Ali Tavakkoli

Effect of Roux-en-Y Gastric Bypass Surgery on Bile Acid Metabolism in Normal and Obese Diabetic Rats

In addition to classic functions of facilitating hepatobiliary secretion and intestinal absorption of lipophilic nutrients, bile acids (BA) are also endocrine factors and regulate glucose and lipid metabolism. Recent data indicate that antiobesity bariatric procedures e.g. Roux-en-Y gastric bypass surgery (RYGB), which also remit diabetes, increase plasma BAs in humans, leading to the hypothesis that BAs may play a role in diabetes resolution following surgery. To investigate the effect of RYGB on BA physiology and its relationship with glucose homeostasis, we undertook RYGB and SHAM surgery in Zucker diabetic fatty (ZDF) and normoglycemic Sprague Dawley (SD) rats and measured plasma and fecal BA levels, as well as plasma glucose, insulin, Glucagon like peptide 1 (GLP-1) and Peptide YY (PYY), 2 days before and 3, 7, 14 and 28 days after surgery. RYGB decreased body weight and increased plasma GLP-1 in both SD and ZDF rats while decreasing plasma insulin and glucose in ZDF rats starting from the first week. Compared to SHAM groups, both SD-RYGB and ZDF-RYGB groups started to have increases in plasma total BAs in the second week, which might not contribute to early post-surgery metabolic changes. While there was no significant difference in fecal BA excretion between SD-RYGB and SD-SHAM groups, the ZDF-RYGB group had a transient 4.2-fold increase (P<0.001) in 24-hour fecal BA excretion on post-operative day 3 compared to ZDF-SHAM, which paralleled a significant increase in plasma PYY. Ratios of plasma and fecal cholic acid/chenodeoxycholic acid derived BAs were decreased in RYGB groups. In addition, tissue mRNA expression analysis suggested early intestinal BA reabsorption and potentially reduced hepatic cholic acid production in RYGB groups. In summary, we present novel data on RYGB-mediated changes in BA metabolism to further understand the role of BAs in RYGB-induced metabolic effects in humans.

Erratum to: The Effect of Laparoscopic Sleeve Gastrectomy with Concomitant Hiatal Hernia Repair on Gastroesophageal Reflux Disease in the Morbidly Obese

Background The effect of laparoscopic sleeve gastrectomy (LSG) on gastroesophageal reflux disease (GERD) is controversial. Although concomitant hiatal hernia repair (HHR) at the time of LSG is common and advocated by many, there are few data on the outcomes of GERD symptoms in these patients. The aim of this study was to evaluate the effect of concomitant HHR on GERD symptoms in morbidly obese patients undergoing LSG.

Distal pancreatic resection for neuroendocrine tumors: is laparoscopic really better than open?

BackgroundThe latest studies on surgical and cost-analysis outcomes after laparoscopic distal pancreatectomy (LDP) highlight mixed and insufficient results. Whereas several investigators have compared surgical outcomes of LDP vs. open distal pancreatectomy (ODP) for adenocarcinomas, few similar studies have focused on pancreatic neuroendocrine tumors (PNETs).MethodsWe reviewed the medical records of PNET patients undergoing distal pancreatectomy between 2004 and 2014. Patients were divided into LDP vs. ODP groups. Demographics, relevant comorbidities, oncologic variables, and cost-analysis data were assessed. Survival and Cox proportional hazards analyses were used to evaluate outcomes.ResultsOf the 171 distal pancreatectomies for PNETs, 73 were laparoscopic, whereas 98 were open. Patients undergoing LDP demonstrated significantly lower rates of postoperative complications (P = 0.028) and had significantly shorter hospital stays (P = 0.008). On multivariable analysis, positive resection margins (P = 0.046), G3 grade (P = 0.036), advanced WHO classification (P = 0.016), TNM stage (P = 0.018), and readmission (P = 0.019) were significantly associated with poor survival; however, method of resection (LDP vs. ODP) was not (P = 0.254). The median total direct costs of LDP vs. ODP did not differ significantly.ConclusionsIn response to the recent considerable controversy surrounding the costs and surgical outcomes of LDP vs. ODP, our results show that LDP for PNETs is cost-neutral and significantly reduces postoperative morbidity without compromising oncologic outcomes and survival.

Insulin cessation and diabetes remission after bariatric surgery in adults with insulin-treated type 2 diabetes.

OBJECTIVE The impact of bariatric surgeries on insulin-treated type 2 diabetes (I-T2D) in the general population is largely undocumented. We assessed changes in insulin treatment after bariatric surgery in a large cohort of I-T2D patients, comparing Roux-en-Y gastric bypass surgery (RYGB) with laparoscopic adjustable gastric banding (LAGB), controlling for differences in weight loss between procedures. RESEARCH DESIGN AND METHODS Of 113,638 adult surgical patients in the Bariatric Outcomes Longitudinal Database (BOLD), 10% had I-T2D. Analysis was restricted to 5,225 patients with I-T2D and at least 1 year of postoperative follow-up. Regression models were used to identify factors that predict cessation of insulin therapy. To control for differences in weight loss patterns between RYGB and LAGB, a case-matched analysis was also performed. RESULTS Of I-T2D patients who underwent RYGB (n = 3,318), 62% were off insulin at 12 months compared with 34% (n = 1,907) after LAGB (P < 0.001). Regression analysis indicated that RYGB strongly predicted insulin cessation at both 1 and 12 months postoperatively. In the case-matched analysis at 3 months, the proportion of insulin cessation was significantly higher in the RYGB group than in the LAGB group (P = 0.03), and the diabetes remission rate was higher at all time points after this surgery. RYGB was a weight-independent predictor of insulin therapy cessation early after surgery, whereas insulin cessation after LAGB was linked to weight loss. CONCLUSIONS I-T2D patients have a greater probability of stopping insulin after RYGB than after LAGB (62% vs. 34%, respectively, at 1 year), with weight-independent effects in the early months after surgery. These findings support RYGB as the procedure of choice for reversing I-T2D.

Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity

SUMMARY Adipose tissue has a dynamic immune system that adapts to changes in diet and maintains homeostatic tissue remodeling. Adipose type 1 innate lymphoid cells (AT1‐ILCs) promote pro‐inflammatory macrophages in obesity, but little is known about their functions at steady state. Here we found that human and murine adipose tissue harbor heterogeneous populations of AT1‐ILCs. Experiments using parabiotic mice fed a high‐fat diet (HFD) showed differential trafficking of AT1‐ILCs, particularly in response to short‐ and long‐term HFD and diet restriction. At steady state, AT1‐ILCs displayed cytotoxic activity toward adipose tissue macrophages (ATMs). Depletion of AT1‐ILCs and perforin deficiency resulted in alterations in the ratio of inflammatory to anti‐inflammatory ATMs, and adoptive transfer of AT1‐ILCs exacerbated metabolic disorder. Diet‐induced obesity impaired AT1‐ILC killing ability. Our findings reveal a role for AT1‐ILCs in regulating ATM homeostasis through cytotoxicity and suggest that this function is relevant in both homeostasis and metabolic disease. Graphical Abstract Figure. No Caption available. HighlightsAT1‐ILCs are enriched in mouse and human adipose tissue and are predominantly tissue residentAT1‐ILCs kill adipose tissue macrophages (ATMs) and maintain ATM homeostasisSubsets of AT1‐ILCs infiltrate adipose tissue during the onset of obesityIn obesity, AT1‐ILCs are reduced and lose their ability to kill &NA; Boulenouar et al. define different subsets of type 1 innate lymphoid cells (AT1‐ILCs) in human and murine adipose tissues and show that at steady state, AT1‐ILCs kill adipose tissue macrophages (ATMs). In obesity, cytotoxicity is impaired. Interference with AT1‐ILC cytotoxicity impacted ATM homeostasis and systemic metabolism, pointing to its importance in homeostasis and disease.

Intestinal sweet sensing pathways and metabolic changes after Roux-en-Y gastric bypass surgery

Studies suggest that improvements in type 2 diabetes (T2D) post- Roux-en-Y gastric bypass (RYGB) surgery are attributable to decreased intestinal glucose absorption capacity mediated by exclusion of sweet taste-sensing pathways in isolated proximal bowel. We probed these pathways in rat models that had undergone RYGB with catheter placement in the biliopancreatic (BP) limb to permit post-RYGB exposure of isolated bowel to sweet taste stimulants. Lean Sprague Dawley (n = 13) and obese Zucker diabetic fatty rats (n = 15) underwent RYGB with BP catheter placement. On postoperative day 11 (POD 11), rats received catheter infusions of saccharin [sweet taste receptor (T1R2/3) agonist] or saline (control). Jejunum was analyzed for changes in glucose transporter/sensor mRNA expression and functional sodium-glucose transporter 1 (SGLT1)-mediated glucose uptake. Saccharin infusion did not alter glucose uptake in the Roux limb of RYGB rats. Intestinal expression of the glucose sensor T1R2 and transporters (SGLT1, glucose transporter 2) was similar in saccharin- vs. saline-infused rats of both strains. However, the abundance of SGLT3b mRNA, a putative glucose sensor, was higher in the common limb vs. BP/Roux limb in both strains of bypassed rats and was significantly decreased in the Roux limb after saccharin infusion. We concluded that failure of BP limb exposure to saccharin to increase Roux limb glucose uptake suggests that isolation of T1R2/3 is unlikely to be involved in metabolic benefits of RYGB, as restimulation failed to reverse changes in intestinal glucose absorption capacity. The altered expression pattern of SGLT3 after RYGB warrants further investigation of its potential involvement in resolution of T2D after RYGB.

Resection or reduction? The dilemma of managing retrograde intussusception after Roux-en-Y gastric bypass.

BACKGROUND Retrograde intussusception (RI) at the jejunojejunostomy can occur after Roux-en-Y gastric bypass (RYGB). Although this complication is rare, it has been encountered more frequently as the number of bariatric procedures have increased. Little data is available to assist surgeons with the optimal management of this condition. Our objectives were to identify the risk factors for RI after RYGB and report on outcomes after surgical intervention at a tertiary academic surgical unit. METHODS We used our prospective longitudinal institutional bariatric surgical database to identify patients with post-RYGB RI from 1996 to 2011. RESULTS We identified 28 post-RYGB RI cases. The median interval between RYGB and RI was 52 months, and the median percentage of excess weight loss was 75%. Patients presented with acute symptoms in 36% of the cases. All patients underwent surgical exploration, including resection and revision of the jejunojejunostomy (46%) or operative reduction with or without enteropexy (54%). Those undergoing resection had a longer hospital stay but similar 30-day complication rates. At a median follow-up of 9 months, only 1 recurrence was documented. CONCLUSIONS RI is a rare and late complication of RYGB and typically occurs after significant weight loss. In the presence of ischemia or nonreducible RI, resection and revision of the jejunojejunostomy is recommended. In less acute patients, laparoscopic management with reduction and/or enteropexy offers a reduced hospital length of stay while maintaining equivalent morbidity and low recurrence compared with resection.

Targeted nanoparticles for colorectal cancer

Colorectal cancer (CRC) is highly prevalent worldwide, and despite notable progress in treatment still leads to significant morbidity and mortality. The use of nanoparticles as a drug delivery system has become one of the most promising strategies for cancer therapy. Targeted nanoparticles could take advantage of differentially expressed molecules on the surface of tumor cells, providing effective release of cytotoxic drugs. Several efforts have recently reported the use of diverse molecules as ligands on the surface of nanoparticles to interact with the tumor cells, enabling the effective delivery of antitumor agents. Here, we present recent advances in targeted nanoparticles against CRC and discuss the promising use of ligands and cellular targets in potential strategies for the treatment of CRCs.

Foregut exclusion disrupts intestinal glucose sensing and alters portal nutrient and hormonal milieu

The antidiabetes effects of Roux-en-Y gastric bypass (RYGB) are well-known, but the underlying mechanisms remain unclear. Isolating the proximal small intestine, and in particular its luminal glucose sensors, from the nutrient stream has been proposed as a critical change, but the pathways involved are unclear. In a rodent model, we tested the effects of isolating and then stimulating a segment of proximal intestine using glucose analogs to examine their impact on glucose absorption (Gabsorp) and hormone secretion after a glucose bolus into the distal jejunum. Analogs selective for sodium-glucose cotransporter (SGLT) family members and the sweet taste receptor were tested, and measurements of the portosystemic gradient were used to determine Gabsorp and hormone secretion, including GLP-1. Proximal intestinal isolation reduced Gabsorp and GLP-1 secretion. Stimulation of the glucose-sensing protein SGLT3 increased Gabsorp and GLP-1 secretion. These effects were abolished by vagotomy. Sweet taste receptor stimulation only increased GLP-1 secretion. This study suggests a novel role for SGLT3 in coordinating intestinal function, as reflected by the concomitant modulation of Gabsorp and GLP-1 secretion, with these effects being mediated by the vagus nerve. Our findings provide potential mechanistic insights into foregut exclusion in RYGB and identify SGLT3 as a possible antidiabetes therapeutic target.

Hiatal hernia repair and gastroesophageal reflux disease in gastric banding patients: Analysis of a national database

BACKGROUND Hiatal hernia (HH) is a risk factor for complications after laparoscopic adjustable gastric banding (LAGB), with recommendation to repair these at the time of LAGB placement. We reviewed the characteristics and outcomes of bariatric patients undergoing HH repair during LAGB. The aim of this study was to determine the prevalence of HH repair in LAGB patients and its potential effect on outcomes. METHODS Using the Bariatric Outcomes Longitudinal Database, we identified patients who had hiatal hernia repair at the time of their LAGB (HHR group) and compared them to other LAGB patients without a HH repair (NonHHR group). RESULTS Of 41,611 patients who underwent LAGB during 2007-2010, 8120 (19.5%) had HH repair (HHR), adding only 4 minutes to the operating time, without an increase in blood transfusion, length of stay, or band-related complications. Preoperatively, the HHR cohort had a higher incidence of gastroesophageal reflux disease (GERD) compared with nonHHR (49% versus 40%, respectively; P<.001) with a higher GERD score (1.13 versus .88, respectively; P<.001). Of those with GERD, similar percentage of patients in the HHR and nonHHR groups experienced improvement 1-year after surgery (53% versus 52%, respectively, P = .4), with similar GERD scores at this time point. CONCLUSION HH are repaired in one fifth of LAGB patients, with a surprisingly minimal increase in operative times and no change in length of stay, morbidity, or mortality. In patients with GERD, HH repair had minimal effect on postoperative improvements in reflux symptoms. These findings suggest that many of the repairs may involve small hernias with unclear clinical effect.