Duodenal-jejunal Bypass Rats Research Articles

Duodenal-Jejunal Bypass Restores Sweet Taste Receptor-Mediated Glucose Sensing and Absorption in Diabetic Rats.

Aim: The aim of the study is to identify the regulatory role of intestinal sweet taste receptors (STRs) and glucose transporters (SGLT1, GLUT2) and gut peptide secretion in duodenal-jejunal bypass (DJB)-ameliorated glycemic control in Type 2 diabetes. Materials and Methods: DJB and sham surgeries were performed in streptozotocin-induced diabetic male rats. The blood GLP-1 and GLP-2 levels were evaluated under feeding and fasting conditions. The expression of STRs (T1R2, T1R3), sweet taste signaling effector (Gα-gustducin), SGLT1, and GLUT2 was detected in the intestinal alimentary limb (A limb), biliopancreatic limb (BP limb), and common limb (C limb). The effects of STR inhibition on glucose control were measured with lactisole. Results: Glucose tolerance was improved in DJB-operated rats compared with the sham group, similar to that of normal control rats, without significant differences in food intake and body weight. The plasma GLP-1 levels of DJB rats were increased under diet-fed condition, and GLP-2 levels were increased after fasting. The villus height and crypt depth were significantly increased in the A limb of DJB-operated rats. In addition, GLP-1 expression was restored in enterocytes. The expression of T1R2, Gα-gustducin, and SGLT1 was elevated in the A limb after DJB, while GLUT2 was downregulated in the A, BP, and C limbs. The localization of GLUT2 was normalized in the three intestinal limbs after DJB. However, the beneficial effects of DJB on glucose control were abolished in the presence of lactisole in vivo. Conclusion: DJB ameliorates glycemic control probably by restoring STR-mediated glucose sensing and absorption with the responses of GLP-1 and GLP-2 to carbohydrate.

Impact of Daikenchuto (TU-100) on the early postoperative period in duodenal-jejunal bypass.

We investigated the effect of Daikenchuto (TU-100) on the early postoperative period in duodenal-jejunal bypass (DJB). Study 1:The effect of TU-100 on diabetic rats was investigated. Rats were sacrificed after receiving TU-100 for one week. Study 2:The effect of TU-100 on DJB was investigated. Rats in the DJB and TU-100 treated DJB groups were sacrificed 24 hours postoperation to evaluate blood glucose, cytokine expression, and gut microbiome. Study 1:TU-100 did not affect glucose or body weight. TU-100 suppressed intestinal inflammation and modified the gut microbiome. Specifically, Bifidobacterium and Blautia were increased, and Turicibacter were decreased in this group. Study 2:Both DJB and TU-100 treated DJB rats showed lower blood glucose at 24 hours postoperation than at preoperation. Cytokine expression in the liver and small intestine of the TU-100 treated DJB group was significantly lower than that of the DJB group. The gut microbiome composition in TU-100 treated DJB rats was altered. In particular, Bifidobacterium and Blautia were increased in this group. DJB suppressed blood glucose during the early postoperative period. TU-100 may enhance the anti-diabetic effect of metabolic surgery by changing the gut microbiome and suppressing inflammation in the early postoperative period. J. Med. Invest. 71 : 210-218, August, 2024.

Duodenal-jejunal bypass surgery activates eNOS and enhances antioxidant system by activating AMPK pathway to improve heart oxidative stress in diabetic cardiomyopathy rats.

Diabetic cardiomyopathy is a serious complication of obesity with type 2 diabetes and is a major cause of mortality. Metabolic surgery, such as duodenal-jejunal bypass (DJB), can effectively improve diabetic cardiomyopathy; however, the underlying mechanisms remain elusive. Oxidative stress is one of the pivotal mechanisms of diabetic cardiomyopathy. Our objective was to investigate the effect and potential mechanisms of DJB on oxidative stress in the heart of diabetic cardiomyopathy rats. High-fat diet combined with intraperitoneal injection of streptozotocin was used to establish diabetic cardiomyopathy rats. DJB was performed on diabetic cardiomyopathy rats, and high glucose and palmitate were used to simulate diabetic cardiomyopathy in H9C2 cells in vitro. Sera from different groups of rats were used for experiments in vivo and in vitro. DJB effectively improved oxidative stress and activated the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway to increase endothelial nitric oxide synthase (eNOS) phosphorylation level and the expression of antioxidative system-related proteins and genes in the heart of diabetic cardiomyopathy rats. AMPK agonists and serum from DJB rats activated the AMPK pathway to increase eNOS phosphorylation level and the expression of antioxidative system-related proteins and genes and decreased the content of reactive oxygen species in H9C2 cells, but this improvement was almost eliminated by the addition of AMPK inhibitors. DJB activates eNOS and enhances the antioxidant system by activating the AMPK pathway-and not solely by improving blood glucose-to improve oxidative stress in the heart of diabetic cardiomyopathy rats.

276-LB: STR-Mediated Glucose Sensing and GLUT2-Regulated Glucose Absorption Are Repaired by DJB Surgery in Diabetic Rats

Abstract: Our previous study demonstrated that duodenal-jejunal bypass (DJB) ameliorated glycemic control in a diabetic rat model but the underlying mechanisms are still unclear. This study aimed to identify the regulatory function of sweet taste receptors and glucose transporters within the DJB-remodeled small intestine and gut peptide secretion. DJB or sham surgeries were performed in streptozotocin (STZ)-induced diabetic rats. The blood GLP-1 and GLP-2 levels were evaluated under feeding and fasting conditions. The effects of sweet taste receptors (STR) inhibition on glucose control were measured in vivo with lactisole (STR inhibitor). The results showed that the glucose tolerance was improved in DJB-operated rats compared with Sham group, similar to that of normal control rats without significant differences in food intake and body weight. The plasma levels of insulin were increased after DJB in both feeding and fasting conditions. The plasma GLP-1 levels of DJB rats were increased under diet-fed condition, and GLP-2 levels of DJB rats were increased after fasting. The villus height and crypt depth were significantly increased in the intestinal alimentary limb (A limb) of DJB-operated rats, while decreased in the biliopancreatic limb (BP limb). The expression levels of T1R2, T1R3, sweet taste signaling effector Gα-gustducin and glucose transporters SGLT1, GLUT2 was downregulated in the BP and common limbs, but was elevated in the A limb after DJB. However, the beneficial effects of DJB on glood control was abolished in the presence of lactisole. Furthermore, the immunofluorescence results displayed that GLUT2 localization was normalized after DJB. In conclusion, these findings indicate that DJB ameliorates glycemic control probably via repairing sweet taste receptor-mediated glucose sensing and absorption with the responses of GLP-1 and GLP-2 to dietary carbohydrate. Keywords: Sweet taste receptor; Lactisole; GLUT2; SGLT1; GLP-1; GLP-2; DJB; Disclosure A. Wang: None. R. Kou: None. X. Zhao: None. S. Sun: None. Y. Wang: None. Z. Gao: None. Funding National Natural Science Foundation of China (82070856, 82100842); Natural Science Foundation of Shandong Province (ZR201807090175, ZR2020QH084)

Duodenal-jejunal bypass attenuates progressive failure of pancreatic islets in streptozotocin-induced diabetic rats

BackgroundPreservation of pancreatic beta cell function has been increasingly appealing in the treatment of type 2 diabetes. Evidence is still limited on how bariatric surgery affects pancreatic beta cell apoptosis. SettingUniversity medical center. ObjectiveThe study aimed to investigate the effect of a major component of Roux-en-Y gastric bypass, duodenal-jejunal bypass, on protecting pancreatic beta cells from progressive loss. MethodsForty-five normal Sprague–Dawley rats were randomly assigned into 3 groups: duodenal-jejunal bypass (DJB) group (n = 16) and sham (S) group (n = 17), based upon the procedure received, and a control (C) group (n = 12) without any procedure performed, to eliminate potential traumatic effects from surgery. Ten days after surgery, streptozotocin (STZ, 45 mg/kg weight) was injected intraperitoneally into each animal, including the control animals, to selectively induce pancreatic beta cell apoptosis. Weight, food intake, plasma glucose level, and the results of an oral glucose tolerance test were measured before surgery, pre-STZ injection, and up to 4 weeks after STZ injection. Plasma insulin and glucagon-like peptide-1 levels were also assayed during oral glucose tolerance test. At the end, pancreatic tissues were sliced and stained for beta cell analysis. ResultsThere were no significant differences in weight among all groups at any time points measured, despite rats in the S and C groups consuming more food than those in the DJB group as measured on day 10 (P<.05) and day 20 (P<.01) after STZ injection. Animals undergoing DJB did not experience symptoms typical of uncompensated diabetes, including hyperphagia and progressive weight loss. After STZ injection, fasting plasma glucose levels in the DJB group were significantly lower than those in the C and S groups (P<.001). When challenged by glucose load, DJB rats also had a better glycemic excursion (P<.01) and incretin response compared with C and S rats (P<.05). In addition, pancreatic beta cell size and mass was better preserved in DJB rats (P< .001). ConclusionDJB is able to protect pancreatic beta cells from apoptosis, which leads to better glycemic control and delayed onset of diabetes. These results imply the necessity of including a DJB component when designing bariatric procedure to achieve a better long-term outcome.

MiR-200a regulates Rheb-mediated amelioration of insulin resistance after duodenal-jejunal bypass.

Objectives:Duodenal–jejunal bypass (DJB) surgery can induce the rapid and durable remission of diabetes. Recent studies indicate that ameliorated hepatic insulin resistance and improved insulin signaling might contribute to the diabetic control observed after DJB. Ras homolog enriched in brain (Rheb) is reported to have an important role in insulin pathway, and some microRNAs (miRNAs) have been found to regulate Rheb. This study was conducted to investigate the effects of DJB on hepatic insulin resistance and the effects of miRNA-200a, a Rheb-targeting miRNA, on the development of DJB-induced amelioration in hepatic insulin resistance.Subjects:We investigated hepatic insulin signaling change and mapped the hepatic miRNAome involved in a rat model of DJB. We studied the effects of miR-200a on Rheb signaling pathway in buffalo rat liver cell lines. Liver tissues were studied and glucose tolerance tests were conducted in DJB rats injected with lentivirus encoding miR-200a inhibitor and diabetic rats injected with miR-200a mimic.Results:Rheb is a potential target of miR-200a. Transfection with an miR-200a inhibitor increased Rheb protein levels and enhanced the feedback action on insulin receptor substrate-dependent insulin signaling, whereas transfection with an miR-200a mimic produced the opposite effects. A luciferase assay confirmed that miR-200a bind to the 3′UTR (untranslated regions) of Rheb. Global downregulation of miR-200a in DJB rats showed impaired insulin sensitivity whereas upregulation of miR-200a in diabetic rats showed amelioration of diabetes.Conclusions:A novel mechanism was identified, in which miR-200a regulates the Rheb-mediated amelioration of insulin resistance in DJB. The findings suggest miR-200a should be further explored as a potential target for the treatment of diabetes.

Changes in one-carbon metabolism after duodenal-jejunal bypass surgery

Bariatric surgery alleviates obesity and ameliorates glucose tolerance. Using metabolomic and proteomic profiles, we evaluated metabolic changes in serum and liver tissue after duodenal-jejunal bypass (DJB) surgery in rats fed a normal chow diet. We found that the levels of vitamin B12 in the sera of DJB rates were decreased. In the liver of DJB rats, betaine-homocysteine S-methyltransferase levels were decreased, whereas serine, cystathionine, cysteine, glutathione, cystathionine β-synthase, glutathione S-transferase, and aldehyde dehydrogenase levels were increased. These results suggested that DJB surgery enhanced trans-sulfuration and its consecutive reactions such as detoxification and the scavenging activities of reactive oxygen species. In addition, DJB rats showed higher levels of purine metabolites such as ATP, ADP, AMP, and inosine monophosphate. Decreased guanine deaminase, as well as lower levels of hypoxanthine, indicated that DJB surgery limited the purine degradation process. In particular, the AMP/ATP ratio and phosphorylation of AMP-activated protein kinase increased after DJB surgery, which led to enhanced energy production and increased catabolic pathway activity, such as fatty acid oxidation and glucose transport. This study shows that bariatric surgery altered trans-sulfuration and purine metabolism in the liver. Characterization of these mechanisms increases our understanding of the benefits of bariatric surgery.

Expedited Biliopancreatic Juice Flow to the Distal Gut Benefits the Diabetes Control After Duodenal-Jejunal Bypass.

Serum bile acids (BAs) are elevated after metabolic surgeries including Roux-en-Y gastric bypass (RYGB), ileal transposition (IT), and duodenal-jejunal bypass (DJB). Recently, BAs have emerged as a kind of signaling molecules, which can not only promote glucagon-like peptide-1 (GLP-1) secretion but can also regulate multiple enzymes involved in glucose metabolism. The aim of this study was to investigate whether expedited biliopancreatic juice flow to the distal gut contributes to the increased serum GLP-1 and BAs and benefits the diabetes control after DJB. DJB, long alimentary limb DJB (LDJB), duodenal-jejunal anastomosis (DJA), and sham operation were performed in diabetic rats induced by high-fat diet (HFD) and low dose of streptozotocin (STZ). Body weight, food intake, oral glucose tolerance, insulin tolerance, glucose-stimulated insulin and GLP-1 secretion, fasting serum total bile acids (TBAs), and lipid profiles were measured at indicated time points. Compared with sham operation, DJA, DJB, and LDJB all achieved rapid and dramatic improvements in glucose tolerance and insulin sensitivity independently of food restriction and weight loss. DJB and LDJB-operated rats exhibited even better glucose tolerance, higher fasting serum TBAs, and higher glucose-stimulated GLP-1 secretion than the DJA group postoperatively. No difference was detected in insulin sensitivity and glucose-stimulated insulin secretion between DJA, DJB, and LDJB groups. Expedited biliopancreatic juice flow to the distal gut was associated with augmented GLP-1 secretion and increased fasting serum TBA concentration, which may partly explain the metabolic benefits of DJB.

Duodenal jejunal bypass attenuates non-alcoholic fatty liver disease in western diet-obese rats

To evaluate the effects of duodenal-jejunal bypass (DJB) on serum and hepatic profiles of obese rats fed on a western diet (WD). Twenty eight male Wistar rats were fed a standard rodent chow diet (CTL group) or WD ad libitum. After 10 weeks, WD rats were submitted to sham (WD SHAM) or duodenal-jejunal bypass (WD DJB). Body weight, fat pad depots, glycemia, insulinemia, HOMA-IR, TyG, lipids profile and hepatic analyses were evaluated two months after surgery. The WD SHAM group presented greater obesity, hyperglycemia, hyperinsulinemia, insulin resistance, hypertriglyceridemia and hepatic steatosis than the CTL group. WD DJB rats presented decreased serum glucose and insulin resistance, when compared to WD SHAM animals, without changes in insulinemia. In addition, DJB surgery normalized serum TG and attenuated TG accumulation and steatosis in the liver of the WD DJB group. Hepatic ACC and FAS protein expressions were similar in all groups. Duodenal-jejunal bypass attenuates hepatic parameters of non-alcoholic fatty liver disease in obese rats fed on a western diet.

Duodenal-jejunal bypass surgery on type 2 diabetic rats reduces the expression of matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in the thoracic aorta

Background Bariatric surgery offers a productive resolution of type 2 diabetes mellitus (T2DM). The development of T2DM vasculopathy is due to chronic inflammation, which increases matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) expression. This study sought to examine MMP-9 and TIMP-1 expression in the thoracic aorta after duodenal-jejunal bypass (DJB) surgery on a T2DM rat model induced by a high-fat diet and low dose streptozotocin (STZ). Methods Twenty-one T2DM Wistar rats induced by high-fat diet and low dose STZ were randomly divided into DJB and sham duodenal-jejunal bypass (S-DJB) groups. Ten Wistar rats were fed a normal diet as a control. Recovery of gastrointestinal function post-operation and resumption of a normal diet completed the experiment. Body weight, blood glucose, blood lipid levels, and MMP-9 and TIMP-1 expression levels in aortic endothelial cells were measured throughout. Results DJB rats showed significant weight loss 2 weeks post-operation compared with S-DJB rats. After surgery, DJB rats showed significant improvement and steady glycemic control with improved insulin sensitivity and glucose tolerance. They also exhibited improved lipid metabolism with a decrease in fasting free fatty acids (FFAs) and triglycerides (all P &lt;0.05). Immunohistochemistry showed decreased MMP-9 and TIMP-1 expression 12 weeks after surgery (P &lt; 0.01). Conclusions DJB surgery on an induced T2DM rat model improves blood glucose levels and lipids, following a high-fat diet and low dose STZ treatment. In addition, DJB decreased MMP-9 and TIMP-1 expression in vascular endothelial cells, which may play an important role in delaying the development of T2DM vascular disease.

Duodenal–Jejunal Bypass Surgery Enhances Glucose Tolerance and Beta-Cell Function in Western Diet Obese Rats

The aim of this study was to investigate the effect of the duodenal-jejunal bypass (DJB) on glucose homeostasis and islet insulin secretion in Western diet (WD) obese rats. Male Wistar rats received a standard rodent chow diet (CTL group) or WD ad libitum. After 32 weeks of diet, WD rats were submitted to duodenal-jejunal bypass (WD DJB) or sham (WD S-DJB) operation. Intraperitoneal (ip) glucose tolerance test was performed 1 week after surgery. Body weight, fat pad depots, glycemia, insulinemia, HOMA-IR, and glucose-induced insulin secretion were evaluated 1 month after surgery. Body weight and fat pads of the WD group were higher than those of the CTL group. Sham and DJB surgeries did not alter these parameters. WD and WD S-DJB rats were glucose intolerant, insulin resistant, and hyperinsulinemic. WD DJB rats showed similar glucose tolerance, insulin sensitivity, and plasma insulin levels to those of CTL rats. WD rats presented higher fat and glycogen contents in the liver. DJB surgery normalized fat and glycogen stores in the liver of the WD DJB group. Insulin release at 11.1-mM glucose, in isolated islets from WD and WD S-DJB rats, was higher than from islets of CTL rats. In contrast, DJB surgery improves the beta-cell secretory capacity with increased glucose-induced secretion at 5.6-, 11.1-, and 22.2-mM glucose in WD DJB islets, compared with CTL islets. DJB surgery improves glucose homeostasis and enhances beta-cell glucose responsiveness in rats submitted to the WD diet without any modification in adiposity.

Bypassing the Duodenum Does Not Improve Insulin Resistance Associated With Diet-Induced Obesity in Rodents

Roux-en-y gastric bypass (RYGB) surgery rapidly improves glucose tolerance and reverses insulin resistance in obese patients. It has been hypothesized that this effect is mediated by the diversion of nutrients from the proximal small intestine. We utilized duodenal-jejunal bypass (DJB) as a modification of gastric bypass to determine the effect of nutrient diversion from the foregut without gastric restriction on insulin resistance in obese rats. The effects of DJB or Sham surgery on glucose homeostasis were determined in both high-fat-fed Long-Evans and Wistar rats. Body weight and food intake were measured weekly postoperatively, and body composition was monitored before and after surgery. Glucose tolerance was tested before and as early as 1 month postoperation; additionally, in Wistar rats, insulin sensitivity was determined by a hyperinsulinemic-euglycemic clamp (HIEC). DJB did not affect body weight, body composition, glucose tolerance, or insulin concentrations over the period of the study. The average glucose infusion rate (GIR) during the HIEC was 6.2 ± 1.16 mg/kg/min for Sham rats compared to 7.2 ± 1.71 mg/kg/min for DJB rats (P = 0.62), and neither endogenous glucose production (EGP; P = 0.81) nor glucose utilization (glucose disappearance (R(d)), P = 0.59) differed between DJB and Sham rats. DJB does not affect insulin resistance induced by a high-fat diet in Long-Evans and Wistar rats. These data suggest that duodenal bypass alone is an insufficient mechanism to alter insulin sensitivity independent of weight loss in obese, nondiabetic rodents.

The Effect of Duodenal–Jejunal Bypass on Glucose-Dependent Insulinotropic Polypeptide Secretion in Wistar Rats

Enteroendocrine K cells secrete the incretin hormone glucose-dependent insulinotropic peptide (GIP) and are predominately located in the duodenum. GIP levels should decrease after gastric bypass due to duodenal exclusion; however, studies have found conflicting data regarding the changes in GIP secretion after gastric bypass and duodenal-jejunal bypass (DJB). We performed a DJB or Sham surgery on Wistar rats followed by an oral glucose tolerance test on postoperative (post-op) day 12 and superior mesenteric lymphatic cannulation on post-op day 14. We measured meal-stimulated GIP concentrations and small bowel GIP and GLP-1 protein content after DJB or Sham surgery. There was no difference in glucose tolerance by 12 days post-op. We found no difference in lymphatic GIP concentration area under the curve between DJB and Sham rats (15,240 pg/ml min +/- 2,651 vs. 17,201 pg/ml min +/- 2,763, respectively, p = 0.62). GIP and GLP-1 protein contents were both significantly increased only in the midjejunum in DJB rats compared to Sham rats (p = 0.009 and p = 0.01, respectively). Plasma and lymphatic GIP concentrations did not significantly change after DJB in Wistar rats. DJB increased GIP protein content in the midjejunum at the new site of nutrient absorption, but this was surprisingly not countered by a decrease in GIP protein content in the bypassed duodenum. Further studies are needed to determine the mechanisms that account for the discrepancy in GIP production and subsequent secretion after DJB as well as what role GIP plays in the effect of gastrointestinal surgery on glucose homeostasis.

The Mechanism of Diabetes Control After Gastrointestinal Bypass Surgery Reveals a Role of the Proximal Small Intestine in the Pathophysiology of Type 2 Diabetes

Most patients who undergo Roux-en-Y gastric bypass (RYGB) experience rapid resolution of type 2 diabetes. Prior studies indicate that this results from more than gastric restriction and weight loss, implicating the rearranged intestine as a primary mediator. It is unclear, however, if diabetes improves because of enhanced delivery of nutrients to the distal intestine and increased secretion of hindgut signals that improve glucose homeostasis, or because of altered signals from the excluded segment of proximal intestine. We sought to distinguish between these two mechanisms. Goto-Kakizaki (GK) type 2 diabetic rats underwent duodenal-jejunal bypass (DJB), a stomach-preserving RYGB that excludes the proximal intestine, or a gastrojejunostomy (GJ), which creates a shortcut for ingested nutrients without bypassing any intestine. Controls were pair-fed (PF) sham-operated and untreated GK rats. Rats that had undergone GJ were then reoperated to exclude the proximal intestine; and conversely, duodenal passage was restored in rats that had undergone DJB. Oral glucose tolerance (OGTT), food intake, body weight, and intestinal nutrient absorption were measured. There were no differences in food intake, body weight, or nutrient absorption among surgical groups. DJB-treated rats had markedly better oral glucose tolerance compared with all control groups as shown by lower peak and area-under-the-curve glucose values (P < 0.001 for both). GJ did not affect glucose homeostasis, but exclusion of duodenal nutrient passage in reoperated GJ rats significantly improved glucose tolerance. Conversely, restoration of duodenal passage in DJB rats reestablished impaired glucose tolerance. This study shows that bypassing a short segment of proximal intestine directly ameliorates type 2 diabetes, independently of effects on food intake, body weight, malabsorption, or nutrient delivery to the hindgut. These findings suggest that a proximal intestinal bypass could be considered for diabetes treatment and that potentially undiscovered factors from the proximal bowel might contribute to the pathophysiology of type 2 diabetes.