Mechanisms Of Type2Diabetes Mellitus Remission After Gastric Bypass And The Recurrence After Initlal Remission:the Role Of Small Intestine

Part Ⅰ:The role of small intestine in the mechanisms of type2diabetes mellitus remission after gastric bypassBackgroundThe twin pandemics of obesity and type2diabetes mellitus (T2DM) have rapidly developed and currently rank among the most devastating health crises worldwide. Bariatric surgery is the most successful treatment for obesity and offers prominent improvement in diabetes. Mounting evidence indicates that the remarkable anti-diabetic effects are results of not only weight loss but also a yet uncharacterized weight-independent mechanism. The latter is believed to be partly related to the two obvious physiological alterations of small intestine after surgery, namely exclusion of the foregut (duodenum and proximal jejunum) from contact with ingested nutrients and expedited delivery of nutrients to the hindgut (distal ileum). Previous studies have revealed changes in glucoregulatory mechanisms and glucose homeostasis after excluding foregut and interposing hindgut alone and lead to the "foregut hypothesis" and "hindgut hypothesis". However, these hypotheses are not mutually exclusive.ObjectiveWe speculated that exclusion of the foregut and interposition of the hindgut might contribute together to changes in glucoregulatory mechanisms and have a synergistic effect in combined procedures, such as gastric bypass. The present study was conducted to investigate (1) the potential interaction between exclusion of foregut and interposition of hindgut in the improvement in glucose homeostasis,(2) the changes in glucose homeostasis produced by different position of interposed hindgut after surgery, and (3) the role of small intestine in the mechanisms of insulin sensitivity and β-cell function in non-obese diabetic Goto-Kakizaki (GK) rats.MethodsTwo novel experimental intestinal procedures were developed in this study, which are the duodenal-jejunal bypass with ileal interposition (DJBIT), a combination of duodenal-jejunal bypass (DJB) and ileal interposition (IT), and the sub-ileal interposition (sIT), in which the position of interposed hindgut after surgery was situated further from the ligament of Treitz than in IT surgery. DJBIT, sIT, DJB, IT and sham-operations were performed on GK rats.Main outcome measures were (1) glucose tolerance assessed by an oral glucose tolerance test (OGTT) at baseline and2,4,8and24weeks after surgery,(2) insulin sensitivity assessed by insulin tolerance test (ITT) at2and24weeks after surgery,(3) beta-cell function assessed by glucose-stimulated insulin secretion and fasting c-peptide levels at2and24weeks after surgery,(4) post-prandial levels of glucagon-like peptide-1(GLP-1), peptide YY (PYY) and glucose-dependent insulinotropic peptide (GIP) at2and24weeks after surgery, and food intake and body weight.Data from the DJB, IT, DJBIT and control groups was analyzed by a two-factor (DJB×IT) univariate analysis of variance (ANOVA) to test interaction between exclusion of foregut and interposition of hindgut. Data from the IT, sIT and control groups was analyzed to evaluate changes in glucose homeostasis produced by different position of interposed hindgut after surgery. Generalized linear mixed models (GLMM) were constructed to the longitudinal measurements of changes over time in glucose tolerance, food intake and body weight to assess for (1) an effect of non-sham operations, sham-operations versus control on improvement in glucose tolerance,(2) an effect of time on improvement in glucose tolerance, and (3) a time-by-treatment interaction (indicating a significant difference between groups in the rate of change in the improvement over time).Results(1) Global body weight in control group was higher than in operative groups2weeks after surgery (P<0.001), but was similar among groups at postoperative week-24(P>0.05).(2) DJBIT surgery induced synergistic improvement in glucose tolerance and insulin sensitivity (all P<0.05). DJBIT surgery induced better glucose tolerance than both DJB and IT surgery at postoperative week-2(both P<0.05), however, the superiority disappeared at postoperative week-4(all P>0.05). There was no significant difference in insulin sensitivity among the three groups (P<0.05). There was no significant difference between sham-operation and control groups at each time points (all P>0.05).(3) GLMM confirmed that glucose tolerance in non-sham operative groups improved over time (P<0.001), with a significant time-by-treatment interaction (P<0.001).(4) Fasting C-peptide, post-prandial insulin levels increased after non-sham operations (both P<0.05) at postoperative week-24but not at postoperative week-2(both P>0.05). GLP-1and PYY levels increased after non-sham operations at both postoperative week-2and24(all P<0.001), however, were not significantly different among DJBIT, DJB and IT groups (P>0.05). None of the surgeries affected glucose-stimulated GIP levels (all P>0.05).(5) Compared with sIT surgery, IT surgery induced better glucose tolerance (P<0.001) and higher post-prandial insulin, GLP-1and PYY levels (all P<0.05), and no significant difference in insulin sensitivity and fasting C-peptide was observed (both P>0.05).ConclusionsThis study provides experimental evidence that excluding foregut and interposing hindgut induced changes in glucose homeostasis and glucoregulatory mechanisms in GK rats, independently and synergistically, but to different degrees. In addition, the time and time-by-treatment interaction also significantly impact these changes. Heightened GLP-1and PYY secretion were observed and associated to both the improvement in insulin sensitivity and enhancement of beta-cell function in rodents. Improved insulin sensitivity played a key role for early improvement in glucose tolerance after surgery, and both improved insulin sensitivity and enhanced beta-cell function contributed to the long-term improvement in glucose tolerance.These findings indicate that the forgut and hindgut are associated with each other in the mechanisms of diabetes remission after surgery, and exclusion of foregut, interposition of hindgut and combination of them improve glucose homeostasis though an identical mechanism, both of which suggest that the entire small intestine mediates the changes of glucose homeostasis after intestinal surgery. Part Ⅱ:The role of small intestine in the recurrence of type2diabtes mellitus after initial remission after gastric bypassBackgroundMounting evidence indicates that bariatric surgery, such as gastric bypass, results in profound, durable weight loss and the most successful resolution of T2DM, and the mechanisms of diabetes control after gastric bypass include the effect of weight loss and a weight-independent anti-diabetic mechanism, in which the small intestine palys an important role. However, a number of patients with initial remission of T2DM after gastric bypass have experienced diabetes recurrence, and the recurrence rate has been reported to be from10%to over40%. Currently, no animal model of T2DM recurrence has been reported, and very limited studies are available on the recurrence phenomenon and factors that influence it. Previous clinical studies have reported that lower percentage of excess weight loss (%EWL) and greater weight regain are involved in the recurrence. Given that both weight loss and as yet undefined weight-independent anti-diabetic mechanisms are responsible for the resolution of T2DM after bariatric bypass, we speculated that factors other than weight loss that are involved in the mechanisms, such as changes of GLP-1and PYY levels, may also effect the recurrence of T2DM.ObjectiveThis study aimed to eatablish an rat model of T2DM recurrence after initial improvement, and identify the effects of weight changes and gut hormones (GLP-1and PYY) that might be involved. Besides, with the model of recurrence of diabetes after initial improvement, this study aimed to better investigate the role of small intestine in the mechanism of diabetes remission. MethodsTwo T2DM rat models were used in this study, which were the non-obese Goto-Kakizaki (GK) rat, and the moderately-obese T2DM rat induced by a combination of a high-fat diet (HFD) and low-dose streptozotocin (HS rats). DJB surgery was performed as the model of gastric bypass. A HFD (40%of calories as fat) was used to induce the reversal of diabetes improvement.The rats were assigned to DJB, sham-operated and non-operated groups. After DJB surgery, all rats were then randomly divided into HFD-and low-fat diet (LFD)-fed groups.Glucose tolerance was assessed by an oral glucose tolerance test (OGTT) at baseline and2,4,8,12and16weeks after surgery. Insulin tolerance, glucose-stimulated insulin, glucagon-like peptide-1(GLP-1) and peptide YY (PYY) secretion were assessed at postoperative week-2and-16. Food intake and body weight were also measured and compared with controls.GLMM was constructed to the longitudinal measurements of changes over time in glucose tolerance, food intake, body weight and post-prandial insulin, GLP-1and PYY levels to assess for (1) the effect of DJB surgery, time after surgery and time-by-surgery interaction on improvement in glucose tolerance, and changes of intake and body weight,(2) difference between groups in post-prandial insulin, GLP-1and PYY levels.Results(1) There was no significant difference in global body weight between DJB-operated and control rats, and between HFD-and LFD-fed rats (all P>0.05). (2) DJB surgery resulted in significant improvement in glucose tolerance in both GK and HS rats fed with either HFD or LFD (all P<0.001). In contrast to LFD-DJB rats, the HFD-DJB rats exhibited less improvement in glucose tolerance (P<0.001), and the improved glucose tolerance was impaired at postoperative week-8in GK rats and at postoperative week-12in HS rats.(3) In addition to the effect of surgery, there was a significant effect of time after surgery and time-by-treatment interaction on the improvement of glucose tolerance in DJB group (both P<0.001).(4) All HFD-DJB and LFD-DJB GK and HS rats exhibited better insulin sensitivity at postoperative week-2and-16(all P<0.05). However, the improvement in insulin sensitivity was not continuous in HFD-DJB rats, and the increased insulin sensitivity was impaired at postoperative week-16and poorer than at postoperative week-2(P<0.05).(5) Post-prandial insulin levels was not different between the DJB and control groups in both GK and HS rats fed with either a HFD or LFD at postoperative week-2(all P<0.05). At postoperative week-16, post-prandial insulin levels increased in DJB-operated and LFD-fed rats (P<0.05), but not in HFD-fed rats (P>0.05).(6) Post-prandial GLP-1and PYY levels were higher in HFD-DJB and LFD-DJB rats than in sham-operated and control rats at postoperative week-2and-16(all P<0.05). And there was no significant difference between HFD-DJB and LFD-DJB rats (P>0.05).Conclusions(1) This study reported the first rat model of T2DM recurrence after intial improvement after gastric bypass surgery. GK rats and HS rats were used as T2DM rat models, DJB surgery was performed as a model of gastric bypass, and a HFD was used to induce the reversal of diabetes improvement.(2) DJB surgery resulted in significant improvement in glucose tolerance in GK and HS rats fed with either HFD or LFD. All the effects of DJB surgery, time after surgery and time-by-surgery interaction were significant for the improvement in glucose tolerance after surgery.(3) The changes in insulin sensitivity are likely responsible for the early improvement and subsequent re-impairment of glucose tolerance after surgery. The change in body weight is not associated with the reversal of T2DM improvement.(4) Post-prandial GLP-1and PYY levels significantly increased after DJB surgery, and they were responsible for the improvement of insulin sensitivity and β-cell function, but not responsible for the reversal of T2DM improvement.