groups(P >0.05);G6PC-1 and PERCK-1: SSJIBIL and BID were lower than those in Sham group(P < 0.05),but there was no significant difference between SSJIBIL and BID groups(P > 0.05);Conclusions:1.Both BID and SSJIBIL had the effect of reducing weight and blood glucose,and SSJIBL was better than BID in two aspects.SSJIBIL is better than BID in reducing blood glucose.2.The liver function was damaged significantly after BID,but not after SSJIBL3.The increase of bile acid level in two kinds of operation depends on the increase of liver synthesis4.Bile acid can reduce blood glucose by inhibiting hepatic gluconeogenesis.