| IntroductionDiabetes mellitus, known as a notorious health-jeopardizing disease, could not be fully cured with traditional therapy. Bariatric surgery has been confirmed to be effective in ameliorating type 2 diabetes rapidly. However, the underlying mechanisms remain unclear. Some patients have diabetes relapse after an initial postoperative diabetes remission. As bariatric surgery has been accepted by the International Diabetes Federation (IDF), an increasing number of patients receive surgeries with the purpose of treating diabetes, aside from losing weight, and accordingly, the solution to reducing postoperative diabetes relapse represents a key problem to be solved. From the point of clinical practice, the present study was designed to investigate the mechanisms and prevention of postoperative diabetes relapse.In the present study, an animal model, characterized by diabetes relapse after an initial postoperative diabetes remission, has been successfully built via a continuous high-fat-diet (HFD) chow after surgery. Based on the animal model, we first performed duodenal-jejunal bypass (DJB) surgery to investigate potential mechanisms involved in postoperative diabetes relapse (eg. gut microbiota, bile acid metabolism, inflammatory level). Then we performed sleeve gastrectomy (SG), which is currently the most widely used bariatric procedure worldwide in recent years, and confirmed that chow enriched with fructooligosaccharide helps control postoperative diabetes relapse, indicating a key role of postoperative diet control. Eventually, we combined two new procedures, jejuno-jejunal loop (JJ) and jejuno-ileal loop (JI) with SG respectively, known as SG-JJ and SG-JI, which proves to be superior to simple SG with regards to improvement of glucose and lipid metabolism.Part ? Alterations and mechanisms of microbiota in T2DM occurrence, remission and recurrence after duodenal-jejunal bypassBackgroundDiabetes mellitus, of which type 2 diabetes mellitus (T2DM) accounts for over 90%, is a human public health crisis. According to data from the international diabetes federation (IDF), there are 415 million adult diabetic patients all over the world, and this number will increase to 642 million in 2040. In addition, more and more new cases are appearing in developing countries, such as China and India.T2DM is characteristized by high morbidity and mortality. Traditional treatments for T2DM include blood glucose monitoring, diet control, physical activity, and drugs. Since this program requires regular follow-up, long-term adherence and good compliance of patients, it's hard to achieve a good blood glucose target, with only 10% of diabetic patients acquiring well diabetes control at the moment.Many studies have suggested that bariatric surgery can achieve a rapid T2DM remission. A meta-analysis demonstrated that the diabetic cure rate and ameliorative rate (including remission and improvement) of bariatric surgery were 78.1% and 86.6%, respectively. However, the long-term response rate reduced over time, and the recurrence of T2DM was observed in a part of patients with initial remission after surgery, which is a severe problem that bariatric surgeons have to face.According to recent data, gut microbiota can regulate host physiology and metabolism by modulating energy intake, lipid metabolism, bile acid biosynthesis, and inflammatory tone. The component of gut microbiota took place remarkable changes, which could result in improvement of glycometabolism. However, there is no research about the change of gut microbiota and relative mechanisms in the diabetes recurrence after bariatric surgery.ObjectivesSHAM and duodenal-jejunal bypass (DJB) procedures were performed in a diabetic rat model induced by high-fat diet (HFD)/low-dose streptozotocin (STZ). After surgery, HFD were provided unceasingly to induce the recurrence of diabetes. The primary objectives included: (1) alterations of gut microbiota during diabetes occurring, remission and recurrence after duodenal-jejunal bypass; (2) to investigate the possible role of alterations of gut microbiota in diabetes occurring, remission and recurrence after duodenal-jejunal bypass.MethodsWe assigned HFD-and low-dose streptozotocin (30 mg/kg)-induced diabetic rats into two major groups to receive DJB and sham operation respectively. When the DJB was completed, we used HFD to induce diabetes recurrence.12 weeks after surgery, we devided the DJB-operated rats by oral glucose tolerance test(OGTT) into the DJB-remission (DJB-RM) group and the DJB-recurrence (DJB-RC) group, comparing with normal Wistar rats as the control group. Before and at a sequence of time points after operations, we compared calorie content in the food intake (calorie intake), body weight, oral glucose tolerance test, homeostasis model assessment of insulin resistance (HOMA-IR), concentrations of glucagon-like peptide 1 (GLP-1), insulin, total bile acids (TBAs) and lipopolysaccharide (LPS) in serum and alterations in colonic microbiota.Results1. The control group had markedly lower body weight and calorie intake compared with rats in the other three groups at any time points. The differences of other groups were not significant.2. The control group had statistically lower preoperative AUCOGTT compared with the other three groups.4 weeks postoperatively, DJB-RM and DJB-RC groups showed comparable AUCOGTT with control group and lower AUCOGTT than SHAM group.12 weeks postoperatively, SHAM and DJB-RC groups showed comparable AUCOGTT and they were both higher than DJB-RM group.3. Four weeks postoperatively, the sham group had higher HOMA-IR compared with the other three groups; 12 weeks postoperatively, the DJB-RC group exhibited higher HOMA-IR values than the DJB-RM group.4. No statistically difference was observed in serum insulin curve among the groups 4 wk and 12 wk postoperatively.5. At both 4 weeks and 12 weeks after surgery, total serum GLP-1 secretion was comparable among the control group, DJB-RM group and DJB-RC group, and rats in the sham group showed a lower total serum GLP-1 secretion.6. Four weeks postoperatively, TBAs levels were higher in the DJB-RC and the DJB-RM group than the control and the sham group. Notably, rats in the DJB-RM group showed higher TBAs than rats in the DJB-RC group at 12 weeks after surgery.7. Four weeks postoperatively, levels of fasting serum LPS in the sham group were higher than the other three groups.12 weeks postoperatively, the sham and the DJB-RC group exhibited similar levels of LPS, but higher levels than the control group and the DJB-RM group.8. The relative abundances of Firmicutes in control and DJB-RM group were higher than the sham and the DJB-RC group, and the relative abundances of Bacteroidetes and Escherichia coli in the control and the DJB-RM group were lower than the sham and the DJB-RC group.Conclusions1. DJB could induce remarkable remission of T2DM, and postoperative HFD could induce T2DM recurrence in a part of rats after DJB.2. Remarkable alterations of gut microbiota occurred in T2DM and T2DM remission and recurrence after DJB, which may play an important role in the above processes.3. TBAs and LPS contributed in the remission and recurrence of T2DM after DJB, and took part in the role of gut microbiota in regulating host's glycometabolism.4. The remission and recurrence of T2DM after DJB primarily due to the alterations in insulin sensitivity but not insulin secretion level. GLP-1 contributs in the remission of T2DM after DJB, but is not associated with the recurrence.Part ? The role and mechanism of oligofructose in T2DM control after sleeve gastrectomyBackgroundBariatric surgery has been considered the most effective treatment for type 2 diabetes mellitus (T2DM). Over the past decade, the total number of bariatric surgical procedures performed, especially sleeve gastrectomy (SG), has increased worldwide. SG is currently the most frequently used procedure in USA, Canada and Asia-Pacific region. Although bariatric surgery can induce rapid and prominent remission of T2DM, long-term remission rate usually decreases over time. SG is a novel bariatric surgical procedure characterized by low complication rate, fast operation, low technical requirements, and low number of associated postoperative nutritional problems; thus, the application of SG markedly increased. Many investigators have reported that SG and Roux-en-Y gastric bypass (RYGB) demonstrated comparable treatment efficacy for T2DM. However, the number of long-term randomized controlled investigation on the impact of SG coupled with RYGB, the gold standard procedure in treatment of T2DM, is surprisingly limited. Moreover, the long-term effect of SG on T2DM is questionable. SG is an independent predictor of relapse of T2DM within 48.7 months of follow-up. Reduction or delay of recurrence of T2DM after SG is a serious concern that clinicians must address. Several factors have been found to be closely related to T2DM recurrence, including preoperative body mass index (BMI), age, course and gravity of T2DM, percentage of excess body weight loss (%EBWL), weight regain, postoperative diet and lifestyle. Our previous studies have confirmed that high-fat diet (HFD) can induce deterioration of glucose tolerance after initial improvement in T2DM rats subjected to duodenal-jejunal bypass. In addition, high-calorie diet is apparently one of the primary factors for obesity and T2DM, and dietary control seems to be more important for SG among the operating methods of bariatric surgery.Prebiotics are non-digestible oligosaccharides, such as oligofructose, galactooligosaccharides, lactulose, and inulin. Prebiotics can promote body weight loss and improve glucose and lipid metabolism in rodents and humans. The mechanisms of these benefits possibly involve reduction in energy intake, regulation of gut microbiota, improved low-grade inflammation, and increased level of gut hormones, such as glucagon-like peptide-1 (GLP-1) and peptide YY. These findings prompted us to explore whether prebiotics can reduce or delay recurrence of T2DM after surgery.ObjectivesWe used the Wistar rats induced by HFD/Nicotinamide/low-dose streptozotocin (STZ) as the T2DM rat model, and performed SHAM and SG on the T2DM rats. After surgery, HFD were provided unceasingly.2 weeks after surgery, a part of T2DM rats undergoing SG were provided with a specific HFD supplemented with 10% oligofructose. The main objectives included:(1) to explore whether oligofructose can prevent the detrimental effect of HFD feeding after SG;(2) to investigate the possible mechanisms of the function of oligofructose in glucolipid metabolism.MethodsThe Wistar rats received 4-wk HFD feeding, which contains 40% fat as calories, to induce insulin resistance. All rats received a single intraperitoneal injection with nicotinamide (170 mg/kg) and streptozotocin (65 mg/kg) in sequence, so that they could reach a T2DM state. SHAM and SG were performed on the T2DM rats. All rats were continuously provided with HFD post-operation.2 weeks after surgery, rats undergoing SG were divided into SG group and SG-OF group. The rats in SG-OF group were provided with a specific HFD supplemented with 10% oligofructose. At baseline,2weeks,12weeks and 24 weeks after surgery, body weight, calorie intake, glucolipid metabolism profile, serum insulin, glucagon-like peptide 1 (GLP-1), total bile acids(TBA) and lipopolysaccharide (LPS) were measured. At 24 weeks after surgery, all rats were euthanized and colonic contents were collected for 16S rDNA sequence analysis.Results1. At baseline, all parameters of the three group has no difference.2. At each postoperative time point, Areas under the curves of OGTT (AUCOGTT) in both SG and SG-OF groups was lower than that in SHAM group. At 24 weeks after surgery, AUCOGTT was significantly lower in the rats of SG-OF group than in the rats of SG group.3. At 2 and 12 weeks after surgery, HOMA-IR was significantly lower in rats that had undergone SG than in rats of SHAM group. At 24 weeks after surgery, HOMA-IR in SHAM and SG groups was comparable and higher than that in SG-OF group.4. Secretion of serum insulin during OGTT was higher in SG and SG-OF groups than in SHAM group at all postoperative time point. A lower secretion of serum insulin in SG group than in SG-OF group was observed from 12 weeks after surgery.5. Triglyceride was significantly higher in SG and SG-OF groups than in SHAM group after surgery. Since 12 weeks after surgery, SG-OF group showed a lower triglyceride than SG group. The cholesterol level showed a similar tendency to triglyceride, except that SG-OF group showed lower serum cholesterol than SG group only from 24 weeks after surgery, at which time SG group was comparable with SHAM group.6. Rats in SG and SG-OF group showed lower body weight and calorie intake than the rats in SHAM group at 2,12, and 24 weeks after surgery. The body weight and calorie intake in SG-OF group were lower than those in SG group from 12 weeks after surgery.7. The SG and SG-OF groups showed higher GLP-1 and TBA level than SHAM group at any postoperative time points. Compared with SG group, SG-OF group displayed higher GLP-1 level from 12 weeks after surgery, but there is no difference in TBA level between SG group and SG-OF group.8. The SG and SG-OF groups showed lower LPS than SHAM group at any postoperative time points, and LPS was lower in SG-OF group than in SG group from 12 weeks after surgery.9. Bacteroidetes were the predominant gut microbes in SHAM group, whereas Firmicuteswas dominant in SG and SG-OF groups. The relative abundance of Bifidobacterium, Lactobacillus and Akkermansiamuciniphila was significantly higher in SG-OF group than in SHAM and SG groups. The relative abundance of Lactobacillus was significantly higher in SG group than in SHAM group.Gonelusions1.SG can remit T2DM promptly, and oral oligofructose can prevent the detrimental effect in glucolipid metabolism of HFD feeding after SG.2. The protective effects of oligofructosemaybe due to the enhanced insulin and GLP-1 secretion, reduced body weight, calorie intake, low-grade inflammation, and regulation of gut microbiota.3. The enhanced serum TBA contributes to the remission of T2DM after SG, but the protective effect of oligofructose is independent of it.Part III The role of sleeve gastrectomy with jejuno-ileal or jejuno-jejunal loop in glucolipid metabolism improvement of diabetic ratsBackgroundRecently, international diabetes organizations made a joint statement in Diabetes Care which indicated that not only type 2 diabetes mellitus (T2DM) patients with class ? [body mass index(BMI) ?40 kg/m2]and class ? (BMI 35.0-39.9 kg/m2) obesity, but also those with class ? obesity (BMI 30.0-34.9 kg/m2) with inadequately control after optimal treatment with oral or injectable medication should consider bariatric surgery. Currently, the most commonly performed procedure in patients of the United States, Canada and the Asia/Pacific region is sleeve gastrectomy(SG). However, as a novel metabolic surgery, the long-term anti-T2DM effects of SG is still questionable. In addition, SG has been reported as an independent predictor for the recurrence of T2DM.Surgeons have designed many additional surgical procedures for SG to improve excessive body weight loss and diabetes control, such as SG with duodenojejunal bypass, loop gastroileostomy, jejuno-ileal bypass, and duodeno-ileal bypass. Although these surgical procedures showed some improvement with regard to excessive body weight loss and T2DM control, they were performed with resection of different segments of small intestine or different intestinal loops. Because of clinical study limitations, most of these procedures stayed in clinical observations and are not in randomized controlled trials (RCTs). Some of them even did not establish the SG as contrast. The experimental designs were even not consummate.ObjectivesIn this study, T2DM rats, which were induced by high-fat diet (HFD), nicotinamide and low-dose streptozotocin (STZ), underwent sham operations, SG, SG with jejuno-ileal loop (SG-JI) and SG with jejuno-jejunal loop (SG-JJ) followed by postoperative HFD. The main objectives of this RCT included:(1) to explore the different effect in glucolipid metabolism improvement among SG, SG-JJ and SG-JI; (2) to investigate the mechanisms of the three procedures in glucolipid metabolism improvement.MethodsDiabetic rats induced by HFD, nicotinamide and low-dose STZ were randomly divided into SHAM, SG, SG-JJ and SG-JI groups, and SHAM operation, SG, SG-JJ and SG-JI were performed on diabetic rats. After surgery, we still provided HFD to the rats. At the time points of baseline and 2,12 and 24 weeks postoperatively, we determined and compared several variables, including the area under the curve for the results of oral glucose tolerance test (AUCOGTT),serum levels of triglyceride, cholesterol and ghrelin in fasting state, homeostasis model assessment of insulin resistance (HOMA-IR), body weight, calorie intake, glucagon-like peptide (GLP)-1 and insulin secretions.Results1.At any postoperative time point, AUCOGTT and HOMA-IR were lower in SG, SG-JJ and SG-JI groups than in SHAM group, and no difference was observed between SG-JJ group and SG-JI group. At 24 weeks after surgery, the AUCOGTT and HOMA-IR in the SG-JJ and SG-JI groups was lower than those in the SG group.2. As the profiles to evaluate lipid metabolism, triglyceride and cholesterol showed a similar trend as AUCOGTT and HOMA-IR except that triglyceride and cholesterol in SG-JI is lower than that in SG-JJ at 24 weeks after surgery.3. At every postoperative time point, compared with the SHAM group, the rats that underwent SG, SG-JJ and SG-JI had lower body weight and calorie intake. Since 12 weeks after surgery, compared with the SG-JJ group and SG-JI group, SG group showed higher body weight, and SG-JI group showed lower body weight than SG-JJ group. No differences, however, were seen for calorie intake among the SG, SG-JJ and SG-JI groups.4. No statistical difference was seen for insulin and GLP-1 secretion at baseline. Secretion of insulin and GLP-1 in the SG, SG-JJ and SG-JI groups was higher than that in the SHAM group at any time postoperatively. At 24 weeks after surgery, SG-JJ and SG-JI group demonstrated comparable insulin and GLP-1 secretion, and they were higher than SG group. From 12 weeks after surgery, rats in the SG group secreted less GLP-1 than those in the SG-JJ and SG-JI groups. Rats in the SG-JJ group had lower GLP-1 secretion than those in the SG-JI group at 24 weeks postoperatively.5. No significant differences were seen for fasting serum ghrelin at baseline in any of the rats or for any other time points for the SG, SG-JJ and SG-JI groups. The SG, SG-JJ and SG-JI groups showed lower fasting serum ghrelin than those in the SHAM group at all postoperative times.Conelusions1. SG, SG-JJ and SG-JI can lose body weight and improve glucolipid metabolism effectively, and these advantages of SG-JJ and SG-JI are more remarkable than SG.2. Compare with SG-JJ, the improvement in lipid metabolism after SG-JI is more apparent.3. The enhanced insulin and GLP-1 secretion play an important roles in loss of body weight and improvement of glucolipid metabolism after SG, SG-JJ and SG-JI. Compared with SG, SG-JJ and SG-JI demonstrated higher insulin and GLP-1 secretion, which may be associated with the advantage in improving glucolipid metabolism of SG-JJ and SG-JI.4. Ghrelin contributes to diabetes control after SG, SG-JJ and SG-JI, but it did not enhance diabetes control of SG after addition of jejuno-jejunal or jejuno-ileal loop. |
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