Effects Of Gastric Bypass Surgery Research Articles

Long-Term Protective Effects and Mechanisms of Gastric Bypass Surgery on the Kidneys in Hypertensive Obese Rat.

Investigate the long-term protective effects of gastric bypass surgery on the kidneys of hypertensive obese rats to better understand the role of gastric bypass surgery in preventing renal injury in humans with hypertension and obesity. Compare 6-week-old spontaneously hypertensive rats, including 30 Roux-en-Y gastric bypass (RYGB) and 30 sham operations. Body weight and blood pressure were monitored before and up to 12 months after the operation. Blood lipids, blood creatinine, and blood urea nitrogen were measured. Kidney pathology was assessed using HE staining, while renal fibrosis was observed via Masson staining. Inflammatory indicators were examined by ELISA. The expression of the NLRP3 gene in the kidney was measured using immunofluorescence and western blot, and the changes in key pathways including ASC/IL-1β protein were verified. RYGB reduced the body weight of hypertensive obese rats and had a protective effect on blood pressure. Additionally, the bypass effectively mitigated renal inflammation and fibrosis. Moreover, RYGB modulated the expression of NLRP3 and prevented kidney damage via the ASC/IL-1 pathway. This study validates that RYGB effectively attains sustained blood pressure control in hypertensive obese rats and has a potential kidney-protective mechanism via the NLRP3-ASC/IL-1β pathway.

Gastric bypass surgery in morbid obesity: Influence on thyroid function tests and insulin resistance status.

There are inconsistent results about the effect of gastric bypass surgery on thyroid function tests in morbidly obese subjects. The aim of this study was to investigate the changes in thyroid function tests and insulin resistance status in euthyroid morbidly obese subjects before and three months after gastric bypass surgery (GBS). Twenty-nine subjects with morbid obesity (BMI≥40) were enrolled in this before-after study. Patients with known thyroid disorders or a history of thyroid ablative therapy, users of drugs that affect thyroid function, or fasting blood sugar and insulin were excluded. TSH, Free T4, total T3, fasting blood sugar and insulin level, and BMI were measured before and 3 months after GBS. Statistical analysis was performed with appropriate tests and p<0.05 was considered significant. Body mass index (BMI), insulin sensitivity index (HOMA-IR), and total T3 significantly decreased after bypass surgery (all with p<0.001) but no significant changes were seen in TSH (P=0.203) and FreeT4 (P=0.33). There was a significant negative correlation between changes in HOMA-IR and changes in FreeT4 (P=0.038, r= -0.38). There was no statistically significant correlation between the percentage of excess BMI loss (%EBMIL) and changes in T3 (P=0.66), Free T4 (P=0.92), TSH (P= 0.27), and HOMA-IR (P=0.17). Although significant changes can occur in BMI, insulin sensitivity index, fasting blood sugar, and T3 in short-time follow-up after bariatric surgery, significant TSH and FreeT4 changes may need longer follow-ups.

Roux-en-Y and One-Anastomosis Gastric Bypass Surgery Are Superior to Sleeve Gastrectomy in Lowering Glucose and Cholesterol Levels Independent of Weight Loss: a Propensity-Score Weighting Analysis.

The superior effects of gastric bypass surgery in preventing cardiovascular diseases compared with sleeve gastrectomy are well-established. However, whether these effects are independent of weight loss is not known. In this retrospective cohort study, we compared the change in cardiometabolic risks of 1073 diabetic patients undergoing Roux-en-Y gastric bypass (RYGB) (n = 265), one-anastomosis gastric bypass (OAGB) (n = 619), and sleeve gastrectomy (SG) (n = 189) with equivalent weight loss from the Min-Shen General Hospital. Propensity score-weighting, multivariate regression, and matching were performed to adjust for baseline differences. After 12 months, OAGB and, to a lesser extent, RYGB exhibited superior effects on glycemic control compared with SG in patients with equivalent weight loss. The effect was significant in patients with mild-to-modest BMI reduction but diminished in patients with severe BMI reduction. RYGB and OAGB had significantly greater effects in lowering total and low-density lipoprotein cholesterol than SG, regardless of weight loss. The results of matching patients with equivalent weight loss yielded similar results. The longer length of bypassed biliopancreatic (BP) limbs was correlated with a greater decrease in glycemic levels, insulin resistance index, lipids, C-reactive protein (CRP) levels, and creatinine levels in patients receiving RYBG. It was correlated with greater decreases in BMI, fasting insulin, insulin resistance index, and C-reactive protein levels in patients receiving OAGB. Diabetic patients receiving OAGB and RYGB had lower glucose and cholesterol levels compared with SG independent of weight loss. Our results suggest diabetic patients with cardiovascular risk factors such as hypercholesterolemia to receive bypass surgery.

The effect of gastric bypass surgery on cognitive function of Alzheimer's disease and the role of GLP1-SGLT1 pathway

ObjectiveGastric bypass surgery has been shown to improve metabolic profiles via GLP1, which may also have cognitive benefits for Alzheimer's disease (AD) patients. However, the exact mechanism requires further investigation. MethodsRoux-en-Y gastric bypass or sham surgery was performed on APP/PS1/Tau triple transgenic mice (an AD mice model) or wild type C57BL/6 mice. Morris Water Maze (MWM) test was used to evaluate the cognitive function of mice and animal tissue samples were obtained for measurements two months after the surgery. Additionally, STC-1 intestine cells were treated with siTAS1R2 and siSGLT1, and HT22 nerve cells were treated with Aβ, siGLP1R, GLP1 and siSGLT1 in vitro to explore the role of GLP1-SGLT1 related signaling pathway in cognitive function. ResultsThe MWM test showed that bypass surgery significantly improved cognitive function in AD mice as measured by navigation and spatial probe tests. Moreover, bypass surgery reversed neurodegeneration, down-regulated hyperphosphorylation of Tau protein and Aβ deposition, improved glucose metabolism, and up-regulated the expression of GLP1, SGLT1, and TAS1R2/3 in the hippocampus. Furthermore, GLP1R silencing down-regulated SGLT1 expression, whereas SGLT1 silencing increased Tau protein deposition and exacerbated dysregulated of glucose metabolism in HT22 cells. However, RYGB did not alter the level of GLP1 secretion in the brainstem (where central GLP1 is mainly produced). Additionally, GLP1 expression was upregulated by RYGB via TAS1R2/3-SGLT1 activation sequentially in the small intestine. ConclusionRYGB surgery could improve cognition function in AD mice through facilitating glucose metabolism and reducing Tau phosphorylation and Aβ deposition in the hippocampus, mediated by peripheral serum GLP1 activation of SGLT1 in the brain. Furthermore, RYGB increased GLP1 expression through sequential activation of TAS1R2/TAS1R3 and SGLT1 in the small intestine.

Effects of gastric bypass surgery on brain connectivity responses to hypoglycemia

IntroductionRoux-en-Y gastric bypass (RYGB) leads to beneficial effects on glucose homeostasis, and attenuated hormonal counterregulatory responses to hypoglycemia are likely to contribute. RYGB also induces alterations in neural activity of cortical and subcortical brain regions. We aimed to characterize RYGB-induced changes in resting-state connectivity of specific brain regions of interest for energy homeostasis and behavioral control during hypoglycemia.MethodTen patients with BMI > 35 kg/m2 were investigated with brain PET/MR imaging during a hyperinsulinemic normo- and hypoglycemic clamp, before and 4 months after RYGB. Hormonal levels were assessed throughout the clamp. Resting-state (RS) fMRI scans were acquired in the glucose-lowering phase of the clamp, and they were analyzed with a seed-to-voxel approach.ResultsRS connectivity during initiation of hypoglycemia was significantly altered after RYGB between nucleus accumbens, thalamus, caudate, hypothalamus and their crosstalk with cortical and subcortical regions. Connectivity between the nucleus accumbens and the frontal pole was increased after RYGB, and this was associated with a reduction of ACTH (r = −0.639, p = 0.047) and cortisol (r = −0.635, p = 0.048) responses. Instead, connectivity between the caudate and the frontal pole after RYGB was reduced and this was associated with less attenuation of glucagon response during the hypoglycemic clamp (r = −0.728, p = 0.017), smaller reduction in fasting glucose (r = −0.798, p = 0.007) and less excess weight loss (r = 0.753, p = 0.012). No other significant associations were found between post-RYGB changes in ROI-to-voxel regional connectivity hormonal responses and metabolic or anthropometric outcomes.ConclusionRYGB alters brain connectivity during hypoglycemia of several neural pathways involved in reward, inhibitory control, and energy homeostasis. These changes are associated with altered hormonal responses to hypoglycemia and may be involved in the glucometabolic outcome of RYGB.

Effect of Gastric Bypass Surgery on the Oxidative Stress Status in Morbidly Obese Patients

Effect of Gastric Bypass Surgery on the Oxidative Stress Status in Morbidly Obese Patients

Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesity

BackgroundBariatric surgery remains the most effective therapy for adiposity reduction and remission of type 2 diabetes. Although different bariatric procedures associate with pronounced shifts in the gut microbiota, their functional role in the regulation of energetic and metabolic benefits achieved with the surgery are not clear.MethodsTo evaluate the causal as well as the inherent therapeutic character of the surgery-altered gut microbiome in improved energy and metabolic control in diet-induced obesity, an antibiotic cocktail was used to eliminate the gut microbiota in diet-induced obese rats after gastric bypass surgery, and gastric bypass-shaped gut microbiota was transplanted into obese littermates. Thorough metabolic profiling was combined with omics technologies on samples collected from cecum and plasma to identify adaptions in gut microbiota-host signaling, which control improved energy balance and metabolic profile after surgery.ResultsIn this study, we first demonstrate that depletion of the gut microbiota largely reversed the beneficial effects of gastric bypass surgery on negative energy balance and improved glucolipid metabolism. Further, we show that the gastric bypass-shaped gut microbiota reduces adiposity in diet-induced obese recipients by re-activating energy expenditure from metabolic active brown adipose tissue. These beneficial effects were linked to improved glucose homeostasis, lipid control, and improved fatty liver disease. Mechanistically, these effects were triggered by modulation of taurine metabolism by the gastric bypass gut microbiota, fostering an increased abundance of intestinal and circulating taurine-conjugated bile acid species. In turn, these bile acids activated gut-restricted FXR and systemic TGR5 signaling to stimulate adaptive thermogenesis.ConclusionOur results establish the role of the gut microbiome in the weight loss and metabolic success of gastric bypass surgery. We here identify a signaling cascade that entails altered bile acid receptor signaling resulting from a collective, hitherto undescribed change in the metabolic activity of a cluster of bacteria, thereby readjusting energy imbalance and metabolic disease in the obese host. These findings strengthen the rationale for microbiota-targeted strategies to improve and refine current therapies of obesity and metabolic syndrome.EwgMgWdyzTrcZAy8SV_UeeVideo Graphical abstractBariatric Surgery (i.e. RYGB) or the repeated fecal microbiota transfer (FMT) from RYGB donors into DIO (diet-induced obesity) animals induces shifts in the intestinal microbiome, an effect that can be impaired by oral application of antibiotics (ABx). Our current study shows that RYGB-dependent alterations in the intestinal microbiome result in an increase in the luminal and systemic pool of Taurine-conjugated Bile acids (TCBAs) by various cellular mechanisms acting in the intestine and the liver. TCBAs induce signaling via two different receptors, farnesoid X receptor (FXR, specifically in the intestines) and the G-protein-coupled bile acid receptor TGR5 (systemically), finally resulting in metabolic improvement and advanced weight management. BSH, bile salt hydrolase; BAT brown adipose tissue.

Evaluating the Effects of Gastric By-Pass Surgery and Sleeve Gastrectomy, as New GDV Treatment Modalities, on Vitamin B12 Values in Dogs

The purpose of this study is to evaluate the effects of gastric bypass surgery and sleeve gastrectomy on vitamin B12 values in dogs. Gastric dilation and volvulus (GDV) is an acute disease with a high mortality rate in dogs. Either gastric bypass surgery or sleeve gastrectomy can be utilized as surgical treatments for GDV. These techniques can provide increased success and fewer complications, however, one undesirable outcome can be vitamin B12 insufficiency. Three groups of dogs received gastric surgeries, one group underwent gastric rotation and derotation with no tissue gastric incisions, the two other groups had gastric bypass surgery and sleeve gastrectomy. Vitamin B12 level was evaluated two weeks prior to surgery, at the time of surgery, two, four, and six weeks after surgery. The results demonstrated no inter-group differences two weeks prior to surgery until four weeks after surgery. However, six weeks post-operation, significant differences between the sleeve gastrectomy group, and the other two groups were shown in vitamin B12 levels. Gastric bypass surgery and sleeve gastrectomy can both be utilized as new surgical managements of GDV. However, as we have demonstrated in this article, an important expected side effect is vitamin B12 insufficiency, in dogs that receive sleeve gastrectomy for GDV treatment. This necessary element must be substituted artificially for all dogs which had received these surgical managements.

Quality of life after gastric bypass surgery in patients with type 2 diabetes: patients\u2019 experiences during 2\xa0years of follow-up

BackgroundTo examine the effects of gastric bypass surgery on health-related quality of life (HRQoL) in obese patients with type 2 diabetes, and to investigate their experiences of life adjustments using quantitative and qualitative methods.MethodsThirteen patients with type 2 diabetes and obesity, (body mass index, BMI > 30 kg/m2), participating in a randomized clinical trial, completed this sub-study. HRQoL was evaluated before, and at 6 months and 2 years after gastric bypass surgery, using the RAND- 36-item health survey. At 2 years, interviews for in-depth analysis of HRQoL changes were performed.ResultsSignificant improvement was observed from baseline to 6 months for 2 of the eight health concepts, general health, and emotional well-being. At 2 years, improvements were also seen in physical functioning, energy/fatigue, as well as sustained improvements in general health and emotional well-being. Multiple regression analyses showed mostly non-significant associations between the magnitude of decrease in weight, BMI, and HbA1c during follow-up and improvement in HRQoL. The analyses from qualitative interviews supported a common latent theme “Finding a balance between the experience of the new body weight and self-confidence”.ConclusionsThe improved HRQoL after gastric bypass surgery in obese patients with type 2 diabetes was not explained specifically by the magnitude of weight loss, but rather by the participants achieving a state of union between body and consciousness.Trial registration ClinicalTrials.gov Identifier NCT02729246. Date of registration 6 April 2016 – Retrospectively registered https://clinicaltrials.gov/ct2/show/NCT02729246?term=bariglykos&draw=2&rank=1

Long-term Effects of Gastric Bypass Surgery in Patients with Obstructive Sleep Apnea

Background: Obstructive sleep apnea is a common disorder involving, intermittent mechanical obstruction of the upper airway during sleep. Obesity is the most powerful risk factor for obstructive sleep apnea. Objective: This study aimed to investigate the long-term effect of Roux-en-Y gastric bypass bariatric surgery on patients with obstructive sleep apnea. Methods: This study included patients were referred for bariatric surgery (Roux-en-Y gastric bypass) to control symptoms and complications of obesity during a 5-year period. An overnight sleep study was performed for each patient before and after the bariatric surgery, to study its effect on different obstructive sleep apnea-related variables. Results: This study included 179 patients (mean age 35.9 ± 10.7 years). The mean duration from preoperative assessment to postoperative assessment was 2.4 ± 2.2 years. The mean change in body mass index and weight showed a decrease of 16.0 ± 16.0 kg/m2 and48.7 ± 25.9 kg, respectively. The apnea hypopnea index decreased by a mean of 22.6 ± 26.3 events/hour. Conclusion: We concluded that a decrease in the body mass index by 1 kg/m2 could predict a decrease in the apnea hypopnea index by 0.46 events/hour. Moreover, after mean follow-up duration of 2.4 years, 84.3% of mild and 83.3% of moderate obstructive sleep apnea patients became normal postoperatively.

Metabolic Effects of Gastric Bypass Surgery: Is It All About Calories?

Bariatric surgery is an efficient method to induce weight loss and also, frequently, remission of type 2 diabetes (T2D). Unpaired studies have shown bariatric surgery and dietary interventions to differentially affect multiple hormonal and metabolic parameters, suggesting that bariatric surgery causes T2D remission at least partially via unique mechanisms. In the current study, plasma metabolite profiling was conducted in patients with (n = 10) and without T2D (n = 9) subjected to Roux-en-Y gastric bypass surgery (RYGB). Mixed-meal tests were conducted at baseline, after the presurgical very-low-calorie diet (VLCD) intervention, immediately after RYGB, and after a 6-week recovery period. Thereby, we could compare fasted and postprandial metabolic consequences of RYGB and VLCD in the same patients. VLCD yielded a pronounced increase in fasting acylcarnitine levels, whereas RYGB, both immediately and after a recovery period, resulted in a smaller but opposite effect. Furthermore, we observed profound changes in lipid metabolism following VLCD but not in response to RYGB. Most changes previously associated with RYGB were found to be consequences of the presurgical dietary intervention. Overall, our results question previous findings of unique metabolic effects of RYGB and suggest that the effect of RYGB on the metabolite profile is mainly attributed to caloric restriction.

1901-P: Individual and Longitudinal Effects of Gastric Bypass Surgery on the Circulating Proteome

Roux-en-Y gastric bypass surgery (RYGB) has been effective for inducing weight-loss and remission of diabetes in obese persons. Nonetheless, the response to RYGB and resulting improvements in glycemic control are heterogeneous and not well understood. To gain molecular insights into how individuals respond to RYGB, we monitored the longitudinal effects of RYGB surgery via circulating proteins. We quantified 368 proteins using multiplexed and sensitive immunoassays (Olink) in sera collected from 146 obese persons with T2D (BMI &amp;gt; 35 kg/m2) prior to, and at one and three months after surgery. We observed an overall longitudinal change in circulating levels for ∼50% of the proteins (FDR &amp;lt; 0.01). This included a post-RYGB increase in levels of GH, IGFBP-2, NT-proBNP, REGA1 and MMP-3, as well as a decrease in levels of SSC4D, SERPINA12, GIF, FBP1, CES1. To deconvolute the inter-individual heterogeneity of the circulating proteomes and protein-related longitudinal dynamics, we clustered the total of ∼44,000 protein profiles into 10 response patterns. Just 8% (28/368) of the proteins’ levels changed in a common manner across the majority of individuals, as these were grouped into 3 or fewer clusters. Among these were proteins related to adipogenesis (LEP, DLK1, GH), white adipocyte differentiation (LEP, FABP4), as well as innate immunity (CHIT1, PTX3, CSTB). However, out of these 28 proteins, only levels of VSIG2 were significantly associated (FDR &amp;lt; 0.01) with diabetes remission at 12 months (HbA1c &amp;lt; 6.5%, no diabetes medication). Overall, our results suggest a wide-reaching, individual-specific, but predominantly short-term impact of RYGB surgery on the circulating proteome. Current investigations examine how genetic variance and mRNA expression in adipose and liver tissue influence the donors’ circulating proteomes in order to explain the observed heterogeneity and its impact on a person’s molecular homeostasis. Disclosure C.E. Thomas: None. R.S. Häussler: None. M. Hong: None. V. Raverdy: None. M. Dale: None. M. Canouil: None. G. Mazzoni: None. A. Viñuela: None. P. Froguel: None. S. Brunak: Board Member; Self; Intomics A/S, Proscion A/S. Research Support; Self; Novo Nordisk Foundation. Stock/Shareholder; Self; Lundbeck, Novo Nordisk A/S. J.M. Schwenk: None. Funding Innovative Medicines Initiative Joint Undertaking (115317); European Union’s Seventh Framework Programme (FP7/2007-2013); Conseil Regional Nord-Pas-de-Calais; European Commission (FEDER 12003944); European Genomic Institute for Diabetes (ANR-10-LABX-46); Foundation Coeur et Arteres (R15112EE); Fonds hospitalier d’aide a l’emergence et a la structuration des activities et des equipes de recherche 2015 (CHRU Lille, France)

Labeling and Characterization of Human GLP-1-Secreting L-cells in Primary Ileal Organoid Culture

SummaryGlucagon-like peptide-1 (GLP-1) from intestinal L-cells stimulates insulin secretion and reduces appetite after food ingestion, and it is the basis for drugs against type-2 diabetes and obesity. Drugs targeting L- and other enteroendocrine cells are under development, with the aim to mimic endocrine effects of gastric bypass surgery, but they are difficult to develop without human L-cell models. Human ileal organoids, engineered by CRISPR-Cas9, express the fluorescent protein Venus in the proglucagon locus, enabling maintenance of live, identifiable human L-cells in culture. Fluorescence-activated cell sorting (FACS)-purified organoid-derived L-cells, analyzed by RNA sequencing (RNA-seq), express hormones, receptors, and ion channels, largely typical of their murine counterparts. L-cells are electrically active and exhibit membrane depolarization and calcium elevations in response to G-protein-coupled receptor ligands. Organoids secrete hormones in response to glucose and other stimuli. The ability to label and maintain human L-cells in organoid culture opens avenues to explore L-cell function and develop drugs targeting the human enteroendocrine system.

OR22-06 Bone Outcomes Following Sleeve Gastrectomy in Adolescents and Young Adults with Obesity Versus Non-Surgical Controls

Background: Sleeve gastrectomy is the most commonly performed weight loss surgery in adolescents with moderate-to-severe obesity. While studies in adults have reported on the deleterious effects of gastric bypass surgery on bone structure and strength estimates, data are lacking for the impact of sleeve gastrectomy on these measures in adolescents. Objective: To evaluate the impact of sleeve gastrectomy on bone outcomes in adolescents and young adults over 12 months using dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT). Participants and Methods: We enrolled 33 youth 14-22 years old with moderate to severe obesity; 17 underwent sleeve gastrectomy and 16 were followed without surgery. DXA was used to assess areal bone mineral density (aBMD). HRpQCT was used to assess bone geometry, microarchitecture and volumetric BMD (vBMD) and finite element analysis to assess strength estimates (stiffness and failure load) at the distal tibia and distal radius at baseline and 12 months. 25(OH) vitamin D (25OHD) levels were obtained at baseline and follow-up. Results: The surgical group lost 28.2% of total body weight compared to 1.4% in the non-surgical group. The groups did not differ for changes in 25OHD levels (P=0.181). After controlling for age and sex, compared to the non-surgical group, the surgical group had reductions in aBMD Z-scores at the femoral neck and total hip (p≤ 0.0005). At the distal tibia, there were reductions in cortical thickness and trabecular number, and increases in trabecular separation and cortical vBMD, without changes in strength estimates in the surgical group vs. controls (p≤0.043). Changes were less marked at the distal radius. While sleeve gastrectomy resulted in deleterious effects on most bone parameters, there was an increase in cortical vBMD at both sites, possibly from a decrease in cortical porosity. Most differences were attenuated after adjusting for changes in BMI over 12 months. Conclusions: Over 12 months, weight loss associated with sleeve gastrectomy in adolescents had deleterious effects on areal BMD, bone geometry and trabecular microarchitecture at weight-bearing sites. However, strength estimates did not decrease, possibly because of a simultaneous increase in cortical volumetric BMD. Additional research is necessary to determine the relative contribution(s) of weight loss and the metabolic effects of surgery, and whether the observed effects on bone stabilize or progress over time.

Effects of gastric bypass surgery on expression of glucose transporters and fibrotic biomarkers in kidney of diabetic fatty rats.

Diabetic nephropathy is the leading cause of chronic kidney disease. Observational studies suggest Roux-en-Y gastric bypass (RYGB) reduces progression of diabetic nephropathy. To unravel the mechanisms by which RYGB is beneficial and protective for diabetic nephropathy. Academic laboratories. Forty-eight Zucker diabetic fatty rats were randomized to RYGB, sham surgery (SHAM), or pair-fed (PF) groups. An oral glucose tolerance test was performed at 25 days post intervention and kidneys were harvested at 30 days. Primary outcome measures included expression of key genes and proteins in the glucose transport, oxidative stress, inflammation, and fibrosis pathways. Thirty days post intervention, RYGB rats weighed 349 ± 8 g, which was lower than SHAM (436 ± 14 g, P < .001), but not PF (374 ± 18 g) rats. RYGB rats had lower fasting glucose than PF animals and improved homeostatic model assessment of insulin resistance compared with PF and SHAM groups. These enhanced metabolic outcomes were accompanied by reduced sodium-glucose co-transporter 1 (Sglt1) gene expression (-23% versus PF, P = .01) in the kidney of RYGB rats. Expression of Sglt2, Glut1, or Glut2 mRNA, or oxidative stress and inflammation markers did not differ significantly. However, RYGB surgery induced a 19% lower expression of transforming growth factor (Tgfβ) mRNA (P = .004) compared with SHAM treated animals. Notably, adenosine monophosphate-activated protein kinase phosphorylation was increased (P = .04) in kidneys of the RYGB surgery animals. Improvement of hyperglycemia after RYGB may reduce the glucose load on the kidney leading to a downregulation of specific glucose transporters. RYGB surgery may also attenuate kidney fibrosis through the adenosine monophosphate-activated protein kinase/TGFβ pathway.

Labelling and Characterization of Human GLP-1 Secreting L-Cells in Primary Ileal Organoid Culture

GLP-1 from intestinal L-cells stimulates insulin secretion and reduces appetite after food ingestion, and is the basis for drugs against type-2 diabetes and obesity. Drugs targeting L- and other enteroendocrine cells are under development, aiming to mimic endocrine effects of gastric bypass surgery, but are difficult to develop without human L-cell models. We engineered human ileal organoids by CRISPR-Cas9 to express the fluorescent protein Venus in the proglucagon locus, enabling maintenance of live identifiable human L-cells in culture. FACS-purified organoid-derived L-cells, analysed by RNAseq, expressed hormones, receptors and ion channels, largely typical of their murine counterparts. L-cells were electrically active and exhibited membrane depolarization and calcium elevations in response to G-protein coupled receptor ligands. Organoids secreted hormones in response to glucose and other stimuli. The ability to label and maintain human L-cells in organoid culture opens new avenues to explore L-cell function and develop drugs targeting the human enteroendocrine system.

Effects of gastric bypass surgery on postprandial gut and systemic lipid handling

Obesity is often associated with increased postprandial triglyceride (TG) concentrations, mainly from chylomicrons- and VLDL-TG. These alterations are usually reverted to normal after gastric bypass surgery (GB), through mechanisms which remain unknown. The objective of this study was therefore to assess the contribution of exogenous labelled fatty acids ingested with a meal to postprandial blood chylomicrons and VLDL-TG concentrations after GB. 7GB patients 3-5 years after surgery (GB: 2M/5F, mean BMI 30±2kg/m2, mean age 40±3 years), 6 overweight non operated subjects (OW: 1M/5F, mean BMI 31±3kg/m2, mean age 38±2 years) and 8 normal weight healthy subjects (NW: 4M/4F, mean BMI 22±1kg/m2, mean age 26±4 years) were studied over 7h following ingestion of a liquid meal containing 18g fat labelled with 250mg 13C16 palmitate, 22g protein, 36g fructose and 36g glucose. TG, 13C palmitate (13C-palm) and apoB48 concentrations were measured hourly in whole plasma and/or in chylomicrons and VLDL lipoprotein sub-fractions. OW subjects had higher chylomicron-than NW (chylo-TG 96.5 (23.1) vs 28.8 (11.8) mmol/l*420min (p=0.02)), but similar total, chylo-13C-palm and apoB48 iAUCs. In GB, chylo- 13C-palm and apoB48 increased earlier after meal ingestion, but then remained lower than in NW and OW throughout the postprandial period. GB also had lower chylo-TG iAUCs than OW (8.9 (11.5) vs 96.5 (23.2) mmol/l*420min, p=0.003). Their apoB48 iAUCs were not different from NW and OW (509.2 (90.5) vs 710.2 (80.5) and 870.1 (297.6) pg/ml*420min, all p>0.05). An accelerated postprandial apoB48 rise, together with unchanged postprandial apoB48 iUAC, suggests that intestinal fat absorption and chylomicron secretion was quantitatively unaltered, but accelerated after gastric bypass. In contrast, the decreased postprandial chylo-TG and 13C-palm iAUCs suggest that plasma chylomicron clearance was enhanced after gastric bypass.

Combined loss of GLP-1R and Y2R does not alter progression of high-fat diet-induced obesity or response to RYGB surgery in mice

ObjectiveUnderstanding the mechanisms underlying the remarkable beneficial effects of gastric bypass surgery is important for the development of non-surgical therapies or less invasive surgeries in the fight against obesity and metabolic disease. Although the intestinal L-cell hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine–tyrosine (PYY) have attracted the most attention, direct tests in humans and rodents with pharmacological blockade or genetic deletion of either the GLP1-receptor (GLP1R) or the Y2-receptor (Y2R) were unable to confirm their critical roles in the beneficial effects gastric bypass surgery on body weight and glucose homeostasis. However, new awareness of the power of combinatorial therapies in the treatment of metabolic disease would suggest that combined blockade of more than one signaling pathway may be necessary to reverse the beneficial effects of bariatric surgery. MethodsThe metabolic effects of high-fat diet and the ability of Roux-en-Y gastric bypass surgery to lower food intake and body weight, as well as improve glucose handling, was tested in GLP1R and Y2R-double knockout (GLP1RKO/Y2RKO) and C57BL6J wildtype (WT) mice. ResultsGLP1RKO/Y2RKO and WT mice responded similarly for up to 20 weeks on high-fat diet and 16 weeks after RYGB. There were no significant differences in loss of body and liver weight, fat mass, reduced food intake, relative increase in energy expenditure, improved fasting insulin, glucose tolerance, and insulin tolerance between WT and GLP1RKO/Y2RKO mice after RYGB. ConclusionsCombined loss of GLP1R and Y2R-signaling was not able to negate or attenuate the beneficial effects of RYGB on body weight and glucose homeostasis in mice, suggesting that a larger number of signaling pathways is involved or that the critical pathway has not yet been identified.

The Feasibility of Examining the Effects of Gastric Bypass Surgery on Intestinal Metabolism: Prospective, Longitudinal Mechanistic Clinical Trial.

BackgroundBariatric surgery, especially Roux-en-Y gastric bypass (RYGB), is the best treatment for severe obesity and its complications including type 2 diabetes mellitus (T2DM). Understanding the mechanisms responsible for the beneficial metabolic effects will help to engineer ways to improve the procedure or produce these effects without surgery.ObjectiveThe aim is to present data on recruitment and feasibility of a translational study designed to collect intestinal samples before and after bariatric surgery. The goal of biobanking is to allow future studies to test the hypothesis that the mechanism of action of RYGB involves specific changes in the postsurgical short- and long-term metabolism and morphology of the jejunum (Roux limb). Specifically, to test whether the intestine enhances its metabolism and activity after RYGB and increases its fuel utilization, we designed a prospective, longitudinal study, which involved the recruitment of candidates for RYGB with and without T2DM. We describe the tissue bank that we have generated, and our experience, hoping to further facilitate the performance of longitudinal mechanistic studies in human patients undergoing bariatric surgery and especially those involving post-RYGB intestinal biology.MethodsWe conducted a trial to characterize the effects of RYGB on intestinal metabolism. Intestinal tissue samples were collected from the jejunum at surgery, 1, 6, and 12 months postoperatively for the analysis of intestinal gene expression and metabolomic and morphologic changes. The target number of patients who completed at least the 6-month follow-up was 26, and we included a 20% attrition rate, increasing the total number to 32.ResultsTo enroll 26 patients, we had to approach 79 potential participants. A total of 37 agreed to participate and started the study; 33, 30, and 26 active participants completed their 1-month, 6-month, and 12-month studies, respectively. Three participants withdrew, and 30 participants are still active. Altruism and interest in research were the most common reasons for participation. Important factors for feasibility and successful retention included (1) large volume case flow, (2) inclusion and exclusion criteria broad enough to capture a large segment of the patient population but narrow enough to ensure the completion of study aims and protection of safety concerns, (3) accurate assessment of willingness and motivation to participate in a study, (4) seamless integration of the recruitment process into normal clinical flow, (5) financial reimbursement and nonfinancial rewards and gestures of appreciation, and (6) nonburdensome follow-up visits and measures and reasonable time allotted.ConclusionsHuman translational studies of the intestinal mechanisms of metabolic and weight changes after bariatric surgery are important and feasible. A tissue bank with unique samples has been established that could be used by investigators in many research fields, further enabling mechanistic studies on the effects of bariatric surgery.Trial RegistrationClinicalTrials.gov NCT02710370; https://clinicaltrials.gov/ct2/show/NCT02710370 (Archived by WebCite at http://www.webcitation.org/75HrQT8Dl)

Roux-en-Y gastric bypass as a cure of iatrogenic - steroid induced diabetes.

Steroid-induced diabetes (SIDM) is a frequently found clinical condition since steroid-based therapies continue to be widely used in hospital and ambulatory care. Recommended optimal treatment of SIDM includes similar glucose lowering strategies as in type 2 diabetes. This typical management cannot cure the disease, it can only control blood glucose. Recently, bariatric surgery has emerged as an effective treatment for type 2 diabetes mellitus. However, up to now, the usefulness of bariatric surgery in treatment of SIDM has not been evaluated. A 49-year-old female oncologic patient with steroid induced diabetes was referred for surgical treatment to the Department of General and Transplant Surgery in November 2009. Six years earlier, she underwent successful oncologic treatment with cladribine and high doses of steroids due to hairy cell leukemia. Finally complete hematologic remission with normalization of morphology and reduction of spleen size has been obtained. Prior to steroid treatment, blood glucose and urine examinations were within normal range. The patient was non-obese and had no family history of diabetes. Nevertheless, the patient developed diabetes secondary to corticosteroid therapy, poorly controlled by oral hypoglycemic agent (acarbosum), successfully converted to insulin therapy. Upon admission to the Department of General and Transplant Surgery, the patient was treated with 58 units of insulin per day. The patient was scheduled for Roux-en-Y gastric bypass (RYGB). Insulin was withdrawn immediately after the surgery and within six months after the surgery, plasma glucose and glycated hemoglobin (HbA1c-5.5%) levels reached and remained within normal range. Currently, eight years after surgery, body weight and BMI are 80 kg and 27.68 kg/m2, respectively. Plasma glucose and glycated hemoglobin are also normal. Importantly, from an oncological point of view, the patient has remained in continuous complete remission since October 2003. Our report is the first to our knowledge describing the effect of gastric bypass surgery on SIDM in a patient with prior hematologic malignancy. It proves that surgically altered anatomy of the small intestine improves glucose homeostasis previously disturbed with pro-diabetic medication.