Sleeve gastrectomy and Roux-en-Y gastric bypass in the treatment of type 2 diabetes. Two-year results from a Swedish multicenter randomized controlled trial.

BACKGROUND: Obesity is a world-wide epidemic and it is a risk factor for type 2 diabetes (T2D). Few randomized controlled studies have compared the 2 most common surgical procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) in the treatment of obese patients with T2D. OBJECTIVES: To compare diabetes remission rates (glycosylated hemoglobin ≤6.0%, without diabetes medications) in obese T2D patients (body mass index, 35-50) undergoing RYGB or SG. SETTING: Three University Hospital clinics and 1 Regional Hospital in Sweden. METHODS: Forty-nine patients with T2D were included. Twenty-five were randomized to RYGB and 24 to SG. There was no difference between groups regarding patient characteristics, duration of T2D, overall usage of antidiabetic medications, or glycosylated hemoglobin levels. All patients (100%) completed 1-year follow-up and 47 (95.9%) 2-year follow-up. RESULTS: Remission of T2D was not significantly different between the RYGB and SG, reaching 44% and 46% (n = 25 and n = 24, respectively, P = .897, power = .80) at 1 year, and 48% and 55% (n = 25 and n = 22, respectively, P = .654) at 2 years of follow-up. Similarly, mean glycosylated hemoglobin was improved in both groups at 1 and 2 years, with no significant differences between the groups (RYGB baseline versus 1 yr; mean ± standard deviation: 7.9 ± 1.5 versus 5.8 ± .6%, P < .0001; versus 2 yr: 5.9 ± .7%, P < .0001; SG baseline versus 1 yr: 8.2 ± 1.9 versus 5.9 ± .7%, P < .0001; versus 2 yr: 5.9 ± 1.1%, P < .0001). Total weight loss was not different but percentage excess weight loss was higher after RYGB compared with SG both at 1 and 2 years; mean ± standard deviation: 78 ± 22 versus 60 ± 22%, and 76 ± 24 versus 54 ± 21%, respectively (P < .01 for both). Waist circumference also decreased significantly more in the RYGB group. CONCLUSIONS: Despite superior excess weight loss after RYGB, T2D remission rates did not differ significantly between RYGB and SG after 2 years. Long-term follow-up data are needed to define the role of SG in the treatment of patients with obesity and T2D.

Fucose-Galactose Polymers Inhibit Cholera Toxin Binding to Fucosylated Structures and Galactose-Dependent Intoxication of Human Enteroids.

A promising strategy to limit cholera severity involves blockers mimicking the canonical cholera toxin ligand (CT) ganglioside GM1. However, to date the efficacies of most of these blockers have been evaluated in noncellular systems that lack ligands other than GM1. Importantly, the CT B subunit (CTB) has a noncanonical site that binds fucosylated structures, which in contrast to GM1 are highly expressed in the human intestine. Here we evaluate the capacity of norbornene polymers displaying galactose and/or fucose to block CTB binding to immobilized protein-linked glycan structures and also to primary human and murine small intestine epithelial cells (SI ECs). We show that the binding of CTB to human SI ECs is largely dependent on the noncanonical binding site, and interference with the canonical site has a limited effect while the opposite is observed with murine SI ECs. The galactose-fucose polymer blocks binding to fucosylated glycans but not to GM1. However, the preincubation of CT with the galactose-fucose polymer only partially blocks toxic effects on cultured human enteroid cells, while preincubation with GM1 completely blocks CT-mediated secretion. Our results support a model whereby the binding of fucose to the noncanonical site places CT in close proximity to scarcely expressed galactose receptors such as GM1 to enable binding via the canonical site leading to CT internalization and intoxication. Our finding also highlights the importance of complementing CTB binding studies with functional intoxication studies when assessing the efficacy inhibitors of CT.

The pros and cons of gastric bypass surgery - The role of the Roux-limb.

The prevalence of overweight and obesity has exploded in the post-industrial era. Life style interventions like dieting and exercise can induce a marked weight loss, but the main problem for most patients is to maintain the reduced body weight over time. Gastric bypass surgery is a commonly performed and very effective method for achieving a pronounced and sustained weight loss including metabolic improvements in obese patients. Despite the therapeutic successfulness there are known side-effects like chronic postprandial nausea and pain that in some patients become intractable. The pathophysiology is complex and partly unexplored. The physician or surgeon handling a patient with "post-bariatric symptoms" must be aware of the risk for symptom aggravations due to iatrogenic opioid-associated intestinal dysmotility. The present paper gives a brief overview of obesity surgery and its associated postsurgical conditions with a focus on the unexplored role of the Roux-limb following gastric bypass surgery.

Roux Limb Motility in Gastric Bypass Patients with Chronic Abdominal Pain-Is There an Association to Prescribed Opioids?

BACKGROUND/AIM: A number of patients continue to suffer from chronic abdominal pain of unknown origin, which may also lead to a prolonged use of opioid analgesics. Symptoms of abdominal pain, nausea and vomiting in this patient group resemble the characteristics of the Roux stasis Syndrome. The aim was to elucidate relationships between chronic abdominal pain, Roux limb motor activity and opioid analgesics. METHODS: Roux limb high-resolution manometry and ratings of abdominal pain and quality of life were analysed in 15 gastric bypass patients reporting abdominal pain of unknown origin. Effect of acute opiate administration (morphine i.v.) on fasting Roux limb motor activity was assessed in asymptomatic and morphine-naïve gastric bypass patients (n = 9) and compared with an untreated control group (n = 11). RESULTS: In the symptomatic patient group, we found disturbed Roux limb motor patterns in 10 out of 15 examinations, but no signs of Roux stasis syndrome. A high prevalence of prescribed opioid analgesics as well as a high number of reoperations in this group. The worst quality of life and the highest number of pain-killing medications were observed among the patients with distal pacemaker activity in Roux limb. In the morphine-naïve and asymptomatic patients, morphine increased the muscular tone in the Roux limb during phase III-like motor activity. A majority of the RYGBP patients with chronic abdominal pain had a disturbed Roux limb fasting motility, and there was a high prevalence of prescribed opioid analgesics. In opiate-naïve RYGBP patients, acute morphine intravenously increased the muscular tone of the Roux limb.

Fucosylated Molecules Competitively Interfere with Cholera Toxin Binding to Host Cells.

Cholera toxin (CT) enters host intestinal epithelia cells, and its retrograde transport to the cytosol results in the massive loss of fluids and electrolytes associated with severe dehydration. To initiate this intoxication process, the B subunit of CT (CTB) first binds to a cell surface receptor displayed on the apical surface of the intestinal epithelia. While the monosialoganglioside GM1 is widely accepted to be the sole receptor for CT, intestinal epithelial cell lines also utilize fucosylated glycan epitopes on glycoproteins to facilitate cell surface binding and endocytic uptake of the toxin. Further, l-fucose can competively inhibit CTB binding to intestinal epithelia cells. Here, we use competition binding assays with l-fucose analogs to decipher the molecular determinants for l-fucose inhibition of cholera toxin subunit B (CTB) binding. Additionally, we find that mono- and difucosylated oligosaccharides are more potent inhibitors than l-fucose alone, with the LeY tetrasaccharide emerging as the most potent inhibitor of CTB binding to two colonic epithelial cell lines (T84 and Colo205). Finally, a non-natural fucose-containing polymer inhibits CTB binding two orders of magnitude more potently than the LeY glycan when tested against Colo205 cells. This same polymer also inhibits CTB binding to T84 cells and primary human jejunal epithelial cells in a dose-dependent manner. These findings suggest the possibility that polymeric display of fucose might be exploited as a prophylactic or therapeutic approach to block the action of CT toward the human intestinal epithelium.

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin.

AIMS/HYPOTHESIS: In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo. METHODS: Six-week-old male C57BL/6J wild-type and Adipoq -/- mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12 weeks and given vehicle or AICAR (500 µg/g) three times/week from weeks 4-12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35-50 kg/m2) individuals were incubated with vehicle or AICAR (1 mmol/l) for 6 h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry. RESULTS: AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8+ T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p < 0.05), urinary H2O2 (p < 0.05) and renal superoxide levels (p < 0.01) in both wild-type and Adipoq -/- mice. AICAR-mediated protection occurred independently of adiponectin, as similar protection was observed in wild-type and Adipoq -/- mice. In addition, AICAR promoted an M1-to-M2 macrophage phenotype switch and reduced TNF-α production in tissue explants from obese human patients. CONCLUSIONS/INTERPRETATION: AICAR may promote metabolic health and protect against obesity-induced systemic diseases in an adiponectin-independent manner. Furthermore, AICAR reduced inflammation in human adipose tissue explants, suggesting by proof-of-principle that the drug may reduce obesity-induced complications in humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT02322073.

Manometry of the Upper Gut Following Roux-en-Y Gastric Bypass Indicates That the Gastric Pouch and Roux Limb Act as a Common Cavity.

BACKGROUND: The motility of the upper gut after Roux-en-Y gastric bypass (RYGBP) is underexplored. We aimed to investigate the oesophago-gastro-Roux limb motor activity during fasting and after food intake. METHODS: Eighteen morbidly obese patients were examined at least 2 years after RYGBP. A high-resolution manometry catheter was positioned to straddle the oesophagogastric junction, the gastric pouch and the proximal Roux limb using transmucosal potential difference measurements. Three patients with vertical banded gastroplasty (VBG) were also studied. RESULTS: During the fasting state, the gastric pouch had low or no activity whereas the Roux limb exhibited regular migrating motility complexes (MMCs) being initiated just distal to gastroenteroanastomosis. Median cycle duration was 72 min, and the median propagating velocity of the phase III MMC phase was 2.7 cm/min (n = 8). When patients were asked to eat until they felt comfortably full, intraluminal pressure increased by 6 to 8 cmH2O without any significant difference between gastric pouch and the Roux limb (n = 9). The increased intraluminal pressure following food intake correlated neither to weight loss nor to meal size or rate of eating. CONCLUSIONS: A successful RYGBP is associated with MMC in the Roux limb during fasting. The gastric pouch and the Roux limb behaved as a common cavity during food ingestion. Data do not support the hypothesis that the alimentary limb pressure in response to food intake influences either meal size or weight loss.

Changes in the mucosa of the Roux-limb after gastric bypass surgery.

AIMS: Roux-en-Y gastric bypass surgery is the most efficient treatment of morbid obesity, but the mechanisms of action are still poorly understood. The aim of this study was to explore the Roux-limb mucosa after gastric bypass surgery, focusing upon basic morphology and inflammation. METHODS AND RESULTS: Jejunal mucosal samples from the Roux-limb were gathered from eight patients at time of surgery and 6-8 months postsurgery. Histological evaluation of inflammation and morphometric investigations were performed, cell proliferation was assessed using immunohistochemistry and inflammatory markers and angiotensin (Ang) II receptors were detected using Western blot. Cell proliferation increased and villous surface area decreased in the Roux-limb mucosa but no signs of active inflammation were observed after surgery. Protein analyses showed increased levels of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, myeloperoxidase (MPO) and the Ang II type 1(AT(1)) receptor after surgery, whereas the levels of inducible nitric oxide synthase (iNOS), nitrotyrosine and the Ang II type 2(AT(2)) receptor remained constant. CONCLUSION: These results indicate that the phenotype of the jejunal mucosa changes once exposed to undigested food and the increased microbial load in the Roux-limb after surgery.

Is the Roux limb a determinant for meal size after gastric bypass surgery?

The Roux-Y gastric bypass (RYGBP) is an effective weight-reducing procedure but the involved mechanisms of action are obscure. The Roux limb is the intestinal segment that following surgery is the primary recipient for food intake. The aims of the study were to explore the mechanosensory and biomechanical properties of the Roux limb and to make correlations with preferred meal size. Ten patients participated and were examined preoperatively, 6 weeks and 1 year after RYGBP. Each subject ingested unrestricted amounts of a standardized meal and the weight of the meal was recorded. On another study day, the Roux limb was subjected to gradual distension by the use of an intraluminal balloon. Luminal volume-pressure relationships and thresholds for induction of sensations were monitored. At 6 weeks and 1 year post surgery, the subjects had reduced their meal sizes by 62% and 41% (medians), respectively, compared to preoperative values. The thresholds for eliciting distension-induced sensations were strongly and negatively correlated to the preferred meal size. Intraluminal pressure during Roux limb distension, both at low and high balloon volumes, correlated negatively to the size of the meal that the patients had chosen to eat. The results suggest that the Roux limb is an important determinant for regulating food intake after Roux-Y bypass bariatric surgery.

Image quality and myocardial scar size determined with magnetic resonance imaging in patients with permanent atrial fibrillation: a comparison of two imaging protocols.

BACKGROUND: Magnetic resonance imaging (MRI) of the heart generally requires breath holding and a regular rhythm. Single shot 2D steady-state free precession (SS_SSFP) is a fast sequence insensitive to arrhythmia as well as breath holding. Our purpose was to determine image quality, signal-to-noise (SNR) and contrast-to-noise (CNR) ratios and infarct size with a fast single shot and a standard segmented MRI sequence in patients with permanent atrial fibrillation and chronic myocardial infarction. METHODS: Twenty patients with chronic myocardial infarction and ongoing atrial fibrillation were examined with inversion recovery SS_SSFP and segmented inversion recovery 2D fast gradient echo (IR_FGRE). Image quality was assessed in four categories: delineation of infarcted and non-infarcted myocardium, occurrence of artefacts and overall image quality. SNR and CNR were calculated. Myocardial volume (ml) and infarct size, expressed as volume (ml) and extent (%), were calculated, and the methodological error was assessed. RESULTS: SS_SSFP had significantly better quality scores in all categories (P = 0.037, P = 0.014, P = 0.021, P = 0.03). SNR(infarct) and SNR(blood) were significantly better for IR_FGRE than for SS_SSFP (P = 0.048, P = 0.018). No significant difference was found in SNR(myocardium) and CNR. The myocardial volume was significantly larger with SS_SSFP (170.7 versus 159.2 ml, P<0.001), but no significant difference was found in infarct volume and infarct extent. CONCLUSION: SS_SSFP displayed significantly better image quality than IR_FGRE. The infarct size and the error in its determination were equal for both sequences, and the examination time was shorter with SS_SSFP.

Late gadolinium uptake demonstrated with magnetic resonance in patients where automated PERFIT analysis of myocardial SPECT suggests irreversible perfusion defect.

BACKGROUND: Myocardial perfusion single photon emission computed tomography (MPS) is frequently used as the reference method for the determination of myocardial infarct size. PERFIT(R) is a software utilizing a three-dimensional gender specific, averaged heart model for the automatic evaluation of myocardial perfusion. The purpose of this study was to compare the perfusion defect size on MPS, assessed with PERFIT, with the hyperenhanced volume assessed by late gadolinium enhancement magnetic resonance imaging (LGE) and to relate their effect on the wall motion score index (WMSI) assessed with cine magnetic resonance imaging (cine-MRI) and echocardiography (echo). METHODS: LGE was performed in 40 patients where clinical MPS showed an irreversible uptake reduction suggesting a myocardial scar. Infarct volume, extent and major coronary supply were compared between MPS and LGE as well as the relationship between infarct size from both methods and WMSI. RESULTS: MPS showed a slightly larger infarct volume than LGE (MPS 29.6 +/- 23.2 ml, LGE 22.1 +/- 16.9 ml, p = 0.01), while no significant difference was found in infarct extent (MPS 11.7 +/- 9.4%, LGE 13.0 +/- 9.6%). The correlation coefficients between methods in respect to infarct size and infarct extent were 0.71 and 0.63 respectively. WMSI determined with cine-MRI correlated moderately with infarct volume and infarct extent (cine-MRI vs MPS volume r = 0.71, extent r = 0.71, cine-MRI vs LGE volume r = 0.62, extent r = 0.60). Similar results were achieved when wall motion was determined with echo. Both MPS and LGE showed the same major coronary supply to the infarct area in a majority of patients, Kappa = 0.84. CONCLUSION: MPS and LGE agree moderately in the determination of infarct size in both absolute and relative terms, although infarct volume is slightly larger with MPS. The correlation between WMSI and infarct size is moderate.

Computer-assisted calculation of myocardial infarct size shortens the evaluation time of contrast-enhanced cardiac MRI.

BACKGROUND: Delayed enhancement magnetic resonance imaging depicts scar in the left ventricle which can be quantitatively measured. Manual segmentation and scar determination is time consuming. The purpose of this study was to evaluate a software for infarct quantification, to compare with manual scar determination, and to measure the time saved. METHODS: Delayed enhancement magnetic resonance imaging was performed in 40 patients where myocardial perfusion single photon emission computed tomography imaging showed irreversible uptake reduction suggesting a myocardial scar. After segmentation, the semi-automatic software was applied. A scar area was displayed, which could be corrected and compared with manual delineation. The different time steps were recorded with both methods. RESULTS: The software shortened the average evaluation time by 12.4 min per cardiac exam, compared with manual delineation. There was good correlation of myocardial volume, infarct volume and infarct percentage (%) between the two methods, r = 0.95, r = 0.92 and r = 0.91 respectively. CONCLUSION: A computer software for myocardial volume and infarct size determination cut the evaluation time by more than 50% compared with manual assessment, with maintained clinical accuracy.