Ileal Interposition Surgery Research Articles

Ileal interposition improves metabolic syndrome parameters in a rat model of metabolic syndrome induced by monosodium glutamate

AimsMetabolic syndrome (MetS) is a cluster of metabolic abnormalities. Anatomically restructuring of the gastrointestinal system has recently been an important subject of research in the treatment of MetS and closely related diseases. The aim of this study is to ensure the remission of parameters that define MetS by ileal interposition (IT) and to examine the effect of IT on plasma total GLP-1 and pancreatic GLP-1R expression. Main methodsTo induce MetS, newborn male Wistar albino rats were given MSG (4 g/mg) on days 0, 2, 4, 6, 8, and 10. The control group was injected with saline. In the 5th month, IT or sham surgery was performed on the MetS rats. The lipid levels, abdominal obesity, insulin level, OGTT, Lee index, HOMA-IR, plasma GLP-1 and pancreas GLP-1R expression were evaluated 2 months after surgery. Key findingsThe results showed that IT significantly improved hyperinsulinemia (p = 0.013) and lipid profile (TG p = 0.0001; TCHOL p = 0.018; HDL p = 0.001). Furthermore, it normalized the Lee index (p = 0.006) and insulin resistance. The IT did not affect the secretion of the GLP-1, but the expression levels of pancreas GLP-1R were increased (p = 0.006). SignificanceIT surgery corrected the MetS parameters in this rat model. The healing effects of IT surgery could be caused by mechanisms in the target tissues of insulin. The decrease in pancreatic GLP-1R levels in the MetS groups might be a compensatory response to the harmful effects of hyperinsulinemia in these groups. These results show that IT can be useful in the treatment of MetS.

Ileal interposition surgery targets the hepatic TGF-β pathway, influencing gluconeogenesis and mitochondrial bioenergetics in the UCD-T2DM rat model of diabetes.

Ileal interposition (IT) is a surgical procedure that increases the delivery of incompletely digested nutrients and biliary and pancreatic secretions to the distal intestinal mucosa. Here, we investigated the metabolic impact of this intervention in 2-mo-old prediabetic University of California, Davis type 2 diabetes mellitus rats by assessing liver gene expression at 1.5 mo post-IT surgery. Pathway analysis indicated decreased signaling via TGF-β/Smad (a family of proteins named mothers against decapentaplegic homologs), peroxisome proliferator-activated receptor (PPAR), and PI3K-Akt-AMPK-mechanistic target of rapamycin, likely targeting hepatic stellate cells because differentiation and activation of these cells is associated with decreased signaling via PPAR and TGF-β/Smad. IT surgery up-regulated the expression of genes involved in regulation of cholesterol and terpenoid syntheses and down-regulated those involved in glycerophospholipid metabolism [including cardiolipin (CL)], lipogenesis, and gluconeogenesis. Consistent with the down-regulation of the hepatic CL pathway, IT surgery produced a metabolic switch in liver, kidney cortex, and fat depots toward decreased mitochondrial fatty acid β-oxidation, the process required to fuel high energy-demanding pathways (e.g., gluconeogenesis and glyceroneogenesis), whereas opposite effects were observed in skeletal and cardiac muscles. This study demonstrates for the first time the presence of metabolic pathways that complement the effects of IT surgery to maximize its benefits and potentially identify similarly effective, durable, and less invasive therapeutic options for metabolic disease, including inhibitors of TGF-β signaling.-Hung, C., Napoli, E., Ross-Inta, C., Graham, J., Flores-Torres, A. L., Stanhope, K. L., Froment, P., Havel, P. J., Giulivi, C. Ileal interposition surgery targets the hepatic TGF-β pathway, influencing gluconeogenesis and mitochondrial bioenergetics in the UCD-T2DM rat model of diabetes.

Adipose depot-specific effects of ileal interposition surgery in UCD-T2D rats: unexpected implications for obesity and diabetes.

Ileal interposition (IT) surgery delays the onset of diabetes in a rat model of type-2 diabetes (UCD-T2DM). Here, to gain a deeper understanding of the molecular events underlying the effects of IT surgery, we examined the changes in the proteome of four white adipose depots (retroperitoneal, mesenteric, inguinal, and epididymal) and plasma-free fatty acid profile in pre-diabetic rats 1.5 months following IT or sham surgery. The IT-mediated changes were exerted mainly in mesenteric fat and spanned from delayed adipocyte maturation to a neuroendocrine remodeling. Conversely, inguinal, retroperitoneal, and epididymal depots showed opposite trends consistent with increased adipocyte maturation and adipogenesis development prior to overt signs of diabetes, probably orchestrated by peroxisome proliferator-activated receptor gamma signaling and higher plasma n-6/n-3 free fatty acid ratios. The resulting scenario suggests a targeted use of surgical strategies that seek to delay or improve diabetes in order to manipulate adipose depot-specific responses to maximize the duration and beneficial effects of the surgery.

Ileal interposition surgery for treatment of type 2 diabetes mellitus-pros and cons.

Nowadays, the surgical techniques for treating type 2 diabetes (T2DM) include: Ileal Interposition (II), Ileal Interposition in combination with Sleeve Gastrectomy (IISG) and Diverted Sleeve Gastrectomy (IIDSG). These procedures are not only for obese subjects, but are also used for non-obese subjects. These types of surgical procedures can improve glycemic control, and lead to a significant reduction in oral hypoglycemic agents (OHAs) and insulin therapy. The results of various studies have shown the safety, feasibility, and efficacy of the surgical procedure for the treatment of T2DM. Although it is an effective treatment option, this procedure is not recommended for general use and long-term studies are needed to confirm these findings and potential side effects on a larger number of patients.

The effect of ileal interposition surgery on enteroendocrine cell numbers in the UC Davis type 2 diabetes mellitus rat

AimTo investigate the short-term effect of ileal interposition (IT) surgery on gut morphology and enteroendocrine cell numbers in the pre-diabetic UC Davis type 2 diabetes mellitus (UCD-T2DM) rat. Study designTwo-month old male UCD-T2DM rats underwent either sham (n=5) or IT (n=5) surgery. Intestines were collected 1.5months after surgery. The jejunum, ileum and colon regions were processed for histochemical and immunohistochemical labeling and stereological analyses of changes in gut morphometry and number of enteroendocrine cells. ResultsStereological analysis showed that intestinal volume, luminal surface area and the number of all chromogranin A-positive enteroendocrine cells were markedly increased in the IT rats compared with sham-operated animals. Subanalyses of the glucagon-like peptide 2, cholecystokinin, serotonin cells and the neurotensin immunoreactive sub-pool of enteroendocrine cells in the IT region revealed an increase in numbers across phenotypes. However, the density of the different cell types varied. ConclusionIT surgery in the UCD-T2DM rat leads to rapid alterations in gut morphometry and an increase in the number of enteroendocrine cells. This effect may potentially explain why IT surgery delays the onset of type 2 diabetes in the UCD-T2DM rat.

Maternal Ileal Interposition Surgery Confers Metabolic Improvements to Offspring Independent of Effects on Maternal Body Weight in UCD-T2DM Rats

Increasing numbers of people are undergoing bariatric surgery, of which approximately half are women in their childbearing years. However, information on the long-term effects of maternal bariatric surgery in their children is lacking. Furthermore, since bariatric surgery is performed to reduce body weight, clinical studies have not been able to differentiate between benefits to the child due to maternal body weight loss versus other maternal postoperative metabolic changes. Therefore, we used the University of California, Davis, type 2 diabetes mellitus (UCD-T2DM) rat model to test the hypothesis that maternal ileal interposition (IT) surgery would confer beneficial metabolic effects in offspring, independent of effects on maternal body weight. IT surgery was performed on 2-month-old prediabetic female UCD-T2DM rats. Females were bred 3 weeks after surgery, and male pups were studied longitudinally. Maternal IT surgery resulted in decreased body weight in offspring compared with sham offspring (P < 0.05). IT offspring exhibited improvements of glucose-stimulated insulin secretion and nutrient-stimulated glucagon-like peptide-2 (GLP-2) secretion (P < 0.05). Fasting plasma unconjugated bile acid concentrations were 4-fold lower in IT offspring compared with sham offspring at two months of age (P < 0.001). Overall, maternal IT surgery confers modest improvements of body weight and improves insulin secretion and nutrient-stimulated GLP-2 secretion in offspring in the UCD-T2DM rat model of type 2 diabetes, indicating that this is a useful model for investigating the weight-independent metabolic effects of maternal bariatric surgery.

A Surgical Model in Male Obese Rats Uncovers Protective Effects of Bile Acids Post-Bariatric Surgery

Bariatric surgery elevates serum bile acids. Conjugated bile acid administration, such as tauroursodeoxycholic acid (TUDCA), improves insulin sensitivity, whereas short-circuiting bile acid circulation through ileal interposition surgery in rats raises TUDCA levels. We hypothesized that bariatric surgery outcomes could be recapitulated by short circuiting the normal enterohepatic bile circulation. We established a model wherein male obese rats underwent either bile diversion (BD) or Sham (SH) surgery. The BD group had a catheter inserted into the common bile duct and its distal end anchored into the middistal jejunum for 4-5 weeks. Glucose tolerance, insulin and glucagon-like peptide-1 (GLP-1) response, hepatic steatosis, and endoplasmic reticulum (ER) stress were measured. Rats post-BD lost significantly more weight than the SH rats. BD rats gained less fat mass after surgery. BD rats had improved glucose tolerance, increased higher postprandial glucagon-like peptide-1 response and serum bile acids but less liver steatosis. Serum bile acid levels including TUDCA concentrations were higher in BD compared to SH pair-fed rats. Fecal bile acid levels were not different. Liver ER stress (C/EBP homologous protein mRNA and pJNK protein) was decreased in BD rats. Bile acid gavage (TUDCA/ursodeoxycholic acid [UDCA]) in diet-induced obese rats, elevated serum TUDCA and concomitantly reduced hepatic steatosis and ER stress (C/EBP homologous protein mRNA). These data demonstrate the ability of alterations in bile acids to recapitulate important metabolic improvements seen after bariatric surgery. Further, our work establishes a model for focused study of bile acids in the context of bariatric surgery that may lead to the identification of therapeutics for metabolic disease.

Ileal interposition surgery-induced improvement of hyperglycemia and insulin resistance in Goto-Kakizaki rats by upregulation of TCF7L2 expression

The aim of this study was to investigate the effects of ileal interposition (IT) on glucose and insulin resistance (IR) in type 2 diabetic mellitus (T2DM), and the role of T-cell factor 7-like 2 (TCF7L2), formerly known as TCF4, in the downregulation of hyperglycemia following IT. Goto-Kakizaki (GK) rats subjected to IT surgery (GK-IT group), GK rats subjected to sham surgery (GK-Sham group) and Wistar (WS) rats subjected to sham surgery (WS-Sham group) were investigated in this study. Fasting plasma glucose, body weight, food intake per 1 kg body weight, insulin and a homeostasis model assessment of insulin resistance (HOMA-IR) were measured pre- and post-surgery. The rats were euthanized 28 days post-surgery and the pancreas of each rat was dissected. The expression levels of TCF7L2 mRNA and protein were analyzed by quantitative RT-PCR and western blotting, respectively. Our results revealed that IT improved both fasting plasma glucose levels and IR in GK rats by upregulating the expression of the TCF7L2 protein. IT provides a valuable therapeutic option for patients with T2DM. Upregulation of TCF7L2 protein expression may be a possible mechanism underlying the improvement of T2DM following IT.

Bile-acid-mediated decrease in endoplasmic reticulum stress: a potential contributor to the metabolic benefits of ileal interposition surgery in UCD-T2DM rats

SUMMARYPost-operative increases in circulating bile acids have been suggested to contribute to the metabolic benefits of bariatric surgery; however, their mechanistic contributions remain undefined. We have previously reported that ileal interposition (IT) surgery delays the onset of type 2 diabetes in UCD-T2DM rats and increases circulating bile acids, independently of effects on energy intake or body weight. Therefore, we investigated potential mechanisms by which post-operative increases in circulating bile acids improve glucose homeostasis after IT surgery. IT, sham or no surgery was performed on 2-month-old weight-matched male UCD-T2DM rats. Animals underwent an oral fat tolerance test (OFTT) and serial oral glucose tolerance tests (OGTT). Tissues were collected at 1.5 and 4.5 months after surgery. Cell culture models were used to investigate interactions between bile acids and ER stress. IT-operated animals exhibited marked improvements in glucose and lipid metabolism, with concurrent increases in postprandial glucagon-like peptide-1 (GLP-1) secretion during the OFTT and OGTTs, independently of food intake and body weight. Measurement of circulating bile acid profiles revealed increases in circulating total bile acids in IT-operated animals, with a preferential increase in circulating cholic acid concentrations. Gut microbial populations were assessed as potential contributors to the increases in circulating bile acid concentrations, which revealed proportional increases in Gammaproteobacteria in IT-operated animals. Furthermore, IT surgery decreased all three sub-arms of ER stress signaling in liver, adipose and pancreas tissues. Amelioration of ER stress coincided with improved insulin signaling and preservation of β-cell mass in IT-operated animals. Incubation of hepatocyte, adipocyte and β-cell lines with cholic acid decreased ER stress. These results suggest that postoperative increases in circulating cholic acid concentration contribute to improvements in glucose homeostasis after IT surgery by ameliorating ER stress.

Early remission of type 2 diabetes mellitus by laparoscopic ileal transposition with sleeve gastrectomy surgery in 23–35 BMI patients

To assess the efficacy of ileal transposition with sleeve gastrectomy (SGIT) surgery in remission of Type 2 Diabetes Mellitus (T2DM) in patients with 23–35 BMI. Diabetes is considered a life style disease. Despite medications and lifestyle changes, (HbA1c) - remains > 7 in 56 % of diabetics, predisposing them to high risk of diabetes related complications. Bariatric surgery results in remission of diabetes in over 84% patients with BMI > 35 m2s/m2. Based on hindgut hypothesis suggesting role of incretins like GLP-1, early trials of ileal interposition surgery have displayed consistent HbA1c levels below 7 in over 80% patients with BMI > 30 m2/m2. In developing countries majority of T2DM patients are not morbidly obese and surgical procedures are to be evaluated for their efficacy in this group. In this study we have assessed the efficacy of ileal transposition with sleeve gastrectomy (SGIT) in 23–35 BMI T2DM patients. Selected T2DM patients [HbA1c > 7, C Peptide > -1 ng/ml] underwent Lap SGIT by a single surgeon. Data of first five patients with minimum 6 months follow up was analyzed for glycemic control and altered need for medications. Data were analyzed using SPSS (SPSS release 16; SPSS Inc. Chicago). The study target (HbA1c < 7) was achieved in 60% of patients within 1 month and in 100% of patients within 6 months. Requirement of medications reduced significantly within 6 months and their HbA1c levels reduced from 9.65% to 6.22%. Laparoscopic SGIT may represent a new paradigm for the treatment of T2DM even in non morbidly obese patients.

Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat

The hindgut hypothesis posits improvements in Type 2 diabetes after gastric bypass surgery are due to enhanced delivery of undigested nutrients to the ileum, which increase incretin production and insulin sensitivity. The present study investigates the effect of ileal interposition (IT), surgically relocating a segment of distal ileum to the proximal jejunum, on glucose tolerance, insulin sensitivity, and glucose transport in the obese Zucker rat. Two groups of obese Zucker rats were studied: IT and sham surgery ad libitum fed (controls). Changes in food intake, body weight and composition, glucose tolerance, insulin sensitivity and tissue glucose uptake, and insulin signaling as well as plasma concentrations of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide were measured. The IT procedure did not significantly alter food intake, body weight, or composition. Obese Zucker rats demonstrated improved glucose tolerance 3 wk after IT compared with the control group (P < 0.05). Euglycemic, hyperinsulinemic clamp and 1-[(14)C]-2-deoxyglucose tracer studies indicate that IT improves whole body glucose disposal, insulin-stimulated glucose uptake, and the ratio of phospho- to total Akt (P < 0.01 vs. control) in striated muscle. After oral glucose, the plasma concentration of glucagon-like peptide-1 was increased, whereas GIP was decreased following IT. Enhanced nutrient delivery to the ileum after IT improves glucose tolerance, insulin sensitivity and muscle glucose uptake without altering food intake, body weight, or composition. These findings support the concept that anatomic and endocrine alterations in gut function play a role in the improvements in glucose homeostasis after the IT procedure.

Intestinal adaptation after ileal interposition surgery increases bile acid recycling and protects against obesity-related comorbidities

Surgical interposition of distal ileum into the proximal jejunum is a bariatric procedure that improves the metabolic syndrome. Changes in intestinal and hepatic physiology after ileal interposition (transposition) surgery (IIS) are not well understood. Our aim was to elucidate the adaptation of the interposed ileum, which we hypothesized, would lead to early bile acid reabsorption in the interposed ileum, thus short circuiting enterohepatic bile acid recycling to more proximal bowel segments. Rats with diet-induced obesity were randomized to IIS, with 10 cm of ileum repositioned distal to the duodenum, or sham surgery. A subgroup of sham rats was pair-fed to IIS rats. Physiological parameters were measured until 6 wk postsurgery. IIS rats ate less and lost more weight for the first 2 wk postsurgery. At study completion, body weights were not different, but IIS rats had reversed components of the metabolic syndrome. The interposed ileal segment adapted to a more jejunum-like villi length, mucosal surface area, and GATA4/ILBP mRNA. The interposed segment retained capacity for bile acid reabsorption and anorectic hormone secretion with the presence of ASBT and glucagon-like-peptide-1-positive cells in the villi. IIS rats had reduced primary bile acid levels in the proximal intestinal tract and higher primary bile acid levels in the serum, suggesting an early and efficient reabsorption of primary bile acids. IIS rats also had increased taurine and glycine-conjugated serum bile acids and reduced fecal bile acid loss. There was decreased hepatic Cyp27A1 mRNA with no changes in hepatic FXR, SHP, or NTCP expression. IIS protects against the metabolic syndrome through short-circuiting enterohepatic bile acid recycling. There is early reabsorption of primary bile acids despite selective "jejunization" of the interposed ileal segment. Changes in serum bile acids or bile acid enterohepatic recycling may mediate the metabolic benefits seen after bariatric surgery.

P-132: Identification of genes with altered expression within the rat ileum following ileal interposition surgery

As the prevalence of morbid obesity and co-morbid conditions such as Type 2 Diabetes Mellitus (T2DM) continues to rise worldwide, treatment has been sought in the form of gastric bypass and other obesity surgeries. Patients of bypass surgery show improvements in glucose control within days after surgery and before significant weight loss has occurred, suggesting that normalization of glucose levels are weight loss-independent. It has been hypothesized that direct delivery of nutrients to the lower intestine (primarily the ileum) may lead to changes in gene expression responsible for the observed resolution of glucose intolerance and reversal of T2DM.

P-146: Early resolution of type 2 diabetes mellitus BY laparoscopic ileal transposition with sleeve gastrectomy surgery in 23 – 35 bmi kg/m 2 patients – a novel therapy

Type 2 Diabetes Mellitus (T2DM) is considered a life style disease. 56% diabetic patients with HbA1c above 7 are at high risk of diabetes related complications. Bariatric surgery results in diabetes resolution in over 84% patients. Based on hindgut hypothesis suggesting role of incretins like GLP-1, early trials of ileal interposition surgery have displayed consistent HbA1c levels below 7 in over 80% patients with > 30 kg/m2 BMI. In developing countries majority of T2DM patients are not morbidly obese and surgical procedures are to be evaluated for their efficacy in this group. In this study we have assessed the efficacy of ileal transposition with Laparoscopic Sleeve Gastrectomy (LSG) in 23 – 35 kg/m2 BMI T2DM patients.

Ileal Interposition Surgery Improves Glucose and Lipid Metabolism and Delays Diabetes Onset in the UCD-T2DM Rat

Bariatric surgery has been shown to reverse type 2 diabetes; however, mechanisms by which this occurs remain undefined. Ileal interposition (IT) is a surgical model that isolates the effects of increasing delivery of unabsorbed nutrients to the lower gastrointestinal tract. In this study we investigated effects of IT surgery on glucose tolerance and diabetes onset in UCD-T2DM (University of California at Davis type 2 diabetes mellitus) rats, a polygenic obese animal model of type 2 diabetes. IT or sham surgery was performed on 4-month-old male UCD-T2DM rats. All animals underwent oral glucose tolerance testing (OGTT). A subset was killed 2 months after surgery for tissue analyses. The remainder was followed until diabetes onset and underwent oral fat tolerance testing (OFTT). IT surgery delayed diabetes onset by 120 +/- 49 days compared with sham surgery (P < .05) without a difference in body weight. During OGTT, IT-operated animals exhibited lower plasma glucose excursions (P < .05), improved early insulin secretion (P < .01), and 3-fold larger plasma glucagon-like peptide-1(7-36) (GLP-1(7-36)) excursions (P < .001), and no difference in glucose-dependent insulinotropic polypeptide responses compared with sham-operated animals. Total plasma peptide YY (PYY) excursions during OFTT were 3-fold larger in IT-operated animals (P < .01). IT-operated animals exhibited lower adiposity (P < .05), smaller adipocyte size (P < .05), 25% less ectopic lipid deposition, lower circulating lipids, and greater pancreatic insulin content compared with sham-operated animals (P < .05). IT surgery delays the onset of diabetes in UCD-T2DM rats which may be related to increased nutrient-stimulated secretion of GLP-1(7-36) and PYY and improvements of insulin sensitivity, beta-cell function, and lipid metabolism.