Duodenal-jejunal Bypass Research Articles

The effect of a duodenal-jejunal bypass liner on lipid profile and blood concentrations of long chain polyunsaturated fatty acids

Duodenal-jejunal bypass liners (DJBLs) prevent absorption in the proximal small intestine, the site of fatty acid absorption. We sought to investigate the effects of a DJBL on blood concentrations of essential fatty acids (EFAs) and bioactive polyunsaturated fatty acids (PUFAs). Sub-study of a multicentre, randomised, controlled trial with two treatment groups. Patients aged 18-65 years with type-2 diabetes mellitus and body mass index 30-50kg/m2 were randomised to receive a DJBL for 12 months or best medical therapy, diet and exercise. Whole plasma PUFA concentrations were determined at baseline, 10 days, 6 and 11.5 months; data were available for n=70 patients per group. Weight loss was significantly greater in the DJBL group compared to controls after 11.5 months: total body weight loss 11.3±5.3% versus 6.0±5.7% (mean difference [95% CI]=5.27% [3.75, 6.80], p<0.001). Absolute concentrations of both EFAs, linoleic acid and α-linolenic acid, and their bioactive derivatives, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid, were significantly lower in the DJBL group than in the control group at 6 and 11.5 months follow-up. Total serum cholesterol, LDL-cholesterol and HDL-cholesterol were also significantly lower in the DJBL group. One year of DJBL therapy is associated with superior weight loss and greater reductions in total serum cholesterol and LDL-cholesterol, but also depletion of EFAs and their longer chain derivatives. DJBL therapy may need to be offset by maintaining an adequate dietary intake of PUFAs or by supplementation. ClinicalTrials.gov Identifier NCT02459561.

Laparotomy for duodenal obstruction, caused by a renal haematoma after extracorporeal shockwave lithotripsy

Extracorporeal shockwave lithotripsy is a widely used, acceptable and common first line treatment for non-conservatively managed renal and ureteric stone disease. Although considered a relatively safe non invasive treatment for renal and ureteric stones, can carry with it significant associated morbiditiy especially in high risk patients, such as those who are anticoagulated. Renal haematomas are not an uncommon finding after extracorporeal shockwave lithotripsy, however, fewer than 1% of patients presenting with a symptomatic renal haematoma require intervention in the form of urgent embolisation under interventional radiology, or emergency nephrectomy. Rare cases of splenic and hepatic haematomas have been reported and rarer still cases of gastro-intestinal perforation following extracorporeal shockwave lithotripsy. We report a case with a significant renal haematoma needing emergency embolisation of the renal artery, and subsequent development of duodenal obstruction from direct haematoma compression requiring a laparotomy and intended duodenal jejunal bypass. Level of evidence: 5

A Preclinical Animal Study of Combined Intragastric Balloon and Duodenal-Jejunal Bypass Liner for Obesity and Metabolic Disease.

INTRODUCTION:Endoscopic bariatric and metabolic therapies can potentially reproduce similar gastric and small intestinal anatomic and physiologic manipulations as Roux-en-Y gastric bypass. This proof of concept animal study was aimed to assess the feasibility, safety, efficacy, and impact on gastrointestinal physiology of combined intragastric balloons (IGB) and duodenal-jejunal bypass liner (DJBL) for the treatment of obesity.METHODS:Five Ossabaw pigs were fed a high-calorie diet to develop obesity and were randomly assigned to receive IGB or DJBL in sequence. The weight gain rate was calculated. Fasting and postprandial blood samples were drawn before any intervention (serving as the baseline group) and 1 month after second device insertion (serving as the combination group) to measure gut neurohormonal changes and metabolic parameters.RESULTS:Four pigs successfully received a sequential device insertion. One pig developed duodenal sleeve prolapse that was spontaneously resolved. One pig was early terminated because of developing a central line infection. The rate of weight gain in the combination group (0.63 ± 1.3 kg/wk) was significantly lower than the baseline group (1.96 ± 2.17 kg/wk) and numerically lower than after insertion of the IGB (1.00 ± 1.40 kg/wk) or the DJBL (0.75 ± 2.27 kg/wk) alone. A trend of higher postprandial glucagon-like peptide-1 was observed in the combination group compared with the baseline group.DISCUSSION:A combination of IGB and DJBL is feasible and well tolerated. A strategy of sequential use of these devices might offer a synergistic approach that can enhance weight loss and metabolic outcomes.

Duodenal-jejunal bypass improves nonalcoholic fatty liver disease independently of weight loss in rodents with diet-induced obesity.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver-related mortality. NAFLD is associated with obesity, hepatic fat accumulation, and insulin resistance, all of which contribute to its pathophysiology. Weight-loss is the main therapy for NAFLD, and metabolic surgery is the most effective treatment for morbid obesity and its metabolic comorbidities. Although has been reported that Roux-en-Y gastric bypass can reverse NAFLD, it is unclear whether such effects result from reduced weight, from a lower calorie-intake, or from the direct influence of surgery on mechanisms contributing to NAFLD. We aimed to investigate whether gastrointestinal (GI) bypass surgery could induce direct effects on hepatic fat accumulation and insulin resistance, independently of weight reduction. Twenty Wistar rats on a high-fat diet underwent duodenal-jejunal-bypass (DJB) or sham operation and were pair fed (PF) for 15 wk after surgery to obtain a matched weight. Outcome measures include ectopic fat deposition, expression of genes and proteins involved in fat metabolism, insulin-signaling, and gluconeogenesis in liver and muscle. Despite no differences in body weight and calorie intake, DJB showed lower ectopic fat accumulation, improved peripheral and hepatic insulin sensitivity, and enhanced lipid droplet degradation. In both tissues, DJB increased insulin signaling, whereas hepatic key enzymes involved in gluconeogenesis and de novo lipogenesis were decreased. These findings suggest that DJB can reverse, independently of weight loss, ectopic fat deposition and insulin resistance, two features of NAFLD that share a mutual pathway, in which perilipin-2 (PLIN2) seems to be the main player, supporting further investigation into strategies that target the gut to treat metabolic liver diseases.NEW & NOTEWORTHY Our findings suggest that duodenal-jejunal bypass can reverse, independently of weight loss, ectopic fat deposition and insulin resistance, two features of nonalcoholic fatty liver disease that share a mutual pathway, in which perilipin-2 seems to be the main player. Our study supports further investigation into the role of proximal small intestine exclusion in the pathophysiology of nonalcoholic fatty liver disease to uncover less invasive treatments that mimic the effects of metabolic surgery and aims to prevent and treat metabolic liver disease.

Comparative efficacy of bariatric endoscopic procedures in the treatment of morbid obesity: a systematic review and network meta-analysis.

The comparative efficacy of bariatric endoscopic procedures has not been completely elucidated. We aimed to comprehensively evaluate the efficacy of bariatric endoscopic procedures. We searched for randomized controlled trials investigating the efficacy of bariatric endoscopic procedures, including the use of an intragastric balloon, duodenal-jejunal bypass liner (DJBL), aspiration therapy, primary obesity surgery endoluminal (POSE) procedure, and botulinum toxin injection to the stomach. Network meta-analyses were performed to determine the percentage of weight loss (%weight loss) and percentage of excess weight loss (%EWL). 22 studies with 2141 patients were included in the meta-analysis. Most endoscopic procedures showed superior efficacy in terms of %weight loss compared with the control (mean difference [MD] [95 % confidence interval (CI)]: aspiration therapy 10.4 % [7.0 % to 13.7 %]; fluid-filled balloon 5.3 % [3.4 % to 7.2 %]; POSE 4.9 % [1.7 % to 8.2 %]; and DJBL 4.5 % [1.4 % to 7.7 %]). In terms of %EWL, aspiration therapy, fluid-filled balloon, POSE, and DJBL were superior to the control (MD [95 %CI]: 27.3 % [15.3 % to 39.3 %]; 22.4 % [15.4 % to 29.4 %]; 15.3 % [2.5 % to 28.0 %]; and 13.0 % [4.9 % to 21.2], respectively). The gas-filled balloon and botulinum toxin injection did not show a significant difference in %weight loss or %EWL compared with the control. For the fluid-filled balloon, the %EWL and %weight loss tended to decrease after balloon removal at 6 months after the procedure. All bariatric endoscopic procedures, except for gas-filled balloon and botulinum toxin injection to the stomach, showed superior short-term efficacy in terms of %weight loss or %EWL compared with lifestyle modification.

Effect of bariatric surgery on circulating FGF-19: A systematic review and meta-analysis.

Fibroblast growth factor-19 (FGF-19) is a gut hormone which interacts with metabolism and is depleted in obesity. There is some indication that the hormone undergoes a resurgence following bariatric surgery (BS), an effect which may contribute to the beneficial outcomes of such procedures. This systematic review and meta-analysis aims to synthesize the available literature on FGF-19 levels before and after BS. MEDLINE, Scopus and Web of Science databases were searched, and the effect of different surgical procedures and degrees of body mass index (BMI) reduction on FGF-19 levels was assessed by DerSimonian and Laird random-effects model in meta-analysis and dose-response analyses. This meta-analysis, which included 474 patients from 25 arms undergoing one of five BS procedures, revealed a significant increase in the levels of circulating FGF-19 following all-type BS. Vertical sleeve gastrectomy, duodenal-jejunal bypass liner and Roux-en-Y gastric bypass all significantly increased circulating FGF-19 levels from baseline. However, gastric banding failed to achieve the same, and in fact, biliopancreatic diversion was associated with decreased circulating FGF-19. Finally, an inverse association between FGF-19 and the degree of BMI-reduction post-operatively was noted. FGF-19 is increased by BS and may represent a pharmaceutical target in efforts to reproduce the beneficial effects of BS in a medical setting.

Mechanism of Bile Acid Reabsorption in the Biliopancreatic Limb After Duodenal-Jejunal Bypass in Rats.

Bile acids (BAs) are important in the metabolic effects of bariatric surgery. Most BAs are reabsorbed in the ileum and recycled back to the liver. We have reported that this enterohepatic circulation was shortened by duodenal-jejunal bypass (DJB), and the biliopancreatic (BP)-limb plays an important role in reabsorption of BAs. However, the mechanism of BA reabsorption in BP-limb remains uncertain. We aimed to investigate the mechanisms of BA reabsorption after DJB, especially focusing on carrier-mediated transport of BAs and the impact of the presence or absence of lipids on BA reabsorption. Otsuka-Long-Evans-Tokushima fatty rats or Sprague-Dawley rats were assigned to a control group and DJB group. BA levels in the divided small intestine were quantified with liquid chromatography-mass spectrometry. Labeled BA was injected and perfused with BA transporter inhibitors or mixture of lipids in the isolated BP-limb, and bile was sampled and analyzed. Conjugated BA levels in the BP-limb were significantly higher than that of the control group. BA absorption tended to decrease by the apical sodium-dependent BA transporter inhibitor and was significantly decreased by the organic anion-transporting peptide (OATP) inhibitor. BA absorption tended to increase in the absence of lipid solutions compared with that in the presence of lipid solutions. We attributed the increased BA reabsorption in the BP-limb to lack of food in the BP-limb, which contains concentrated BAs and no lipids. OATP played an important role in BA reabsorption in the BP-limb. Therefore, BAs would be reabsorbed in different manners after DJB.

Induction of Meal-related Symptoms as a Novel Mechanism of Action of the Duodenal-Jejunal Bypass Sleeve.

Treatment with a duodenal-jejunal bypass sleeve (DJBS) induces clinically significant weight loss, but little is known about the mechanisms of action of this device. The aim of this study was to characterize the mechanisms of action of the DJBS and determine the durability of weight loss and metabolic improvements. We studied a cohort of 19 subjects with severe obesity and type 2 diabetes (baseline body mass index: 43.7±5.3 kg/m). Anthropometry, body composition, blood pressure, biochemical measures, and dietary intake were monitored for 48 weeks after DJBS implantation, and then for 1 year after device removal. Gastric emptying and triglyceride absorption were measured at baseline, 8 weeks after implant, and within 3 weeks of device explant. Visceral sensory function was assessed at baseline, 4 weeks after implant, and within 3 weeks after explant. Significant weight loss (P<0.01) occurred following DJBS placement, with a mean weight reduction of 17.0±6.5% at 48 weeks. The symptom burden following a standardized nutrient challenge was increased after DJBS implantation (P<0.05), returning to baseline after DJBS removal. Neither gastric emptying nor triglyceride absorption changed with the device in situ. A significant reduction in energy intake was observed [baseline: 7703±2978 kJ (1841±712 kcal), 24 weeks: 4824±2259 kJ (1153±540 kcal), and 48 weeks: 4474±1468 kJ (1069±351 kcal)]. After 1 year, anthropometry remained significantly improved, but there was no durable impact on metabolic outcomes. DJBS treatment resulted in substantial weight loss. Weight loss is related to reduced caloric intake, which seems linked to an augmented upper gastrointestinal symptom response, but not altered fat absorption.

Single-Anastomosis Duodenal Jejunal Bypass Improve Glucose Metabolism by Regulating Gut Microbiota and Short-Chain Fatty Acids in Goto-Kakisaki Rats.

In recent years, bariatric surgery has emerged as a promising treatment for type 2 diabetes. Bariatric surgery is known to cause alterations in the relative abundance and composition of gut microbiota, which may lead to alterations in the levels of Short-Chain Fatty Acids (SCFAs) that are produced during fermentation by gut microbes. However, little is known about the mechanism of improved glucose metabolism mediated by gut microbiota following bariatric surgery. The aim of our study was to explore whether changes in gut microbiota and in fecal SCFA could be detected following single-anastomosis duodenal jejunal bypass (DJB-sa) surgery, a type of bariatric surgery, and whether these alterations might be related to the improvement of glucose metabolism. To this end, we performed DJB-sa or SHAM surgery on Goto-Kakisaki (GK) rats. We then compared the glucose metabolism as well as changes in gut microbiota and SCFAs levels between both groups. Our results showed that DJB-sa surgery was associated with a significant decrease in fasting blood glucose (FBG), intraperitoneal glucose tolerance test (IPGTT), and fasting serum insulin (FSI). And, DJB-sa led to a change in the composition of gut microbiota including an increase in the relative abundance of SCFA-producing bacteria (Bifidobacterium and Subdoligranulum). Moreover, the levels of six SCFAs in feces, as well as the intestinal expression of SCFA receptors including G-protein-coupled receptor 41 (GPR41), G-protein-coupled receptor 43 (GPR43), and G-protein-coupled receptor 109A (GPR109A), and the expression of Glucagon-like peptide-1 (GLP-1) displayed a significant increase following DJB-sa compared with the Sham group. Thus, the gut microbiota may contribute to the improvement of glucose metabolism in type 2 diabetes following DJB-sa. In conclusion, our study shows that DJB-sa improves glucose metabolism by modulating gut microbiota and by increasing short-chain fatty acid production.

Influence of glucometric 'dynamical' variables on duodenal-jejunal bypass liner (DJBL) anthropometric and metabolic outcomes.

The endoscopically implanted duodenal-jejunal bypass liner (DJBL) is an attractive alternative to bariatric surgery for obese diabetic patients. This article aims to study dynamical aspects of the glycaemic profile that may influence DJBL effects. Thirty patients underwent DJBL implantation and were followed for 10 months. Continuous glucose monitoring (CGM) was performed before implantation and at month 10. Dynamical variables from CGM were measured: coefficient of variation of glycaemia, mean amplitude of glycaemic excursions (MAGE), detrended fluctuation analysis (DFA), % of time with glycaemia under 6.1 mmol/L (TU6.1), area over 7.8 mmol/L (AO7.8) and time in range. We analysed the correlation between changes in both anthropometric (body mass index, BMI and waist circumference) and metabolic (fasting blood glucose, FBG and HbA1c) variables and dynamical CGM-derived metrics and searched for variables in the basal CGM that could predict successful outcomes. There was a poor correlation between anthropometric and metabolic outcomes. There was a strong correlation between anthropometric changes and changes in glycaemic tonic control (∆BMI-∆TU6.1: rho = - 0.67, P < .01) and between metabolic outcomes and glycaemic phasic control (∆FBG-∆AO7.8: r = .60, P < .01). Basal AO7.8 was a powerful predictor of successful metabolic outcome (0.85 in patients with AO7.8 above the median vs 0.31 in patients with AO7.8 below the median: Chi-squared = 5.67, P = .02). In our population, anthropometric outcomes of DJBL correlate with improvement in tonic control of glycaemia, while metabolic outcomes correlate preferentially with improvement in phasic control. Assessment of basal phasic control may help in candidate profiling for DJBL implantation.

Duodenal-Jejunal Bypass Liner (DJBL) Improves Cardiovascular Risk Biomarkers and Predicted 4-Year Risk of Major CV Events in Patients with Type 2 Diabetes and Metabolic Syndrome.

The duodenal-jejunal bypass liner (DJBL) represents a novel endoscopic minimally invasive treatment option for obesity-associated type 2 diabetes (T2D), affecting body weight and metabolic control. Until now, the effects of DJBL on cardiovascular risk have never been investigated. Between 2012 and 2017, 71 patients with T2D and metabolic syndrome (MS) were recruited for implantation of DJBL for 9-12months. Within DJBL treatment and a follow-up period of 6months, patients were analysed for dynamics of cardiovascular biomarkers. Overall cardiovascular risk was estimated by the ADVANCE Risk Engine at time of implantation, explantation and 6months after explantation of DJBL. DJBL-induced weight loss and improvements in blood sugar control were accompanied by significant decreases of the cardiovascular biomarkers high-sensitive CRP, lipoprotein-associated phospholipase A2 and small dense lipoprotein fraction LDL-4 (p = 0.001, p < 0.001 and p = 0.04, respectively). Estimated overall cardiovascular risk decreased significantly after DJBL implantation and remained stable within 6months after explantation. In addition to beneficial effects of DJBL on weight loss, glycaemic control and lipid parameters in patients with MS, this is the first study that could further reveal significant impact on serological cardiovascular biomarkers and estimated CV risk, suggesting putative protective effects of DJBL on CV outcome.

DUODENAL-JEJUNAL BYPASS REDUCES LIPID ACCUMULATION IN THE BROWN ADIPOSE TISSUE OF HYPOTHALAMIC OBESE RATS.

ABSTRACT Background: Thermogenic activity in the brown adipose tissue (BAT) of obese individuals is reduced, and this condition may be modified by bariatric surgery (BS). Aim: To characterize fat deposition in BAT from hypothalamic obese (HyO) rats submitted to duodenal-jejunal-bypass (DJB) surgery. Methods: For induction of hypothalamic obesity, newborn male Wistar rats were treated with subcutaneous injections of monosodium glutamate (MSG). The control (CTL) group received saline solution. At 90 days, the HyO rats were submitted to DJB or sham operation, generating the HyO-DJB and HyO-SHAM groups. At 270 days, the rats were euthanized, and the BAT was weighed and submitted to histological analysis. Results: Compared to BAT from CTL animals, the BAT from HyO-SHAM rats displayed increased weight, hypertrophy with greater lipid accumulation and a reduction in nucleus number. DJB effectively increased nucleus number and normalized lipid deposition in the BAT of HyO-SHAM rats, similar to that observed in CTL animals. Conclusion: DJB surgery avoided excessive lipid deposition in the BAT of hypothalamic obese rats, suggesting that this procedure could reactivate thermogenesis in BAT, and contribute to increase energy expenditure.

Metabolic benefits of gastric bypass surgery in the mouse: The role of fecal losses

ObjectiveRoux-en-Y gastric surgery (RYGB) promotes a rapid and sustained weight loss and amelioration of glucose control in obese patients. A high number of molecular hypotheses were previously tested using duodenal-jejunal bypass (DJB) performed in various genetic models of mice with knockouts for various hormones or receptors. The data were globally negative or inconsistent. Therefore, the mechanisms remained elusive. Intestinal gluconeogenesis is a gut function that has been suggested to contribute to the metabolic benefits of RYGB in obese patients. MethodsWe studied the effects of DJB on body weight and glucose control in obese mice fed a high fat-high sucrose diet. Wild type mice and mice with a genetic suppression of intestinal gluconeogenesis were studied in parallel using glucose- and insulin-tolerance tests. Fecal losses, including excretion of lipids, were studied from the feces recovered in metabolic cages. ResultsDJB induced a dramatic decrease in body weight and improvement in glucose control (glucose- and insulin-tolerance) in obese wild type mice fed a high calorie diet, for 25 days after the surgery. The DJB-induced decrease in food intake was transient and resumed to normal in 7–8 days, suggesting that decreased food intake could not account for the benefits. Total fecal losses were about 5 times and lipid losses 7 times higher in DJB-mice than in control (sham-operated and pair-fed) mice, and could account for the weight loss of mice. The results were comparable in mice with suppression of intestinal gluconeogenesis. There was no effect of DJB on food intake, body weight or fecal loss in lean mice fed a normal chow diet. ConclusionsDJB in obese mice fed a high calorie diet promotes dramatic fecal loss, which could account for the dramatic weight loss and metabolic benefits observed. This could dominate the effects of the mouse genotype/phenotype. Thus, fecal energy loss should be considered as an essential process contributing to the metabolic benefits of DJB in obese mice.

Distal gastric mucosa ablation induces significant weight loss and improved glycemic control in type 2 diabetes Sprague-Dawley rat model.

Excluding the foregut (distal stomach and duodenum) from food transit in RYGB normalizes glucose tolerance. Excluding/removing the duodenal mucosa partly improves glycemic control. So far, the effect of excluding/removing the gastric mucosa remains unknown. To observe the effect of removing the distal gastric mucosa on glucose tolerance. Thirty fatty Sprague-Dawley rats received low-dose streptozotocin (STZ) to induce type 2 diabetes (T2D), then randomly assigned to Roux-en-Y gastric bypass (RYGB, n = 8), distal gastric mucosa removal (DGMR, n = 8), duodenal-jejunal bypass (DJB, n = 8), and Sham (n = 6) groups. In the DGMR group, the distal third of the gastric mucosa was removed by thermal ablation using an electrocautery. Rats were followed for 8 weeks postoperatively. Preoperative oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and mixed-meal tolerance test (MMTT) were repeated 3 and 6 weeks postoperatively. Changes in body weight, food intake, and fasting blood glucose were also recorded. Gastrin AUC decreased significantly (p < 0.05) in the DGMR group after surgery. A significantly increased GLP-1 AUC was found in the RYGB, DGMR, and DJB groups at week 3 and only the RYGB group at week 6 postoperatively. The improved glucose tolerance in the RYGB group was significantly greater than the improved glucose tolerance in the DGMR and DJB groups. The improved glucose tolerance 3 and 6weeks after surgery in the DGMR group was significantly greater than the improved glucose tolerance in the DJB group. Body weight decreased significantly in the RYGB, DGMR, and DJB groups postoperatively. Removing the distal gastric mucosa induced significant weight loss and improved glycemic control in T2D SD rat model. Therefore, the gastric mucosa exclusion in RYGB may be key to the weight loss and diabetes remission, which perhaps warrants a new theory.

Duodenal-Jejunal Bypass Ameliorates Type 2 Diabetes Mellitus by Activating Insulin Signaling and Improving Glucose Utilization in the Brain.

Duodenal-jejunal bypass (DJB) can dramatically improve type 2 diabetes independent of weight loss and food restriction. Increasing evidence has demonstrated that brain insulin signaling plays an important role in the pathophysiology of type 2 diabetes. This study explores whether the antidiabetic effect of DJB is involved in brain insulin signaling activation and brain glucose utilization. A diabetic rat model was established by high-fat and high-glucose diet. DJB or sham surgery was performed in diabetic rats. 18F-FDG PET scanning was used to detect glucose uptake in different organs, particularly in the brain. The levels of glucose transporters, glucose utilization-related proteins (HK1 and PFK2), insulin, and insulin signaling pathway-related proteins (InsR, IRS1/2, PI3K, and p-Akt) in the brain tissues were evaluated and analyzed. The results showed that DJB significantly improved basal glycemic parameters and reversed the decreasing glucose uptake in the brains of type 2 diabetic rats. DJB significantly increased not only the expression levels of brain insulin, IRS1/2, PI3K, and p-Akt but also the levels of the glucose utilization enzymes HK1 and PFK2 in the brain. These results indicate that enhanced brain insulin signaling transduction and brain glucose utilization play important roles in the antidiabetic effect of DJB.

Improved FGF21 Sensitivity and Restored FGF21 Signaling Pathway in High-Fat Diet/Streptozotocin-Induced Diabetic Rats After Duodenal-Jejunal Bypass and Sleeve Gastrectomy.

Objective: Bariatric surgery can profoundly improve glucose and lipid metabolism in diabetic rats. Fibroblast growth factor 21 (FGF21) is an important hormone with multiple metabolic beneficial effects. Alteration in serum FGF21 level after bariatric surgery has been reported with conflicting results. Here, we investigated the effect of bariatric surgeries on FGF21 expression and sensitivity.Methods: We performed duodenal-jejunal bypass (DJB), sleeve gastrectomy (SG) and sham surgery in diabetic rats induced by high fat diet and streptozotocin. Metabolic parameters, including body weight, food intake, glucose tolerance, and lipid profiles, were monitored. FGF21 levels in both serum and liver were measured after surgery. FGF21 signaling pathway including FGF receptor 1 (FGFR1), β-klotho (KLB), and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) was detected in the liver and white adipose tissue (WAT). We also determined FGF21 sensitivity post-operatively by acute recombinant human FGF21 injection. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were conducted immediately after FGF21 injection. Serum triglyceride (TG) and non-esterified fatty acid (NEFA) were measured and the mRNA levels of early growth response 1 (Egr1) and c-Fos in the liver and WAT were detected after FGF21 injection.Results: Improvements in glucose tolerance, insulin sensitivity, and lipid profiles were observed after bariatric surgeries along with ameliorated lipid metabolism in the liver and WAT. Serum and hepatic FGF21 levels decreased in both DJB and SG groups. FGFR1 and phosphorylated ERK1/2 levels increased in both DJB and SG groups 8 weeks after surgery. The expression of KLB was downregulated only in the WAT after DJB and SG. Significant alteration of OGTT and ITT were observed after acute FGF21 administration in DJB and SG groups. Serum TG and NEFA in DJB and SG groups also decreased after FGF21 administration. And increased mRNA levels of Egr1 and c-Fos were detected in the liver and WAT after DJB and SG surgeries.Conclusions: DJB and SG surgeries can downregulate hepatic expression of FGF21, restore FGF21 signaling pathway and improve FGF21 sensitivity in high-fat diet/streptozotocin-induced diabetic rats.

Duodenal-Jejunal Bypass Maintains Gut Permeability by Suppressing Gut Inflammation.

The aim of this study was to investigate gut inflammation and permeability in rats after duodenal-jejunal bypass (DJB) and in rats injected with a glucagon-like peptide-1 (GLP-1) receptor analog. Twelve male 16-week-old obese diabetic rats were divided into three groups: the DJB group, the sham group, and the group injected daily with a GLP-1 receptor agonist (liraglutide). Gut inflammation and the expression of tight junction protein (claudin-1) were analyzed in the three groups at 8weeks after surgery. The DJB group showed significantly lower levels of gut inflammatory cytokines than the liraglutide group. Claudin-1 showed stronger intensity on immunofluorescent staining in the DJB group than that in the liraglutide group. In summary, DJB surgery might maintain gut permeability via suppression of gut inflammation.

2010-P: Increasing POMC Positive Neurons and Ameliorating the Brain Inflammation Played an Important Role in DJB Improving Glucose Homeostasis in Diabetic Rats

This study was focused on the effect of duodenal-jejunal bypass (DJB) on brain inflammation, activation brain insulin signaling and POMC positive neurons in type 2 diabetic (T2DM) rats. T2DM rats were induced by high-fat diet (HFD) and low dose streptozotocin (STZ) injection. Twelve T2DM rats were randomly divided into 2 groups, DJB group (T2DM-DJB, n=6) and T2DM group (T2DM-Sham, n=6). Six health Wistar rats were used as normal control rats (Wistar-Control, n=6). The results showed DJB group was significantly reduced the HOMA-IR and increased HOMA-ISI of T2DM rats 6 weeks after surgery. The Q-RT-PCR and Western-blot results showed DJB intervene significantly decreased the expression of inflammatory factors IL-6, TNF-α, IL-1β and NF-κB in the brain. Our data also showed that DJB activated the brain insulin by increasing the expression of insulin, IRS1 and IRS2 in the brain of T2DM rats. Immunohistochemical assay showed that DJB increased the number of POMC positive neurons in brain, and increased the expression of BDNF in neurons. Those results indicated that DJB might fulfill the antidiabetic effect by increasing POMC positive neurons and decreasing the brain inflammation in T2DM rats. Disclosure H. Wang: None. B. Jiang: None. J. Li: None. W. Wang: None. N. Li: None. Q. Yan: None. Z. Gao: None. M. Qu: None. Funding National Natural Science Foundation of China (81871892, 31671208, 81500798, 81471048); Shandong Province Natural Science Foundation (ZR2015HL128); Technology Development Plan of Weifang (2018YX027)

1806-P: Improvement Brain Insulin Signaling in Antidiabetic Effect of Duodenal Jejunal Bypass Surgery

Duodenal-Jejunal bypass (DJB) can dramatically improve type 2 diabetes independent of weight loss and food restriction, while the mechanism underlying remains unclear. The most important characteristic of diabetes is hyperglycemia due to impaired glucose homeostatic regulation, increasing evidences have demonstrated that the brain can directly initiate behavioral and metabolic responses to control energy and peripheral glucose homeostasis. This study mainly focused on exploring the role of brain insulin signaling activation and brain glucose utilization in the antidiabetic mechanism of DJB. The diabetic rats that induced by Streptozotocin (STZ) injection were grouped and proceeded with DJB or Sham operation, respectively. Basal glycemic parameters, such as fasting glucose, fasting plasmid insulin, OGTT, HOMA-IR and Hb1Ac, were detected by ELISA kits. In different treated (DJB, Sham or Control) rats models, 18F-FDG PET scanning was used to detect the glucose uptake in different organs, and of the level of insulin as well as insulin signaling pathway related proteins (InsR, IRS1/2, PI3K, AKT) and glucose utilization related proteins (HK1, PFK2) was evaluated by Q-RT-PCR, Western blot or IHC in the brain. Results showed that DJB surgery significantly improved basal glycemic parameters (Blood glucose, Insulin, HOMA-IR, HbA1c and OGTT) and reversed the decreased glucose uptake in the brain which was caused by type 2 diabetes. DJB surgery not only induced the gene expression of the brain insulin as well activated the insulin related signals, but also increased the expression of glucose utilization enzymes, such as HK1 and PFK2 in the brain. These results indicated that activation of brain insulin signaling and elevation of brain glucose metabolism might play an important role in the antidiabetic effect of DJB. Disclosure Q. Yan: None. N. Li: None. R. Pan: None. H. Wang: None. B. Jiang: None. W. Wang: None. Z. Gao: None. M. Qu: None. Funding National Natural Science Foundation of China (81871892, 31671208, 81500798, 81471048); Shandong Province Natural Science Foundation (ZR2015HL128); Technology Development Plan of Weifang (2018YX027)

161-LB: Inhibition of Kidney SGLT2 Expression following Bariatric Surgery in Mice

Background: Bariatric surgery is known to improve glucose tolerance and weight loss, but can also cause a postprandial increase in renal glucose excretion following oral glucose tolerance test. Both effects have also been observed following treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors. Aim: To investigate whether there is an effect of bariatric surgery (Vertical Sleeve Gastrectomy; VSG) on renal SGLT2 expression in mice. Methods: Fourteen lean mice underwent VSG (n=8) or sham (n=6) surgery. Glucose Tolerance tests with or without treatment with the SGLT2 inhibitor dapagliflozin were performed four weeks post operatively, in order to assess if exogenous SGLT2 inhibition has the same euglycemic effects as bariatric surgery. Kidneys were harvested from fed mice and analysed using Quantitative real-time PCR (qRT-PCR) and immunofluorescence. Results: VSG did not cause any weight loss when compared to sham operated mice (p=0.37, Mann-Whitney test). However, VSG mice displayed significantly improved glucose tolerance (AUC=103 ±6.8; AUC =66.6 ±2.9 in control and VSG mice, respectively; p&amp;lt;0.001), which was not further affected by dapagliflozin (10 mg/kg; p&amp;gt;0.05). In contrast, treatment of sham mice with dapagliflozin increased glucose tolerance, though to a lesser extent than VSG. Nevertheless, qPCR and immunofluorescence analysis on mouse kidneys demonstrated a significant lowering of SGLT2 expression at both the protein (n=5, p=0.0007) and mRNA (n=7, 0&amp;lt;0.0001) levels four weeks after VSG. Correspondingly, glycosuria was observed in 2/5 VSG mice, but not in controls. Conclusions: Both gastric and intestinal surgery in lean animals causes a significant inhibition of SGLT2 in the kidney cortex. These findings are in line with our previous results on the effects of Duodenal Jejunal Bypass in lean rats, and point towards a physiologically-relevant gut-kidney axis. SGLT2 inhibition may thus be an important mechanism through which bariatric surgery improves glucose tolerance in man. Disclosure E. Akalestou: None. L. Lopez Noriega: None. P.L. Chabosseau: None. I. Leclerc: None. G.A. Rutter: Consultant; Self; Sun Pharma. Funding UK Wellcome Trust