The twin pandemics of obesity and type 2 diabetes mellitus
(T2DM) have markedly developed in the last decade, and are ranked among the most devastating health crises worldwide.1-4
Currently, bariatric surgery is indicated in patients refractory to nonsurgical therapy with a body mass index (BMI) ≥35 kg/m2
and serious obesity-related comorbidities, especially T2DM.5
The most frequently performed bariatric operation, Roux-en-Y gastric bypass, causes profound, durable weight loss and markedly improves glucose homeostasis.6-9
However, the mechanism mediating such anti-diabetic effects remains poorly understood. Previous studies have indicated that purely restrictive procedures, such as adjustable gastric banding, have also induced diabetes resolution,7,10
and that a greater percentage of excess weight loss (%EWL) is associated with a higher remission rate of T2DM.11
These findings indicate that surgically induced weight loss plays an important role in diabetes remission after bariatric surgery
. On the other hand, diabetes remission is frequently observed within days to weeks after gastric bypass, long before substantial weight loss has been achieved.6,8
Additionally, remission with gastric bypass is greater than with equivalent weight loss from purely restrictive procedures or nonsurgical interventions.12-14
Therefore, the remarkable T2DM remission after bariatric surgery results not only from weight loss but also from weight-independent anti-diabetic mechanisms
Although mounting evidence indicates that bariatric surgery results in significant weight loss and resolution of T2DM, a number of patients with initial remission of T2DM after gastric bypass surgery have experienced diabetes recurrence. Buchwald et al7 have reported that the percentage of resolution of diabetes in the first 2 years after surgery is 82%; however, the percentage more than 2 years after surgery has decreased to 62%. This indicates that approximately 24.5% of patients have experienced recurrence of diabetes after initial resolution. Recurrence of diabetes has been reported in over 40% of patients within 5 years by Chikunguwo et al.15 Currently, very limited studies are available on the recurrence of T2DM and factors that influence it. Chikunguwo et al have also reported that the durability of T2DM remission is correlated with sustained weight loss and recurrence occurs with weight regain.15 Therefore, weight loss plays an important role in the remission of diabetes after bariatric surgery and recurrence of diabetes. Other factors, such as sex, age, preoperative BMI and T2DM severity, have also been reported to be associated with recurrence of T2DM.11,15-17
Given that both weight loss and as yet undefined weight-independent anti-diabetic mechanisms are responsible for the resolution of T2DM after bariatric bypass, factors other than weight loss that are involved in the mechanisms may also affect the recurrence of T2DM. One potential theory, known as the hindgut hypothesis, involves the expedited delivery of ingested nutrients to the hindgut due to an intestinal bypass. This physiological alteration accentuates secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), thereby improving glucose homeostasis.18,19 The foregut hypothesis is another well-known theory proposed by Rubino et al, based on studies of duodenal-jejunal bypass (DJB).20 This theory posits that exclusion of the foregut (duodenum and proximal jejunum) from contact with ingested nutrients exerts direct anti-diabetic effects, probably via one or more unidentified duodenal factors or processes that influence glucose homeostasis. Interestingly, DJB surgery has also been reported to result in increased GLP-1 secretion.19,21,22 GLP-1 and PYY are involved in the weight-independent mechanism of diabetes control. However, it is unknown whether these gut hormones are involved in diabetes recurrence and further research is required.
The purpose of this study was to induce a reversal in improvement of diabetes in T2DM rats,
which experienced initial improvement after surgery, and to identify the effects of weight changes, and GLP-1 and PYY levels. A high-fat diet
(HFD) was applied to induce the reversal in improvement of diabetes in this study. Two animal models of T2DM were used in the study, both of which have been reported in previous studies of bariatric surgery. One model was the Goto-Kakizaki (GK) rat, which is the most widely used non-obese T2DM rat model, and this rat is commonly fed with a 5% fat rat chow diet.19,20,23,24
The other model was a moderately-obese T2DM rat model induced by combination of an HFD (commonly 40% of calories as fat) and low-dose streptozotocin (STZ).25,26
These rats underwent DJB surgery, which is a well studied and generally accepted experimental procedure and has also been applied in patients for T2DM.27,28
Animals and diet
Male 9-week-old GK rats were purchased from the National Rodent Laboratory Animal Resources (Shanghai, China) and fed with a 5% fat rat chow diet (14% of
calories as fat) before surgery. Male Sprague-Dawley rats
(160–180 g) were purchased from the Laboratory Animal Center of Shandong University of Traditional Chinese Medicine (Jinan, China), and fed with an HFD (40% of calories as fat)
for a period of 4 weeks, and then injected with STZ (35 mg/kg intraperitoneally). One week later, the rats were deprived of food overnight and then received administration of 1 g/kg glucose by oral gavage, and blood glucose was measured 30 minutes later. Rats with a blood glucose of ≥16.0 mmol/L were considered diabetic and selected for further studies.
All rats were housed in individual cages under constant ambient temperature and humidity in a 12-hour light/dark cycle, and had free access to tap water and food. The study was approved by the Animal Care and Utilization Committee of Shandong University.
After the rats were acclimated for 10 days, food intake, weight and oral glucose tolerance were measured. The GK rats were then randomly grouped (n=20) and underwent one of the following: DJB, sham-DJB or untreated (controls). The HFD-fed and low-dose STZ-treated (HS) rats were grouped the same as the GK rats.
After surgery, the GK rats in each group were randomly assigned to a low-fat diet (LFD) and HFD group (n=10 in each group), and fed with the same diet (14% of calories as fat) as preoperatively and a diet with 40% of calories as fat, respectively. The operated HS rats were assigned to a HFD group (n=10) fed with the same diet as preoperatively (40% of calories as fat) and LFD group (n=10) fed with a diet with 14% of calories as fat.
Weight and food intake following surgeries were monitored and recorded. The oral glucose tolerance test (OGTT) was performed at post-surgery weeks 2, 4, 8, 12 and 16
. Areas under the curves for OGTT (AUCOGTT
) were calculated to evaluate the diabetes status. A higher AUCOGTT
than at the last time of examination was considered as re-impairment of glucose tolerance, indicating reversal of an improvement in diabetes. The insulin tolerance test (ITT) was performed and areas under the curves for ITT (AUCITT
) were calculated to evaluate insulin sensitivity at post-surgery weeks 2
and 16. Glucose-stimulated insulin, GLP-1 and PYY secretion
were measured at postoperative weeks 2 and 16.
Rats undergoing operations were restricted to a non-residue diet for 36 hours prior to surgery, and were then fasted overnight and anesthetized with 10% chloral hydrate.
DJB surgery was performed as described by Rubino et al.20 The duodenum was transected at 0.5 cm from the pylorus and the distal limb was closed using 7-0 silk suture (Ningbo Resto Medical Instruments, Zhejiang, China). The distal jejunum was transected at 10 cm from the ligament of Treitz and the distal limb was connected to the duodenal end, and then the proximal limb was reinserted 10 cm distally.
For the sham-DJB, the same transections of the intestine were performed, but no removal was made, such that all transections were immediately followed by anastomosis in the original position. The operative time was prolonged to produce a similar degree of anesthetic operative stresses as the rats receiving DJB. During the procedures, the transected and bypassed segment of small intestine remained innervated and with its vasculature intact.
Access to water was given at 2 hours after surgery. The weight-limited non-residue diet was initiated at 24 hours after surgery and maintained for 3 days, then followed by 10 days of weight-limited low-residue diet or normal diet. Food intake was completely unrestricted at 14 days after surgery. Rats in the control group were given the same perioperative diet as in DJB group.
Weight and food intake were measured once a week for the first 2 weeks after the intervention, and then twice a week until the end of the study.
For the OGTT, rats were deprived of food overnight and then received administration of 1 g/kg glucose by oral gavage. Blood was obtained from the tail in conscious rats before (baseline) and at 10, 30, 60, 120, and 180 minutes after administration, and glucose levels were measured using a glucometer (Lifescan One Touch® Ultra; Johnson & Johnson, Milpitas, CA, USA).
For the ITT, a dose of 0.5 IU/kg human insulin was injected intraperitoneally in conscious, fasting rats. Blood glucose levels were measured before and at 30, 60, 120, and 180 minutes after insulin injection.
For insulin, GLP-1 and PYY measurements, blood was sampled from the tail of conscious, fasted rats at baseline and 15, 30, 60, and 120 minutes after glucose gavage (1 g/kg) and collected in serum tubes containing a dipeptidyl peptidase IV inhibitor. After centrifugation at 3000 r/min for 15 minutes, serum was immediately separated and stored at –80°C until analyzed. Rat enzyme-linked immunosorbent assay kits (ELISA; R&D systems, Minneapolis, MN, USA) were used for measurement of the hormones with the serum collected at the indicated time intervals to evaluate responses to oral glucose load.
Data are expressed as mean ± standard deviation (SD). AUCOGTT and AUCITT were calculated by trapezoidal integration. Data that were not normally distributed or did not satisfy homogeneity of variance were logarithmically transformed prior to statistical analysis. All statistical analyses were performed with SPSS 15.0 (Chicago, IL, USA). The AUCOGTT data at baseline and four time points postoperatively were compared by two-factor (surgery×time) repeated measures (RM) analysis of variance (ANOVA). AUCOGTT and AUCITT data for the HFD and LFD groups at the same time points were compared by one-way ANOVA. The insulin, GLP-1 and PYY data were also compared by 2-factor (surgery×time) RM ANOVA to estimate the difference between groups. Differences were considered significant at P <0.05.
General effects of treatments and diet plan
There were no significant differences among the groups of GK or HS rats in body weight and oral glucose tolerance before treatment. Changes in food intake and body weight after intervention are shown in Figures 1 and 2, respectively. We observed that all rats lost weight due to the effect of surgical stress and food restriction. Food intake gradually recovered after surgery and body weight increased over time. There was no significant difference in food intake or body weight among either GK rats or HS rats fed with the same diet (all P >0.05), indicating that DJB surgery had no effect on intake or weight loss. HFD-fed HS rats gained no more body weight than LFD-fed rats at post-operative weeks 2, 4 and 8 (all P >0.05), but gained more at post-operative weeks 12 and 16 (both P <0.05). Furthermore, total body weight was not significantly different between rats fed with an HFD and LFD (P >0.05, two-factor RM ANOVA). There was no significant difference in body weight between HFD- and LFD-fed GK rats (all P >0.05) (Figure 2A).
DJB surgery improves glucose tolerance in both GK and HS rats fed with an LFD
All GK and HS rats fed with an LFD exhibited a significant improvement in glucose tolerance after DJB surgery, as shown by lower AUCOGTT
curves (both P
<0.001, two-factor RM ANOVA; Figure 3) and lower AUCOGTT values
than control rats at postoperative weeks 2, 4, 8, 12 and 16 (all P
<0.05, one-way ANOVA; Figure 3). Glucose tolerance in sham-operated LFD-fed GK rats and HS rats was not significantly different compared with that in untreated rats, indicating that surgical stress was not responsible for the improvement in glucose tolerance.
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Figure 1. Food intake. Food intake in GK rats (1A) and HS rats (1B). *P >0.05 by two-factor (surgery×time) RM ANOVA for the difference between groups.
Figure 2. Body weight. Body weight in GK rats (2A) and HS rats (2B). *P <0.05 by one-way ANOVA for DJB-HFD vs. DJB-LFD. †P >0.05 by two-factor (surgery×time) RM ANOVA for the difference in total body weight between HFD- and LFD-fed rats.
Figure 3. Oral glucose tolerance test. AUCOGTT curves in GK rats (3A) and HS rats (3B). *P <0.001 by two-factor (surgery×time) RM ANOVA for the difference in total AUCOGTT between the groups (DJB-HFD vs. control-HFD; DJB-LFD vs. control-LFD; and DJB-HFD vs. DJB-LFD). †P <0.05 by two-factor RM ANOVA for the effect of time after surgery (DJB-HFD vs. control-HFD; and DJB-LFD vs. control-LFD). ‡P <0.001 by two-factor RM ANOVA for the effect of surgery×time interaction (DJB-HFD vs. control-HFD; and DJB-LFD vs. control-LFD). §P <0.001 by two-factor RM ANOVA for the effect of surgery×time interaction (DJB-LFD vs. control-LFD); P=0.083 for DJB-HFD vs. control-HFD.
In addition to the effect of surgery, there was a significant effect of time after surgery and surgery×time interaction on the improvement of glucose tolerance in DJB group (both P <0.05, two-factor RM ANOVA). The significance observed for time after surgery indicated that the glucose tolerance further improved over time. The significant surgery×time interaction indicated that the degrees of improvement in glucose tolerance differed over time.
HFD reverses the improvement in glucose tolerance induced by DJB surgery and results in less improvement than an LFD
Both GK and HS rats fed with an HFD showed a significant improvement in glucose tolerance after DJB surgery at postoperative week 2 than control rats (P <0.05, one-way ANOVA); however, this improvement did not last long. As expected, the improvement in glucose tolerance was reversed, and some rats exhibited poorer glucose tolerance after initial improvement. The number of rats that experienced reversal of improvement in glucose tolerance is shown in Table 1. The DJB-operated and HFD-fed GK rats achieved the best improved glucose tolerance at postoperative week 2, as shown by an associated nadir point in the AUCOGTT excursion of this group (Figure 3A). However, the improved glucose tolerance was impaired starting from postoperative week 8 and continued to be impaired at the later time points (all P <0.05, one-way ANOVA). Similarly, AUCOGTT values of DJB-operated and HFD-fed HS rats reached a nadir at postoperative week 4 (Figure 3B). Additionally, improved glucose tolerance was impaired starting at postoperative week 12.
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Table 1. The number of HFD-fed and DJB-operated rats that experienced reversal of improvement in glucose tolerance (a) and that survived (b)
Although the improvement in glucose tolerance induced by DJB surgery was reversed in HFD-fed rats, both GK and HS rats in DJB group still showed better glucose tolerance than that in the control groups, as shown by lower AUCOGTT curves (both P <0.001, two-factor RM ANOVA) and lower AUCOGTT values at postoperative weeks 2, 4, 8, 12 and 16 (all P <0.05, one-way ANOVA; Figure 3). Similar to LFD-fed rats, there was a significant effect of DJB surgery, time after surgery and surgery×time interaction on improvement in glucose tolerance in HS rats (both P <0.001, two-factor RM ANOVA). In GK rats, the time after surgery significantly affected the improvement in glucose tolerance (P <0.001), but the surgery×time interaction was not significant (P=0.083).
Compared with the LFD-fed rats, the HFD-fed rats had less improvement in glucose tolerance after DJB surgery, as shown by higher AUCOGTT values (both P <0.005, two-factor RM ANOVA; Figure 3).
An HFD impairs increased insulin sensitivity induced by DJB surgery and results in less improvement in insulin sensitivity than an LFD
At postoperative weeks 2 and 16, all DJB-operated GK and HS rats fed with either an HFD or LFD demonstrated improved insulin tolerance compared with that in control rats, as shown by lower AUCITT values (all P <0.05, one-way ANOVA; Figure 4). At postoperative week 16, the LFD-fed and DJB-operated GK and HS rats still had improved insulin tolerance, and the insulin tolerance was better than at postoperative week 2 (both P <0.05, one-way ANOVA). However, the improvement in insulin tolerance was not continuous in HFD-fed rats, and the increased insulin sensitivity was impaired and poorer than at postoperative week-2 (both P <0.05, one-way ANOVA), as shown by higher AUCITT values (Figure 4). These results suggested that an HFD impaired the increased insulin sensitivity, which was induced by DJB surgery, and resulted in less improvement in insulin sensitivity.
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Figure 4. Insulin tolerance test. AUCITT for GK rats (A) and HS rats (B). *P <0.05 by post-hoc tests after one-way ANOVA for DJB-HFD vs. control-HFD. †P <0.05 for DJB-LFD vs. control-LFD. ‡P <0.05 for the difference in AUCITT at post-operative week 16 vs. week 2 in the DJB-HFD groups.
An HFD results in failure in enhancement of glucose-stimulated insulin secretion
At postoperative week 2, glucose-stimulated insulin
secretion was not significantly different between the DJB and control groups in both GK and HS rats fed with either an HFD or LFD (all P
>0.05, two-factor RM ANOVA; Figure 5A, 5C), suggesting that beta-cell function was not enhanced in a short time after surgery. Sixteen weeks after DJB surgery, insulin levels in response to oral glucose gavage increased in both GK and HS rats fed with an LFD (both P
<0.05, two-factor RM ANOVA), but not in rats fed with an HFD (Figure 5B, 5D), suggesting that an HFD reduced the effect of DJB surgery on enhancing beta-cell function.
Glucose-stimulated GLP-1 and PYY secretion after DJB surgery
As shown in Figures 6 and 7, oral glucose gavage resulted in higher GLP-1 and PYY levels in DJB-operated rats than those in control rats, fed with either HFD or LFD at postoperative weeks 2 and 16 (all P <0.05, two-factor RM ANOVA). GLP-1 and PYY levels in DJB groups at postoperative week 16 were higher than those at postoperative week 2 (both P <0.05, two-factor RM ANOVA). Furthermore, circulating GLP-1 and PYY levels were not significantly different between HFD- or LFD-fed rats after DJB surgery (both P >0.05, two-factor RM ANOVA).
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Figure 5. Glucose stimulated insulin secretion. Serum insulin levels after an oral glucose gavage (1 g/kg) at postoperative week 2 (5A) and week 24 (5B) in GK rats, and at postoperative week 2 (5C) and week 24 (5D) in HS rats. *P >0.05 by two-factor (surgery×time) RM ANOVA for the difference between either HFD-fed or LFD-fed groups. †P <0.001 for the difference between LFD-fed groups. ‡P >0.05 for the difference between HFD-fed groups.
Glucose stimulated GLP-1 secretion. Serum GLP-1 levels
after an oral glucose gavage (1 g/kg) at postoperative week 2 (6A
) and week 24 (6B
) in GK rats, and at postoperative week 2 (6C
) and week 24 (6D
) in HS rats. *P
<0.001 by two-factor (surgery×time) RM ANOVA for the difference between either HFD-fed or LFD-fed groups.
Figure 7. Glucose stimulated PYY secretion. Serum PYY levels after an oral glucose gavage (1 g/kg) at postoperative week 2 (7A) and week 24 (7B) in GK rats, and at postoperative week 2 (7C) and week 24 (7D) in HS rats. *P <0.001 by two-factor (surgery×time) RM ANOVA for the difference between either HFD-fed or LFD-fed groups.
In the present study, we attempted to induce reversal of improvement in diabetes after DJB surgery, using a high caloric diet in two T2DM rat models, and we investigated the effects of weight changes, and levels of gut hormones GLP-1 and PYY on this reversal. To the best of our knowledge, this study represents the first animal model-based study on T2DM recurrence. Given that a great number of patients undergoing bariatric surgery experienced diabetes recurrence after initial improvement, it is important to investigate the factors involved in this recurrence before widespread acceptance of bariatric surgery as a definitive treatment for T2DM. As expected, DJB surgery resulted in a rapid and significant improvement in glucose tolerance compared with controls. In contrast with the continuous improvement in LFD-fed and DJB-operated rats, glucose tolerance was re-impaired after initial improvement in part of HFD-fed and DJB-operated rats. This observation indicates that the high-caloric diet is an important cause for the reversal of improvement in diabetes after surgery, which is consistent with previous reports.29
It has been acknowledged that the rate of T2DM remission is closely related to the %EWL achieved after bariatric surgery, regardless of whether gastric bypass or adjustable gastric banding is used.7,8,10
Several studies have concluded that a lower weight loss and greater weight regain after bariatric surgery are associated with a higher incidence of T2DM
recurrence in patients with initial resolution or improvement.11,15,16
These reports indicate that T2DM recurrence is strongly associated with changes in body weight. In the present study, all DJB-operated rats experienced a continuous increase in body weight after the perioperative period. However, only HFD-fed rats experienced a reversal of improvement in diabetes. Furthermore, body weight was not significantly different between the rats that experienced reversal of improvement in diabetes and those whose diabetes remained improved, especially when the reversal occurred. These results indicated that the changes in body weight were not responsible for the reversal of improvement in diabetes in this study.
We observed an increases in glucose-stimulated GLP-1 and PYY secretion accompanied by a rapid and marked improvement in glucose tolerance in DJB-operated rats, which confirmed that elevated GLP-1 and PYY secretion were strongly related to T2DM resolution after surgery. However, circulating GLP-1 and PYY levels were not significantly different between rats with reversal of improvement in diabetes and those with continuous improvement. Additionally, in those rats that experienced a reversal of improvement in diabetes, GLP-1 and PYY levels were much higher at post-operative week 16 when glucose tolerance was re-impaired than those at post-operative week 2 when it was initially improved. Taken together, these results indicated that circulating GLP-1 and PYY levels were not associated with the reversal of improvement in diabetes.
Previous studies using both GK and HS rats have reported the anti-diabetic effect of bariatric surgery.19,23,24,26
Using these T2DM rat models, the present study successfully induced a reversal of improvement in diabetes with HFD. Compared with the continuous improvement of diabetes that has been reported in previous studies, our model of recurrence of diabetes in rats with initial improvement after surgery is a much better model for the investigation of the mechanism of T2DM resolution after bariatric surgery. As discussed above, DJB surgery had little effect on reducing body weight. In addition, the changes in body weight were not responsible for the reversal of improvement in diabetes. Therefore, we conclude that changes in body weight are not essential for the improvement of
diabetes after gastrointestinal bypass procedures, such as DJB. In the current study, although the rapid improvement of diabetes was reversed by HFD, DJB surgery still resulted in a better glucose tolerance in HFD-fed rats compared with control rats. Combined with the results of continuous improvement in glucose tolerance in DJB-operated and LFD-fed rats, these observations provide further evidence for the foregut hypothesis that exclusion of the foregut from contact with ingested nutrients exerts direct anti-diabetic effects, independent of weight loss. With regard to the difference in glucose tolerance between DJB-operated and control rats, our finding of a significant effect of time after surgery indicated that glucose tolerance increasingly improved over time. Additionally, the significant surgery×time interaction indicated that the degrees of improvement induced at different periods of time after surgery differed from each other.
Based on the synchronous improvement and re-impairment of both glucose tolerance and insulin sensitivity, we concluded that the changes in insulin sensitivity played a key role for the early improvement and subsequent re-impairment of glucose tolerance after surgery. In conjunction with the early increased insulin sensitivity in DJB groups, we observed enhancement of glucose-stimulated GLP-1 and PYY secretion, both of which have been previously demonstrated to be associated with the improvement of insulin sensitivity.30-32 However, in HFD-fed and DJB-operated rats, although the elevation of GLP-1 and PYY secretion remained, the increased caloric intake reduced their beneficial effects and resulted in decreased insulin sensitivity, thus leading to re-impairment of glucose tolerance and reversal of the improvement. Up-regulation in key insulin signaling pathway has been reported to be associated with improvement in insulin resistance after gastric bypass.33,34 The expression of insulin receptor (IR), its substrates IRS1 and IRS2, and their phosphorylated state (p-IR and p-IRS1/2) in skeletal muscle and liver increased after gastric bypass in rats. We speculate that elevation of GLP-1 and PYY secretion after bariatric surgery might result in up-regulation in insulin signaling pathway and post-operative high caloric diet down-regulated the pathway, which lead to the initial improvement in diabetes and later reversal. Further investigation is required to confirm the speculation.
We observed that glucose-stimulated insulin secretion was increased at postoperative week 16 in LFD-fed and DJB-operated rats than in LFD-fed control rats, possibly resulting from elevated GLP-1 and PYY secretion.21,35,36
Therefore, the long-term improvement of glucose tolerance resulted from the increased insulin sensitivity and enhanced beta-cell function, at least in LFD-fed and DJB-operated rats. It is uncertain whether beta-cell function was enhanced in HFD-fed and DJB-operated rats because we only examined glucose-stimulated insulin secretion at post-operative weeks 2 and 16. Therefore, further investigation is required to determine whether changes in beta-cell function were involved in the reversal of diabetes improvement.
Our study has several limitations. Only part of the DJB-operated and HFD-fed rats experienced the reversal of improvement in diabetes, and therefore, the small sample size might have increased the likelihood of beta error. Furthermore, we did not examine the lipid profile (triglycerides, cholesterol and free fatty acids), and therefore, cannot further discuss the effect of a high caloric diet on the reversal of improvement in diabetes.
This study demonstrates that an HFD reverses the improvement in diabetes induced by DJB surgery. The changes in insulin sensitivity are likely responsible for the early improvement and subsequent re-impairment of glucose tolerance after surgery. Changes in body weight and GLP-1 and PYY levels are not associated with the reversal of T2DM improvement. In addition to the effect of surgery, the time after surgery was also involved in the weight-independent improvement of T2DM after DJB surgery.
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