Effects And Mechanisms Of Jejunoileal Bypass And Small Bowel Resection In Non-obese Diabetic Rats

Part1Effects of glucose homeostasis submitted to three different modified jejunoileal bypass surgical modelsObjective:This study was to develop three different jejunoileal bypass surgical models and thereby observe their curative effects on non-obese diabetic rats.Methods:Sprague-Dawley rats were treated with65mg/kg streptozotocin (STZ). The STZ-treated diabetic rats were randomized into jejunoileal bypass by side-to-side intestinal anastomosis plus proximal loop ligation (SSJIBL), jejunoileal bypass by side-to-side intestinal anastomosis (SSJIB), jejunoileal bypass by end-to-side intestinal anastomosis (ESJIB) and sham operation groups. Rats were observed for3weeks after the operation. The main outcome measures were weight, food intake, non-fasting glucose (FBG), and oral glucose tolerance test (OGTT).Results:The SSJIBL and SSJIB groups exhibited higher weight than ESJIB and Sham groups, and food intake in ESJIB and SSJIBL groups were lower than SSJIB and Sham groups3weeks after surgery. When compared to the Sham controls, the SSJIBL group displayed an significant improvement in FBG and OGTT at3weeks post operation, SSJIB and ESJIB groups elicited an improved OGTT at3weeks post operation.Conclusions:This study established three different jejunoileal bypass surgical models and our findings confirm that SSJIBL is a simple and more effective surgical model for treating non-obese diabetic rats; Both "malabsorption" and "hindgut hypothesis" are main mechanisms of improving the glucose homeostasis on NOD rats after jejunoileal bypass. Part2Effects and mechanisms of mid to distal small bowel resection in non-obese diabetic ratsObjective:The aim of this study was to develop a novel surgical model to test the "hindgut hypothesis" and "bile acid signaling" and thereby study the role of the terminal ileum in glucose homeostasis and the mechanism of action of small bowel resection.Methods:Sprague-Dawley rats were given a high-fat and high-sugar diet and treated with25mg/kg streptozotocin (STZ). The fat-sugar-fed/STZ-treated rats were randomized into mid to distal small bowel resection with the preservation of the terminal ileum (DBRPI) and sham operation (which had a formal celiotomy with bowel manipulation only) groups. Rats were observed for12weeks after the operation. The main outcome measures were weight, food intake, non-fasting glucose, an oral glucose tolerance test (OGTT), an insulin tolerance test (ITT), the levels of fasting and glucose-induced insulin, glucagon-like peptide-1(GLP-1) peptide YY (PYY), serum bile acids, and lipid profile.Results:The DBRPI and sham groups exhibited no difference in weight and food intake after surgery. When compared to the sham controls, the DBRPI group displayed an improvement in nonfasting glucose, oral glucose tolerance, and insulin tolerance at4weeks and12weeks post resection. DBRPI elicited an increased fasting PYY level and enhanced glucose-induced insulin and GLP-1levels at12weeks postoperation; furthermore, DBRPI resulted in higher serum levels of triglyceride, total bile acids, total bilirubin, and direct bilirubin levels and lower free fatty acid level at12weeks.Conclusions:This study provides strong evidences for the key role of terminal ileum in the amelioration of diabetes by increasing GLP-1through elevated total bile acids after DBRPI. Moreover, these findings confirm that DBRPI is a simple and effective surgical model for testing the "hindgut hypothesis" and focused study of biliary enterohepatic recycling in the context of bariatric operations. Part3Effects and mechanisms of jejunoileal bypass and small bowel resection in non-obese diabetic ratsObjective:The present study was conducted to investigate (1) whether different modus operandi of jejunoileal bypass yielded different effects in NOD rats or not;(2) whether different retained intestinal length of jejunoileal bypass yielded different effects in NOD rats or not;(3) the potential interaction between the two factors (Surgery and Length) in the improvement in glucose homeostasis;(4) whether the small bowel resection yielded better effect of lowering glucose concentrations in NOD rats than the small bowel exclusion, and whether the two operations improved the glucose homeostasis of NOD rats through the same mechanism or not;(5) the possible mechanisms contributed to improved glucose homeostasis after jejunoileal bypass and proximal small bowel resection.Methods:Three types of experimental intestinal procedures were developed in this study, which were jejunoileal bypass by side-to-side intestinal anastomosis (SSJIBL), jejunoileal bypass by end-to-side intestinal anastomosis (ESJIB) and proximal small bowel resection (PBR). Each type of surgery included two subgroups, in which30cm or40cm distal small bowel was retained. Main outcome measures were (1) body weight, food intake and fasting blood glucose levels (FBG) at baseline and1,2,4,6,8,10and12weeks after surgery,(2) glucose tolerance assessed by an oral glucose tolerance test (OGTT) at baseline and2,4,8and12weeks after surgery,(3) insulin sensitivity assessed by insulin tolerance test (ITT) at baseline and2and12weeks after surgery,(4) fasting and glucose-stimulated serum levels of insulin, glucagon-like peptide-1(GLP-1) and Leptin at12weeks after surgery,(5) fasting serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total bilirubin (TBIL), direct bilirubin (DBIL), total bile acids (TBA), triglyceride (TG), cholesterol (CHOL), high density lipoprotein (HDL), high density lipoprotein (LDL), Free Fatty Acid (FFA).Results:(1) Global body weight in L-40cm group was higher than it in L-30cm group and Sham group (P<0.05), global body weight in L-30cm group was lower than it in Sham group (P<0.05), but was similar among SSJIBL, ESJIB, PBR and Sham groups (P>0.05).(2)24hour food intake in both L-30cm and L-40cm groups were significantly lower than it in Sham group (P<0.01),24hour food intake in L-30cm group was lower than it in L-40cm group (P<0.01);24hour food intake in SSJIBL, ESJIB and PBR groups were lower than it in Sham group (P<0.05), but was similar among SSJIBL, ESJIB and PBR groups (P>0.05).(3)SSJIBL induced better improvement in global FBG and OGTT than ESJIB and PBR (both P<0.01), and there was no significant difference between ESJIB and PBR groups (P>0.05); L-30cm group induced better improvement in global FBG and OGTT than L-40cm (P<0.01); the two factors (Surgery and Length) induced synergistic improvement in global FBG and OGTT.(4)SSJIBL surgery induced better improvement in insulin sensitivity than ESJIB and PBR (both P<0.05), and there was no significant difference between ESJIB and PBR groups (P>0.05); L-30cm group induced better improvement in insulin sensitivity than Sham group (P<0.05), however, there was no significant difference between L-30cm and L-40cm group; there was no interaction between the two factors (Surgery and Length) in the improvement in insulin sensitivity (P>0.05).(5)At12weeks after surgery, no significant difference in serum fasting and glucose-stimulated insulin and leptin levels was detected between groups with different modus operandi (including SSJIBL, ESJIB, PBR and Sham groups) and with different Length(including L-30cm and L-40cm groups)(P>0.05); serum level of glucose-stimulated GLP-1in SSJIBL, ESJIB and PBR group were higher than Sham group (P<0.05), and serum level of glucose-stimulated GLP-1in SSJIBL was higher than ESJIB and PBR(P<0.05), there was no significant difference between ESJIB and PBR(P>0.05); serum level of glucose-stimulated GLP-1in L-30cm group and L-40cm group were higher than Sham group (P<0.05), and there was no significant difference between L-30cm group and L-40cm group (P>0.05).(6) At12weeks after surgery, no significant difference in serum fasting levels of ALT, AST, ALB, TG, CHOL, HDL and LDL was detected between groups with different modus operandi (including SSJIBL, ESJIB, PBR and Sham groups) and with different Length (including L-30cm and L-40cm groups)(P>0.05); serum fasting levels of TBIL, DBIL and TBA in SSJIBL, ESJIB and PBR were higher than Sham group (P<0.05), and serum fasting level of DBIL in SSJIBL group was higher than ESJIB and Sham groups (P<0.05); serum fasting level of FFA in SSJIBL group was lower than ESJIB, PBR and sham groups (P<0.05), and serum fasting level of FFA in ESJIB and PBR groups were higher than Sham group(P<0.05); serum fasting levels of TBIL, DBIL and TBA in L-30cm and L-40cm groups were higher than Sham group (P<0.05), and serum fasting levels of DBIL in L-30cm group were higher than L-40cm group. Conclusions:This study established a novel experimental jejunoileal bypass model (SSJIBL) in NOD rats, which is a simpler, safer, and more effective procedure for the treatment of non-obese diabetic rats. The SSJIBL induced better glucose tolerance than ESJIB and PBR. SSJIBL, ESJIB and PBR with30cm retained distal small bowel yielded better glucose tolerance than operations with40cm retained distal small bowel and induced weight loss in NOD rats. Heightened GLP-1, TBIL and TBA secretion were observed in rodents. Improved insulin sensitivity played a key role for early and long-term in restored glucose homeostasis after SSJIBL. Weight loss may play a role for improvement in glucose tolerance after ESJIB and PBR. The retained length of distal small bowel in modified jejunoileal bypass or proximal small bowel resection played a key role for improvement in glucose tolerance. This study provided experimental evidence that there was a positive interaction between the operational manner and the retained intestinal length in the improvement in glucose homeostasis following modified jejunoileal bypass and proximal small bowel resection.