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Aims To investigate whether the elevation in postprandial concentrations of the gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and peptide YY (PYY) accounts for the beneficial changes in food preferences, sweet taste function and eating behaviour after Roux-en-Y gastric bypass (RYGB). Materials and methods This was a secondary analysis of a randomized single-blind study in which we infused GLP-1, OXM, PYY (GOP) or 0.9% saline subcutaneously for 4 weeks in 24 subjects with obesity and prediabetes/diabetes, to replicate their peak postprandial concentrations, as measured at 1 month in a matched RYGB cohort (ClinicalTrials.gov NCT01945840). A 4-day food diary and validated eating behaviour questionnaires were completed. Sweet taste detection was measured using the method of constant stimuli. Correct sucrose identification (corrected hit rates) was recorded, and sweet taste detection thresholds (EC50s: half maximum effective concencration values) were derived from concentration curves. The intensity and consummatory reward value of sweet taste were assessed using the generalized Labelled Magnitude Scale. Results Mean daily energy intake was reduced by 27% with GOP but no significant changes in food preferences were observed, whereas a reduction in fat and increase in protein intake were seen post-RYGB. There was no change in corrected hit rates or detection thresholds for sucrose detection following GOP infusion. Additionally, GOP did not alter the intensity or consummatory reward value of sweet taste. A significant reduction in restraint eating, comparable to the RYGB group was observed with GOP. Conclusion The elevation in plasma GOP concentrations after RYGB is unlikely to mediate changes in food preferences and sweet taste function after surgery but may promote restraint eating.

Obesity surgery remains the most effective treatment for obesity and its complications. Weight loss was initially attributed to decreased energy absorption from the gut but has since been linked to reduced appetitive behavior and potentially increased energy expenditure. Implicated mechanisms associating rearrangement of the gastrointestinal tract with these metabolic outcomes include central appetite control, release of gut peptides, change in microbiota, and bile acids. However, the exact combination and timing of signals remain largely unknown. In this review, we survey recent research investigating these mechanisms, and seek to provide insights on unanswered questions over how weight loss is achieved following bariatric surgery which may eventually lead to safer, nonsurgical weight-loss interventions or combinations of medications with surgery. E.A. was supported by a grant from the Rosetrees Trust (M825) and from the British Society for Neuroendocrinology. A.D.M. has been supported from grants from the JP Moulton Charitable Foundation, National Institute of Health Research, Imperial College Healthcare Charity and Novo Nordisk. The Section of Investigative Medicine is funded by grants from the MRC, BBSRC, NIHR, an Integrative Mammalian Biology Capacity Building Award, an FP7-HEALTH-2009-241592 EuroCHIP grant and is supported by the NIHR Biomedical Research Centre Funding Scheme. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care. G.A.R. was supported by a Wellcome Trust Investigator Award (212625/Z/18/Z), MRC program grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), an Experimental Challenge Grant (DIVA, MR/L02036X/1), a Diabetes UK Project grant (BDA16/0005485). This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking, under grant agreement no. 115881 (RHAPSODY). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA. C.lR. is funded by the Irish Research Council (IRCLA/2017/234) and The Health Research Board (USIRL-2016-2).

ObjectivesGlucocorticoids produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis. Glucocorticoid activation is catalysed by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). Excess glucocorticoids are associated with insulin resistance and hyperglycaemia. A small number of studies have demonstrated effects on glucocorticoid metabolism of bariatric surgery, a group of gastrointestinal procedures known to improve insulin sensitivity and secretion, which were assumed to result from weight loss. In this study, we hypothesize that a reduction in glucocorticoid action following bariatric surgery contributes to the widely observed euglycemic effects of the treatment.MethodsGlucose and insulin tolerance tests were performed at ten weeks post operatively and circulating corticosterone was measured. Liver and adipose tissues were harvested from fed mice and 11β-HSD1 levels were measured by quantitative RT-PCR or Western (immuno-) blotting, respectively. 11β-HSD1 null mice (Hsd11b1-/-) were generated using CRISPR/Cas9 genome editing. Wild type and littermate Hsd11b1-/- mice underwent Vertical Sleeve Gastrectomy (VSG) or sham surgery. ResultsUnder the conditions used, no differences in weight loss were observed between VSG treated and sham operated mice. However, both lean and obese WT VSG mice displayed significantly improved glucose clearance and insulin sensitivity. Remarkably, VSG restored physiological corticosterone production in HFD mice and reduced 11β-HSD1 expression in liver and adipose tissue post-surgery. Elimination of the 11β-HSD1/Hsd11b1 gene by CRISPR/Cas9 mimicked the effects of VSG on body weight and tolerance to 1g/kg glucose challenge. However, at higher glucose loads, the euglycemic effect of VSG was superior to Hsd11b1 elimination.ConclusionsBariatric surgery improves insulin sensitivity and reduces glucocorticoid activation at the tissular level, under physiological and pathophysiological (obesity) conditions, irrespective of weight loss. These findings point towards a physiologically relevant gut-glucocorticoid axis, and suggest that lowered glucocorticoid exposure may represent an additional contribution to the health benefits of bariatric surgery.

Objective Postprandial hyperinsulinemic hypoglycemia with neuroglycopenia is an increasingly recognized complication of Roux-en-Y gastric bypass and gastric sleeve surgery that may detrimentally affect patient quality of life. One likely causal factor is glucagon-like peptide-1 (GLP-1), which has an exaggerated rise following ingestion of carbohydrates after bariatric surgery. This paper sought to assess the role of GLP-1 receptor agonists (GLP-1RAs) in managing postprandial hypoglycemia following bariatric surgery. Methods MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Scopus were systematically and critically appraised for all peer-reviewed publications that suitably fulfilled the inclusion criteria established a priori. This systematic review was developed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P). It followed methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions and is registered with PROSPERO (International Prospective Register of Systematic Reviews; identifier CRD420212716429). Results and Conclusions Postprandial hyperinsulinemic hypoglycemia remains a notoriously difficult to manage metabolic complication of bariatric surgery. This first, to the authors' knowledge, systematic review presents evidence suggesting that use of GLP-1RAs does not lead to an increase of hypoglycemic episodes, and, although this approach may appear counterintuitive, the findings suggest that GLP-1RAs could reduce the number of postprandial hypoglycemic episodes and improve glycemic variability.

OBJECTIVE Weight loss achieved with very-low-calorie diets (VLCDs) can produce remission of type 2 diabetes (T2D), but weight regain very often occurs with reintroduction of higher calorie intakes. In contrast, bariatric surgery produces clinically significant and durable weight loss, with diabetes remission that translates into reductions in mortality. We hypothesized that in patients living with obesity and prediabetes/T2D, longitudinal changes in brain activity in response to food cues as measured using functional MRI would explain this difference. RESEARCH DESIGN AND METHODS Sixteen participants underwent gastric bypass surgery, and 19 matched participants undertook a VLCD (meal replacement) for 4 weeks. Brain responses to food cues and resting-state functional connectivity were assessed with functional MRI pre- and postintervention and compared across groups. RESULTS We show that Roux-en-Y gastric bypass surgery (RYGB) results in three divergent brain responses compared with VLCD-induced weight loss: 1) VLCD resulted in increased brain reward center food cue responsiveness, whereas in RYGB, this was reduced; 2) VLCD resulted in higher neural activation of cognitive control regions in response to food cues associated with exercising increased cognitive restraint over eating, whereas RYGB did not; and 3) a homeostatic appetitive system (centered on the hypothalamus) is better engaged following RYGB-induced weight loss than VLCD. CONCLUSIONS Taken together, these findings point to divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast to enduring weight loss after RYGB.

Over the past 50 years, many countries around the world have faced an unchecked pandemic of obesity and type 2 diabetes (T2DM). As best practice treatment of T2DM has done very little to check its growth, the pandemic of diabesity now threatens to make health-care systems economically more difficult for governments and individuals to manage within their budgets. The conventional view has been that T2DM is irreversible and progressive. However, in 2016, the World Health Organization (WHO) global report on diabetes added for the first time a section on diabetes reversal and acknowledged that it could be achieved through a number of therapeutic approaches. Many studies indicate that diabetes reversal, and possibly even long-term remission, is achievable, belying the conventional view. However, T2DM reversal is not yet a standardized area of practice and some questions remain about long-term outcomes. Diabetes reversal through diet is not articulated or discussed as a first-line target (or even goal) of treatment by any internationally recognized guidelines, which are mostly silent on the topic beyond encouraging lifestyle interventions in general. This review paper examines all the sustainable, practical, and scalable approaches to T2DM reversal, highlighting the evidence base, and serves as an interim update for practitioners looking to fill the practical knowledge gap on this topic in conventional diabetes guidelines.

Background: Metabolic syndrome (MetS) is defined by at least three of the following five criteria: blood pressure ⩾130/85 mmHg, fasting blood glucose ⩾5.6 mmol/l, triglycerides concentration ⩾1.7 mmol/l, waist circumference ⩾102 cm (for men), and high-density lipoprotein cholesterol concentration Materials and Methods: MEDLINE, Cochrane, ClinicalTrials.gov, and SCOPUS were critically appraised for all peer-reviewed manuscripts that suitably fulfilled our protocol’s inclusion criteria established a priori. Meta-analytical and meta-regression calculations were performed in R using the Sidik–Jonkman and Hartung–Knapp random effects model and predefined covariates. Results: A total of 70 studies ( n = 90,206) were included in qualitative synthesis. From these, 60 studies focused on MetS and LUTS: 44 reported positive correlations, 5 reported negative correlations, 11 reported no association, and 10 studies focused on MetS and total prostate volume (TPV). MetS positively correlated with moderate LUTS [odds ratio (OR) = 1.56, 95% confidence interval (CI) = 1.35–1.80], severe LUTS (OR = 2.35, 95% CI = 1.82–3.03), overactive bladder (OAB; OR = 3.2, 95% CI = 1.6–5.8), and nocturia severity (OR = 2.509, 95% CI = 1.571–4.007) at multivariate analysis. A total of 30 studies ( n = 22,206) were included in meta-analysis; MetS was significantly associated with higher TPV (mean differences = 4.4450 ml, 95% CI = 2.0177–6.8723), but no significant predictive factors for effect sizes were discovered. Conclusion: Our meta-analysis demonstrates a significant association between the aggravating effects of MetS, which commonly coexists with obesity and benign prostate enlargement.

Introduction Undiagnosed obstructive sleep apnoea (OSA) is increasingly recognized as a serious post-operative risk with bariatric surgery, hence increasing demand for pre-operative screening and a need for simpler ways for screening than the clinical standard, respiratory polygraphy, to mitigate strain on sleep services. WatchPAT 300 (WP) is a finger-mounted sensor that uses peripheral arterial tonometry to estimate the apnoea hyponoea index (AHI). While its use is increasing it has not yet been validated in patients with a BMI >35, the target population in bariatric surgery. Aims To validate WP against polygraphy in pre-bariatric surgery patients with clinically suspected OSA and a BMI>35 and to assess patient acceptability of WP. Methods AHI was measured simultaneously with WP and Embletta. Outcome measures were 1) autoscored AHI from WP and 2) manually re-scored AHI from Embletta. Agreement between AHI from Embletta and WP was assessed using intra-class correlation coefficient (ICC), bland Altman and ROC plots. Results 28 patients (22 female/6 male, mean ± SD age 44.1 ± 11.6, BMI 45.7 ± 7.5) participated. One study failed due to the patient removing the WP probe prematurely. AHI was higher in WP than Embletta (28.1± 17.9 versus 15.0 ±13.4; p 15 (Area under the curve 0.917; p Discussion WP accurately estimates the AHI in pre bariatric surgery patients, has a low failure rate and is clinically acceptable in this group. Further larger scale studies are needed to confirm these findings before incorporating into clinical guidelines.

The hypothalamus is the main integrator of peripheral and central signals in the control of energy homeostasis. Its functional relevance for the effectivity of bariatric surgery is not entirely elucidated. Studying the effects of bariatric surgery in patients with hypothalamic damage might provide insight.Prospective study to analyze the effects of bariatric surgery in patients with hypothalamic obesity (HO) vs. matched patients with common obesity (CO) with and without bariatric surgery.65 participants were included (HO-surgery: n = 8, HO-control: n = 10, CO-surgery: n = 12, CO-control: n = 12, Lean-control: n = 23). Body weight, levels of anorexic hormones, gut microbiota, as well as subjective well-being/health status, eating behavior, and brain activity (via functional MRI) were evaluated.Patients with HO lost significantly less weight after bariatric surgery than CO-participants (total body weight loss %: 5.5 % vs. 26.2 %, p = 0.0004). After a mixed meal, satiety and abdominal fullness tended to be lowest in HO-surgery and did not correlate with levels of GLP-1 or PYY. Levels of PYY (11,151 ± 1667 pmol/l/h vs. 8099 ± 1235 pmol/l/h, p = 0.028) and GLP-1 (20,975 ± 2893 pmol/l/h vs. 13,060 ± 2357 pmol/l/h, p = 0.009) were significantly higher in the HO-surgery vs. CO-surgery group. Abundance of Enterobacteriaceae and Streptococcus was increased in feces of HO and CO after bariatric surgery. Comparing HO patients with lean-controls revealed an increased activation in insula and cerebellum to viewing high-caloric foods in left insula and cerebellum in fMRI.Hypothalamic integrity is necessary for the effectiveness of bariatric surgery in humans. Peripheral changes after bariatric surgery are not sufficient to induce satiety and long-term weight loss in patients with hypothalamic damage.

Objective: The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation.Summary of background data: This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery.Methods: In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months.Results: There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44-2.0; P = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8-39; P = .007). The DJBL group experienced superior reductions in systolic blood pressure, serum cholesterol, and alanine transaminase at 12 months. There were more adverse events in the DJBL group.Conclusions: The addition of the DJBL to intensive medical care was associated with superior weight loss, improvements in cardiometabolic risk factors, and fatty liver disease markers, but not glycemia, only while the device was in situ. The benefits of the devices need to be balanced against the higher rate of adverse events when making clinical decisions.Trial registration: ISRCTN30845205. isrctn.org; Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership reference 12/10/04.

Background\ud Duodenal mucosal resurfacing (DMR) is a novel day-case endoscopic intervention which results in weight loss-independent reductions in HbA1c in patient with type 2 diabetes mellitus (T2DM). We hypothesized that DMR works by increasing insulin sensitivity and we aimed to investigate the mechanism of action of DMR through longitudinal metabolic phenotyping in humans.\ud \ud Methods\ud Thirty-two insulin-resistant women with polycystic ovary syndrome (PCOS) and obesity were randomised in a double-blinded manner to DMR or sham endoscopy. They underwent measurements of insulin sensitivity using euglycaemic hyperinsulinaemic clamps, insulin secretion using oral glucose tolerance tests and reproductive function using weekly reproductive hormone profiles and ovarian ultrasonography for 6 months post-intervention.\ud \ud Results\ud A small increase in total body insulin sensitivity measured by the clamp was observed in both groups at week 12. An increase in insulin sensitivity, as measured by HOMA-IR, was observed in both groups at week 24. There was an increase in the number of menses (median 2 DMR, 0.5 sham). There were no significant differences between the two groups in these outcomes or insulin secretion.\ud \ud Conclusions\ud These findings suggest that DMR does not work by increasing insulin sensitivity in euglycaemic, insulin resistant women with PCOS. The procedure may exert its effects only in the context of hyperglycaemia or pathologically hyperplastic, insulin-desensitised duodenal mucosa.

Summary Background Many patients with type 2 diabetes do not achieve sustained diabetes remission after metabolic (bariatric) surgery for the treatment of obesity. Liraglutide, a glucagon-like peptide-1 analogue, improves glycaemic control and reduces bodyweight in patients with type 2 diabetes. Our aim was to assess the safety and efficacy of liraglutide 1·8 mg in patients with persistent or recurrent type 2 diabetes after metabolic surgery. Methods In the GRAVITAS randomised double-blind, placebo-controlled trial, we enrolled adults who had undergone Roux-en-Y gastric bypass or vertical sleeve gastrectomy and had persistent or recurrent type 2 diabetes with HbA1c levels higher than 48 mmol/mol (6·5%) at least 1 year after surgery from five hospitals in London, UK. Participants were randomly assigned (2:1) via a computer-generated sequence to either subcutaneous liraglutide 1·8 mg once daily or placebo, both given together with a reduced-calorie diet, aiming for a 500 kcal per day deficit from baseline energy intake, and increased physical activity. The primary outcome was the change in HbA1c from baseline to the end of the study period at 26 weeks, assessed in patients who completed the trial. Safety was assessed in the safety analysis population, consisting of all participants who received either liraglutide or placebo. This trial is registered with EudraCT, number 2014-003923-23, and the ISRCTN registry, number ISRCTN13643081. Findings Between Jan 29, 2016, and May 2, 2018, we assigned 80 patients to receive either liraglutide (n=53) or placebo (n=27). 71 (89%) participants completed the study and were included in the principal complete-cases analysis. In a multivariable linear regression analysis, with baseline HbA1c levels and surgery type as covariates, liraglutide treatment was associated with a difference of −13·3 mmol/mol (−1·22%, 95% CI −19·7 to −7·0; p=0·0001) in HbA1c change from baseline to 26 weeks, compared with placebo. Type of surgery had no significant effect on the outcome. 24 (45%) of 53 patients assigned to liraglutide and 11 (41%) of 27 assigned to placebo reported adverse effects: these were mainly gastrointestinal and in line with previous experience with liraglutide. There was one death during the study in a patient assigned to the placebo group, which was considered unrelated to study treatment. Interpretation These findings support the use of adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery. Funding JP Moulton Foundation.

Baseline albuminuria in patients with diabetic kidney disease (DKD) is strongly associated with progressive deterioration in kidney function (1). The remission of microalbuminuria in patients with type 2 diabetes and obesity attenuates the decline in estimated glomerular filtration rate (2). In the Microvascular Outcomes after Metabolic Surgery (MOMS) randomized controlled trial (RCT) (3), we demonstrated that the combination of best medical care and Roux-en-Y gastric bypass (RYGB) surgery is more effective in inducing remission of microalbuminuria than best medical care alone. During the MOMS RCT, type 2 diabetes care guidelines were updated to reflect the potent renoprotective effects of sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in people with DKD (4). Thus, the rate of use of the combination of these two agents (Combo) in the study was increased. In this post hoc analysis of the MOMS RCT, our objective was to determine whether the combination of two potent renoprotective medications can match the reductions of albuminuria observed after RYGB. The MOMS RCT protocol has previously been described in detail (3). In brief, 100 patients with CKDG1–3a, A2–3, urine albumin–to–creatinine-ratio …

Background & aims: Duodenal-jejunal bypass liners (DJBLs) prevent absorption in the proximal small intestine, the site of fatty acid absorption. We sought to investigate the effects of a DJBL on blood concentrations of essential fatty acids (EFAs) and bioactive polyunsaturated fatty acids (PUFAs). Methods: Sub-study of a multicentre, randomised, controlled trial with two treatment groups. Patients aged 18–65 years with type-2 diabetes mellitus and body mass index 30–50 kg/m 2 were randomised to receive a DJBL for 12 months or best medical therapy, diet and exercise. Whole plasma PUFA concentrations were determined at baseline, 10 days, 6 and 11.5 months; data were available for n = 70 patients per group. Results: Weight loss was significantly greater in the DJBL group compared to controls after 11.5 months: total body weight loss 11.3 ± 5.3% versus 6.0 ± 5.7% (mean difference [95% CI] = 5.27% [3.75, 6.80], p < 0.001). Absolute concentrations of both EFAs, linoleic acid and α-linolenic acid, and their bioactive derivatives, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid, were significantly lower in the DJBL group than in the control group at 6 and 11.5 months follow-up. Total serum cholesterol, LDL-cholesterol and HDL-cholesterol were also significantly lower in the DJBL group. Conclusion: One year of DJBL therapy is associated with superior weight loss and greater reductions in total serum cholesterol and LDL-cholesterol, but also depletion of EFAs and their longer chain derivatives. DJBL therapy may need to be offset by maintaining an adequate dietary intake of PUFAs or by supplementation. Trial registration: ClinicalTrials.gov Identifier NCT02459561.

Women with obesity are at risk of pelvic floor dysfunction with a 3-fold increased incidence of urge urinary incontinence (UUI) and double the risk of stress urinary incontinence (SUI). The National Institute for Health and Care Excellence (NICE) and European Association of Urology (EAU) recommend that women with a body mass index ≥30 kg/m2 should consider weight loss prior to consideration for incontinence surgery. This systematic review and meta-analysis will assess this recommendation to aid in the counselling of women with obesity-related urinary incontinence (UI). Medical Literature Analysis and Retrieval System online (MEDLINE), EMBASE, Cochrane, ClinicalTrials.gov, and SCOPUS were systematically and critically appraised for all peer reviewed manuscripts that suitably fulfilled the inclusion criteria established a priori and presented original, empirical data relevant to weight loss intervention in the management of urinary incontinence. Thirty-three studies and their outcomes were meta-analysed. Weight loss interventions were associated in a decreased prevalence in UI (OR 0.222, 95% CI [0.147, 0.336]), SUI (OR 0.354, 95% CI [0.256, 0.489]), UUI (OR 0.437, 95% CI [0.295, 0.649]) and improved quality of life (PFDI-20, SMD -0.774 (95% CI [−1.236, −0.312]). This systematic review and meta-analysis provide evidence that weight loss interventions are effective in reducing the prevalence of obesity-related UI symptoms in women. Bariatric surgery in particular shows greater sustained weight loss and improvements in UI prevalence. Further large scale, randomized control trials assessing the effect of bariatric surgery on women with obesity-related UI are needed to confirm this study's findings.\ud \ud

Introduction Trimethylamine N-oxide (TMAO) is formed in the liver from trimethylamine, and is exclusively generated by gut microbiota from the metabolism of dietary carnitine and choline. Elevated plasma levels have been implicated in the pathogenesis of Type 2 Diabetes and cardiovascular disease. The Endobarrier is an endoscopically implanted duodenal jejunal bypass liner (DJBL) designed to mimic the effects of bariatric surgery leading to significant weight loss and improvements in glycaemic control and we present novel data of its effects on the plasma metabolic profile of these patients. Methods The Endobarrier Trial (NCT02459561) is a large multicentre, randomised, controlled trial across two sites in the UK which recruited 170 patients with Type 2 Diabetes and BMI 30–50 kg/m2. Participants were randomised to receive the DJBL (n=85) for one year or conventional medical therapy, diet and exercise (n=85). Plasma samples were collected from all participants at baseline, 6 months and 1 year and analysed using 1H NMR spectroscopy and multivariate statistical analysis to identify key metabolic perturbations between both patient cohorts. Results A total of 112 patients were followed up for one year. 309 plasma samples were processed and then analysed. A typical 1H NMR plasma spectrum is shown in figure 1. Reduction in plasma concentrations of trimethylamine N-oxide (TMAO) were found in the DJBL group at 6 months and 1 year compared with the control group. Conclusions Raised levels of Plasma TMAO have been associated with the development of diabetes and in this study were found to reduce following 6 months and 1 year of DJBL therapy compared with controls. This is the first study of its kind to explore alterations in the metabolic profiles of patients receiving the DJBL by utilising high field 1H nuclear magnetic resonance (NMR) spectroscopy technique. These results may provide a possible insight into the mechanisms of how this device may elicit its effect on weight loss and glycaemic improvement, by reducing plasma TMAO and potentially altering the gut microbial metabolic function.

BackgroundGlucocorticoids produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis. Glucocorticoid activation is catalyzed by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and signalling is achieved through the glucocorticoid receptor (GR), a ligand-dependent transcription factor. Excess glucocorticoids are associated with insulin resistance and hyperglycaemia. A small number of studies have investigated the effects of bariatric surgery, a gastrointestinal procedure known to improve insulin sensitivity, on glucocorticoid metabolism, but the hypothesised mechanism is assumed to be via weight loss.AimTo investigate the effect of bariatric surgery on glucocorticoid metabolism in lean and obese mice.MethodsLean mice and HFD mice underwent Vertical Sleeve Gastrectomy (VSG) or sham surgery. Glucose and insulin tolerance tests were performed at four and ten weeks post operatively and circulating corticosterone was measured. Liver and adipose tissues were harvested from fed mice and 11β-HSD1 and GR levels were measured by quantitative RT-PCR or Western (immuno-) blotting, respectively.ResultsVSG did not cause excess weight loss in lean mice when compared to sham operated mice. However, both lean and HFD VSG mice displayed significantly improved glucose clearance and insulin sensitivity. Remarkably, VSG restores physiological corticosterone production in HFD mice and reduces11β-HSD1 levels at four and ten weeks post-surgery. Additionally, lean mice displayed significantly lowered mRNA levels of 11β-HSD1 in subcutaneous adipose tissue and GR in liver.ConclusionsBariatric surgery improves insulin sensitivity and reduces glucocorticoid activation at tissular level, under physiological and pathophysiological (obesity) conditions, irrespective of weight loss. The reduction of glucocorticoid exposure may represent an additional contribution to the health benefits of bariatric surgery. These findings point towards a physiologically relevant gut-adrenal axis.

‘Imperial Satiety Protocol’ (I-SatPro) is a new multifaceted approach to weight loss for people with obesity (PwO), encompassing dietary advice, time-restricted eating, physical activity and coaching to support behaviour change. Participants (n = 84) attended fortnightly I-SatPro group sessions for 30 weeks, with 70% of participants completing. On completion at 30 weeks, the mean weight loss was 15.2 ± 1.1 kg (13.2 ± 0.8% from baseline, P

OBJECTIVE Roux-en-Y gastric bypass (RYGB) is an established treatment for type 2 diabetes and obesity. The study objective was to establish RYGB’s effects on glycemic variability (GV) and hypoglycemia. RESEARCH DESIGN AND METHODS This was a prospective observational study of 10 participants with obesity and prediabetes or type 2 diabetes who underwent RYGB. Patients were studied before RYGB (Pre) and 1 month, 1 year, and 2 years postsurgery with continuous glucose measurement (CGM). A mixed-meal test (MMT) was conducted at Pre, 1 month, and 1 year. RESULTS After RYGB, mean CGM decreased (at 1 month, 1 year, and 2 years), and GV increased (at 1 year and 2 years). Five of the 10 participants had a percent time in range (%TIR) CONCLUSIONS Patients undergoing RYGB are at risk for development of postbariatric hypoglycemia due to a combination of reduced mean glucose, increased GV, and increased GLP-1 response.

BackgroundThe EndoBarrier®(GI Dynamics Inc., Boston, MA, USA) is an endoluminal duodenal–jejunal bypass liner developed for the treatment of patients with obesity and type 2 diabetes mellitus. Meta-analyses of its effects on glycaemia and weight have called for larger randomised controlled trials with longer follow-up.ObjectivesThe primary objective was to compare intensive medical therapy with a duodenal–jejunal bypass liner with intensive medical therapy without a duodenal–jejunal bypass liner, comparing effectiveness on the metabolic state as defined by the International Diabetes Federation as a glycated haemoglobin level reduction of ≥ 20%. The secondary objectives were to compare intensive medical therapy with a duodenal–jejunal bypass liner with intensive medical therapy without a duodenal–jejunal bypass liner, comparing effectiveness on the metabolic state as defined by the International Diabetes Federation as a glycated haemoglobin level of DesignA multicentre, open-label, randomised controlled trial.SettingImperial College Healthcare NHS Trust and University Hospital Southampton NHS Foundation Trust.ParticipantsPatients aged 18–65 years with a body mass index of 30–50 kg/m2and with inadequately controlled type 2 diabetes mellitus who were on oral glucose-lowering medications.InterventionsParticipants were randomised equally to receive intensive medical therapy alongside a duodenal–jejunal bypass liner device (n = 85) or intensive medical therapy alone for 12 months (n = 85), and were followed up for a further 12 months.ResultsThere was no significant difference between groups in the percentage of patients achieving the glycaemic primary or secondary outcomes [primary outcome at 12 months: duodenal–jejunal bypass liner group 54.5% vs. control group 55.2% (odds ratio 0.93, 95% confidence interval 0.44 to 1.98;p = 0.85); primary outcome at 24 months: duodenal–jejunal bypass liner group 39.7% vs. control group 36.5% (odds ratio 1.13, 95% confidence interval 0.52 to 2.47;p = 0.75)]. Significantly more patients in the duodenal–jejunal bypass liner group than in the control group lost > 15% of their total body weight (duodenal–jejunal bypass liner group 24.2% vs. control group 3.7%; odds ratio 8.33, 95% confidence interval 1.78 to 39.0;p = 0.007) and achieved blood pressure targets (duodenal–jejunal bypass liner group 68.2% vs. control group 44.4%; odds ratio 2.57, 95% confidence interval 1.21 to 5.48;p = 0.014). These differences were observed at 12 months but not at 24 months. There were more adverse events in the duodenal–jejunal bypass liner group, including one liver abscess. The increase in peripheral insulin sensitivity was superior in the duodenal–jejunal bypass liner group. Spectroscopic analyses of plasma, urine and faeces revealed several distinct metabolic perturbations in the duodenal–jejunal bypass liner group but not in the control group. Brain reward responses to food cues were not different between groups. The number of mean quality-adjusted life-years gained was similar in both groups and the additional costs of the duodenal–jejunal bypass liner may outweigh the value of the health benefits by £2560 per patient treated.ConclusionsThe results show that the endoluminal duodenal–jejunal bypass liner was not superior to intensive medical therapy for glycaemic control and was associated with more adverse events. The duodenal–jejunal bypass liner was associated with significant weight loss and improvement in cardiometabolic parameters at 12 months but not at 24 months. Economic evaluation showed that the bypass liner was not cost-effective for glycaemic control or for weight loss.Trial registrationCurrent Controlled Trials ISRCTN30845205.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full inEfficacy and Mechanism Evaluation; Vol. 7, No. 6. See the NIHR Journals Library website for further project information. This study was executed with the support of GI Dynamics Inc. and with the kind support of Nutricia Advanced Medical Nutrition for providing oral nutritional supplements.

Metabolic surgical procedures, such as Roux-en-Y gastric bypass (RYGB), uniquely reprogram feeding behavior and body weight in obese subjects. Clinical neuroimaging and animal studies are only now beginning to shed light on some of the underlying central mechanisms. We present here the roles of key brain neurotransmitter/neuromodulator systems in food choice, value, and intake at various stages after RYGB. In doing so, we elaborate on how known signals emanating from the reorganized gut, including peptide hormones and microbiota products, impinge on newly mapped homeostatic and hedonic brain feeding circuits. Continued progress in the rapidly evolving field of metabolic surgery will inform the design of more effective weight-loss compounds.

Chemerin, a chemoattractant protein, acts via a G-protein coupled chemokine receptor, i.e. Chemokine like Receptor 1/ChemR23; levels of which are elevated in pro-inflammatory states such as obesity and type 2 diabetes mellitus (T2DM). Obesity and T2DM patients are at high risk of developing cardiovascular disorders such as atherosclerosis. We have reported that chemerin induces human endothelial cell angiogenesis and since dysregulated angiogenesis and endothelial dysfunction are hallmarks of vascular disease; we sought to determine the effects of chemerin on monocyte-endothelial adhesion, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a critical pro-inflammatory transcription factor. Human endothelial cells were transfected with pNF-kappaB-Luc plasmid. Chemerin induced NF-κB activation via the MAPK and PI3K/Akt pathways. Western blot analyses and monocyte-endothelial adhesion assay showed that chemerin increased endothelial cell adhesion molecule expression and secretion, namely E-selectin (Endothelial Selectin), VCAM-1 (Vascular Cell Adhesion Molecule-1) and ICAM-1 (Intracellular Adhesion Molecule-1), leading to enhancement of monocyte-endothelial adhesion. Additionally, we showed a synergistic response of the pro-inflammatory mediator, Interleukin-1β with chemerin induced effects. Chemerin plays an important role in endothelial inflammation, as it induces monocyte-endothelial adhesion, a critical step in the development of atherosclerosis.

Objective: The objective of this study was to assess the utility of the 2-hour oral glucose tolerance test (OGTT) value to discriminate between different cardiometabolic profiles and examine the role of body composition in predicting the associated increased risk for glucose impairment, beta-cell dysfunction, and cardiovascular disease (CVD). Methods: Subjects with normal fasting glucose completed a 2-hour OGTT and were categorized to the carbohydrate metabolism alterations (CMAs) or the control group based on a 2-hour glucose threshold of 7.8 mmol/L. Body composition, visceral adipose tissue, OGTT-based parameters, and cardiovascular risk factors (CVRFs) such as hypertension, dyslipidemia, obstructive sleep apnea, nonalcoholic fatty liver disease, and smoking status were measured. Results: Subjects with CMAs exhibited a significantly higher 1-hour postload glucose level and a greater decline in beta-cell function and CVRF profiles. After multivariate adjustment, an excess of total body and visceral fat was associated with an increased risk of CMAs, beta-cell dysfunction, CVRFs, and lower whole-body insulin sensitivity. Conclusions: These data support the etiopathogenic role of body and visceral fat in the development of glucose derangements and CVRFs early on in the metabolic dysregulation process. Thus, body composition analysis and OGTT assessment performed in individuals with normal fasting glucose enable a better identification of patients at risk of developing type 2 diabetes and CVD.

ObjectiveRoux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment for diabetes and obesity. An increasingly recognized and highly disabling complication of RYGB is postprandial hypoglycaemia (PPH). The pathophysiology of PPH remains unclear with multiple mechanisms suggested including nesidioblastosis, altered insulin clearance and increased glucagon-like peptide-1 (GLP-1) secretion. Whilst many PPH patients respond to dietary modification, some have severely disabling symptoms. Multiple treatments are proposed, including dietary modification, GLP-1 antagonism, GLP-1 analogues and even surgical reversal, with none showing a more decided advantage over the others. A greater understanding of the pathophysiology of PPH could guide the development of new therapeutic strategies.MethodsWe studied a cohort of PPH patients at the Imperial Weight Center. We performed continuous glucose monitoring to characterize their altered glycaemic variability. We also performed a mixed meal test (MMT) and measured gut hormone concentrations.ResultsWe found increased glycaemic variability in our cohort of PPH patients, specifically a higher mean amplitude glucose excursion (MAGE) score of 4.9. We observed significantly greater and earlier increases in insulin, GLP-1 and glucagon in patients who had hypoglycaemia in response to an MMT (MMT Hypo) relative to those that did not (MMT Non-Hypo). No significant differences in oxyntomodulin, GIP or peptide YY secretion were seen between these two groups.ConclusionAn early peak in GLP-1 and glucagon may together trigger an exaggerated insulinotropic response to eating and consequent hypoglycaemia in patients with PPH.

OBJECTIVE Roux-en-Y gastric bypass (RYGB) characteristically enhances postprandial levels of glucagon-like peptide 1 (GLP-1), a mechanism that contributes to its profound glucose-lowering effects. This enhancement is thought to be triggered by bypass of food to the distal small intestine with higher densities of neuroendocrine L-cells. We hypothesized that if this is the predominant mechanism behind the enhanced secretion of GLP-1, a longer intestinal bypass would potentiate the postprandial peak in GLP-1, translating into higher insulin secretion and, thus, additional improvements in glucose tolerance. To investigate this, we conducted a mechanistic study comparing two variants of RYGB that differ in the length of intestinal bypass. RESEARCH DESIGN AND METHODS A total of 53 patients with type 2 diabetes (T2D) and obesity were randomized to either standard limb RYGB (50-cm biliopancreatic limb) or long limb RYGB (150-cm biliopancreatic limb). They underwent measurements of GLP-1 and insulin secretion following a mixed meal and insulin sensitivity using euglycemic hyperinsulinemic clamps at baseline and 2 weeks and at 20% weight loss after surgery. RESULTS Both groups exhibited enhancement in postprandial GLP-1 secretion and improvements in glycemia compared with baseline. There were no significant differences in postprandial peak concentrations of GLP-1, time to peak, insulin secretion, and insulin sensitivity. CONCLUSIONS The findings of this study demonstrate that lengthening of the intestinal bypass in RYGB does not affect GLP-1 secretion. Thus, the characteristic enhancement of GLP-1 response after RYGB might not depend on delivery of nutrients to more distal intestinal segments.

BACKGROUND: Obesity surgery has pronounced effects on metabolic profile of patients with type 2 diabetes mellitus (T2DM); however, reports on long-term remission rates based on the standardised and holistic criteria by the International Diabetes Federation (IDF) and effects on T2DM microvascular complications are scarce in the literature. In this retrospective clinical trial, our objectives were to assess these variables 5 years after surgery. METHODS: Clinical data and direct measurements of renal and retinal damage were collected prospectively and analysed retrospectively for 82 patients with T2DM who underwent obesity surgery and were followed up for 5 years. RESULTS: The cohort of 82 patients with T2DM that were followed up 5 years after obesity surgery was predominantly female (71%) with a median age of 51 years, weight of 133.5 kg, BMI of 46.8 kg/m2 and pre-operative duration of T2DM of 8 years; 6% of patients had diet-controlled T2DM, 57% were on non-insulin treatment and 37% were on insulin treatment pre-operatively. Of the total 82 patients, 59 patients underwent Roux-en-Y gastric bypass, 15 sleeve gastrectomy and 8 patients underwent gastric band operations. At 5 years, 5% and 15% patients achieved optimisation and improvement of the metabolic state based on the IDF criteria respectively. Surgery was associated with almost halving of the albumin-creatinine ratio in 22 patients with pre-existing albuminuria (follow-up data available for 64 patients) and an overall stabilisation of retinopathy in 24 patients with retinal images available at 5 years. CONCLUSION: Whilst the findings on microvascular complications are encouraging, the rates of metabolic remission were lower than expected and raise the need for validated protocols to assist clinicians in managing these patients more aggressively post-operatively to achieve optimum cardio-metabolic risk factor control and hopefully further reduction in microvascular and macrovascular complications.