Bariatric surgery is very effective at inducing weight loss and diabetes resolution in morbidly obese patients. Whether WL or increased incretin response is the crucial factor in normalising diabetes is still debatable. This thesis work prospectively investigated how bariatric surgery affected insulin action and beta-cell function in patients with morbid obesity and type 2 diabetes. Understanding these can help us to optimise diabetes treatments in patients with morbid obesity. I first discussed how obesity affects insulin sensitivity and beta-cell function, evidences that bariatric surgery is superior to conventional medical therapy at inducing weight loss and euglycaemia, and its associated mechanisms. I concluded that more robust data are needed to understand the effects of LAGB and RYGB surgery on glucose homeostasis, as this will have clinical implications for patients undergoing bariatric surgery (Chapter 1). I then described and justified the methods used for investigating insulin sensitivity and insulin secretion in the two studies (GLIPO and ISP) that make up this thesis (Chapter 2). I demonstrated that at 1 week post-op, improvements in glycaemia, insulin sensitivity and weight were the same in all patients, despite unilateral increase in incretin responses in the RYGB group. At 18 months I found that RYGB (n=32) had induced greater weight loss than LAGB (n=17). This resulted in better glycaemic control, further insulin sensitivity enhancement and marked improvements in insulin secretion and pancreatic secretory reserve in this group (Chapter 3&4). Finally, I demonstrated that marked weight loss after RYGB normalised insulin signalling (PI3K-Akt), but not glucose uptake in muscle. This suggested that major defects in the insulin signalling pathway still exist and may explain why not all patients can achieve diabetes remission after RYGB (Chapter 5). In conclusion, the degree of weight loss, not enhanced incretin response, is the major determinant of glycaemic improvement after bariatric surgery. This improvement is first brought about by improvements in insulin sensitivity followed by improvements in insulin secretion.

Laparoscopic adjustable gastric banding (LAGB) is a commonly performed bariatric procedure worldwide. Some of the short-term outcomes from LAGB are well documented but little is known about the mid-to-long term outcomes following this procedure in the UK within the National Health Service (NHS) framework. This thesis will focus specifically on the outcomes of LAGB on an NHS population of patients. A review of the literature will summarise the current evidence supporting the use of bariatric surgery in the morbidly obese population. Following on from this introduction into the subject, a small case series is presented. The results of this pilot study suggest that LAGB can be considered as a valid treatment for idiopathic (benign) intracranial hypertension. Over the following two chapters the results from a prospective cohort study will explore in depth the outcomes of a cohort of morbidly obese, type 2 diabetic patients following LAGB. This will address both potential improvements in diabetes and the evolution of several obesity-related co-morbidities following surgically induced weight loss. Subsequent chapters will attempt to clarify some of the controversy associated with long-term complications following LAGB. An in-depth literature review will highlight variations in the definition and reporting of several of the well recognised complications associated with this procedure and suggest a reporting framework to aid clarity in future publications. This is followed by a prospective cohort study addressing those complications specifically associated with oesophageal function, and clinical outcomes following the implication of a simple management regimen when such complications arise. It is hoped that the detailed and transparent analysis of a large surgical cohort reported within this thesis will provide guidance for surgical teams within the NHS who perform this bariatric procedure.

The aim of this thesis was to study the effect of symbiotic administration on measurable parameters of gut-barrier function and clinical outcome in the following groups of surgical patients;  Elective surgical admissions, Intensive Care patients, Irritable Bowel Syndrome sufferers and Crohn’s Disease patients. Each study was performed as a double blind, randomised and placebo controlled trial.  The symbiotic preparation contained oligofructose and the probiotic bacteria Lactobacillus acidophilus La5, Bifidobacterium lactis Bb-12, Streptococcus thermophilus and Lactobacillus bulgaricus. The preoperative ingestion of synbiotics had no influence on the rate of bacterial translocation, endotoxin exposure or subsequent septic morbidity in elective surgical patients.  Nasogastric colonisation by potentially pathogenic organisms was significantly reduced in the population of critically ill patients after symbiotic therapy, but was not associated with improved clinical outcome.  Physical and psychological symptom scores improved in both the placebo and active symbiotic groups of irritable Bowel Syndrome patients, representing a significant placebo response.  Synbiotic dietary supplementation had no significant effect on relapse rate, markers of disease activity or nutritional status in patients with Crohn’s Disease over a one year period. Synbiotic administration significantly altered nasogastric colonisation by potentially pathogenic bacteria, but had no effect on any other quantifiable measure of gut-barrier function.  The clinical significance of this finding is uncertain, but warrants further investigation.  To date, there is insufficient scientific evidence to recommend the routine use of synbiotics in surgical patients.

Introduction: Obesity is associated with an increase in morbidity and mortality. Over the past 30 years the rate of obesity has been rising in almost all countries. The number of weight loss surgery procedures has also increased in England in recent years. Research into the psychological impact of weight loss surgery has found positive outcomes (e.g. reduced emotional distress and depression) as well as tensions (e.g. loss of identity and feeling vulnerable). Despite research into preparation for generic surgery, there is a gap in the literature on preparation for weight loss surgery patients. The present study was designed firstly to examine what preparation a UK sample of weight loss surgery patients have received, and secondly to explore the individual experiences of the weight loss surgery journey. Method: A mixed methods approach was used. An online questionnaire developed for this study was completed by 148 participants who have had weight loss surgery. A sample of seven adults were recruited from a weight loss surgery support group and participants were interviewed using a semi-structured interview schedule. Interviews were transcribed and analysed using Interpretative Phenomenological Analysis. Results: Participants reported receiving information on; the different parts of the weight loss surgery process, changes in diet, eating behaviour, and physical changes. Participants reported that information was lacking on relationship and psychological changes. Five master themes and 16 super-ordinate themes emerged following the group analysis of the interviews. Participants reflected on their lead up to surgery and their experience of preparing for surgery. Participants tried to make sense of their relationship with food and their emotional attachment to it. They reflected on their experience of changing relationships and identity post-surgery. Participants highlighted the value of support groups and the internet in preparing them for surgery, particularly communicating with individuals who have had weight loss surgery. Discussion: Preparation for weight loss surgery is an important part of the process. More preparation is needed for the psychological changes, emotional challenges, and adjustments experienced throughout the journey. A group intervention is recommended. This would be efficient and cost effective. It would provide opportunities for social inclusion and peer support.

Background: The dogma that persisted for many years was that malabsorption plays a significant role in contributing to the weight loss following bariatric surgery. The aim was to assess for evidence of malabsorption after bariatric procedures; adjustable gastric banding (AGB), Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion-duodenal switch (BPD-DS). Methods: This cross sectional study recruited participants into four groups: obese controls (n=7), AGB (n=6), RYGB (n=7) and BPD-DS (n=5). Biochemical tests were used to assess; (i) entire gut: sulphasalazine test for oro-caecal transit time (OCTT) & plasma citrulline for functional enterocyte mass. (ii) foregut: faecal elastase-1 (FE1) for exocrine pancreatic function. (iii) mid-gut: Lactulose:rhamnose (L:R) ratio for gut permeability, faecal calprotectin (FCp) for gut inflammation & plasma and urine bile acids (BAs) for BA metabolism. (iv) hindgut: Faecal fat (Ffat) excretion for fat malabsorption. Results: (i) entire gut: There was no difference in OCTT (p=0.935) or functional enterocyte mass (p=0.819). (ii) foregut: FE1 was lower in the RYGB vs. the control group (p=0.002), with no difference between other groups (all p>0.05). (iii) mid-gut: L:R ratio was higher in the BPD-DS vs. the control (p=0.012), AGB (p=0.016) and RYGB (p=0.012), with no difference between other groups. FCp was higher in the RYGB vs. the control (p=0.016), with no difference between other groups. The fasting plasma and urine BAs were elevated in BPD-DS vs. the control, ABG and RYGB (all p<0.05). (iv) hindgut: The BPD-DS had higher Ffat excretion vs. the control (p=0.038), AGB (p=0.046) and RYGB (p=0.024). The RYGB had higher Ffat excretion vs. the control (p=0.033). There was no difference between the RYGB and AGB (p=0.808). Conclusion: There was no evidence to support the notion that RYGB causes severe malabsorption of fats or sugars. However, BPD-DS does cause fat malabsorption.

Obesity is becoming the healthcare epidemic of this century. Weight loss surgery is the only effective treatment for morbid obesity. Furthermore glycaemic control in type 2 diabetic patients is improved after metabolic surgery. Here I observed that with gastric bypass, type 2 diabetes can be improved and even rapidly put into a state of remission irrespective of weight loss. This is achieved via an improvement of both insulin resistance and insulin production. Reduced insulin resistance within the first week after surgery remains unexplained, but increased insulin production in the first week after surgery may be explained by the enhanced postprandial GLP-1 response. In addition, I demonstrate that bile flow changes lead to increased gut hormone response in animal models. Roux-en-Y gastric bypass in humans causes changes in bile flow leading to increased plasma bile acid concentrations. This phenomenon may explain the improved glycaemic control following gastric bypass. In conclusion I investigated the mechanism of diabetes remission after metabolic surgery and explored the role of gut hormones and bile acids in the changes in glucose homeostasis following metabolic surgery.

This portfolio has three parts. The first is a systematic literature review, in which the psychological and social factors associated with successful weight loss after bariatric surgery are reviewed. The second part is an empirical paper, which investigates the experiences of women who have successfully lost weight following bariatric surgery, specifically with reference to changes in self-concept. Seven women were interviewed and emergent themes were analysed using interpretative phenomenological analysis. Nine subthemes were identified, clustered into three superordinate themes: (1) 'obesity as socially unacceptable', (2) 'making a case for surgery', and (3) 'the slim self as socially acceptable'. Links to self-concept were made, and clinical implications were discussed. The third part of the portfolio comprises of the reflective statement and appendices.

Introduction: L’obésité est un facteur connu d’hypercoagulabilité in vitro et in vivo. Cependant peu d’études se sont intéressées aux facteurs de risque d’hypercoagulabilité biologique chez le patient obèse morbide, à sa variation après chirurgie bariatrique (CB) ainsi qu’aux facteurs de risques de maladie thromboembolique veineuse (MTEV) postopératoire après CB. Matériel et Méthodes: Tous les patients destinés à une CB entre le 1er Septembre 2014 et le 31 Janvier 2016 au CHU de Brest étaient éligibles pour notre étude de cohorte locale et ont bénéficié d’un large bilan sanguin préopératoire et à 12 mois postopératoires, incluant des tests de génération de thrombine (GT) avec mesure du potentiel endogène de thrombine (ETP), une méthode validée globale d’évaluation de la coagulation. En parallèle, nous avons extrait de la base du SNIIRAM de l’assurance maladie, tous les patients opérés d’une CB entre le 1er Janvier 2012 et le 30 Septembre 2014 et déterminer la fréquence d’une MTEV dans les 90 jours suivants la CB. Résultats: Cent-deux patients étaient inclus dans notre étude de cohorte brestoise. Les facteurs de risque (OR (95% IC)) de présenter un ETP dans le 4ème quartile de distribution étaient : taux de cholestérol total augmenté (Pas=1mmol/l) (2,6 (1,2-5,4);P =0,01) et taux de fibrinogène augmenté (Pas=1 g/l) (2,2; (1,1-4,5);P = 0,03). A un an post-opératoire (%perte de poids: 33.1±8.3), on retrouvait une baisse significative de l’ETP (%) (111 (96-129) vs. 84 (72-102) ; P<0.001), du taux de fibrinogène (g/l) (4,2±0,8 vs. 3,6±0,8 ; P<0.001) et une baisse non significative du taux de cholestérol total (mmol/l) (4,8±0,8 vs. 4,6±1,0; P=0,08). Apres extraction à partir du SNIIRAM, 110.824 patients étaient inclus. Le taux de MTEV dans les 90 jours était de 0,51%. Les principaux facteurs de risque de MTEV retrouvés en analyse multivariée étaient (P<0.001): un antécédent de MTEV (6,41 (4,50-9,14)), des complications post-opératoires (9,23 (7,30-11,68)), une défaillance cardiaque (2,45 (1,48-4,06), une chirurgie par laparotomie (2,38 (1,59-3,45)), un IMC ≥ 50 kg/m² (1,67 (1,28-2,18)), une sleeve gastrectomy (2,02 (1,39-2,93)) et une procédure de deuxième intention (1,37 (1,10-1,72)). Conclusion : Sur une étude de cohorte de plus de 110.000 patients, nous identifions un taux faible de MTEV dans les 90 jours post-opératoires après CB dépendant de facteurs de risque individuels et liés à la chirurgie. De surcroit nous identifions une baisse de la GT à 1 an post-opératoire en parallèle à une perte de poids massive et à une diminution de l’état inflammatoire. / Introduction: Obese patients are known to be in an in vitro and in an in vivo hypercoagulable state relative to normal-weight patients. Studies focusing exclusively on morbidly obese patients are lacking. Our study aimed to identify markers of enhanced coagulability, to compare its evolution one year after bariatric surgery (BS) and to determine risk factors of venous thromboembolism (VTE) within 90 postoperative days. Methods: All patients scheduled for bariatric surgery (BS) between September 1, 2014 and January 31, 2016 in Brest University Hospital were eligible for our prospective local study. In vitro coagulation was assessed using thrombin generation (TG) tests (Endogenous thrombin potential (ETP)). Data on all patients undergoing BS in France from 1st January 2012 to 30 September 2014 were also extracted from the database of the French national health care (SNIIRAM) to determine the rate of VTE in the 90 days after surgery. Results: One hundred and two patients were included in our study assessing TG. Risk factors for enhanced TG (ETP in the 4th quartile) were increased total cholesterol level (Step=1mmol/l) (2.6 (1.2-5.4); P =0.01) and increased fibrinogen level (Step=1g/l) (2.2 (1.1-4.5); P=0.03). At 12 postoperative months, we found a significant lower ETP (%) (111 (96-129) vs. 84 (72-102 P<0.001)), fibrinogen level (g/l) (4.2±0.8 vs. 3.6±0.8; P<0.001)) and a non-significant trend for lower total cholesterol level (mmol/l) (4.8±0.8 vs. 4.6±1.0; P=0.08). After extraction of the SNIIRAM database, 110,824 patients were included with a rate of VTE of 0.51% (90 post-operative days). Main risk factors for postoperative VTE were (p<0.001): history of VTE (6.41 (4.50-9.14)), postoperative complications (9.23 (7.30-11.68)), heart failure (2.45 (1.48-4.06), open approach (2.38 (1.59-3.45)), BMI ≥ 50 kg/m² (1.67 (1.28-2.18)), sleeve gastrectomy (2.02 (1.39-2.93)) and redo procedure (1.37 (1.10-1.72)). Conclusions: Our study highlights the role of total cholesterol and blood inflammatory marker levels in enhancing TG in morbidly obese patients and shows a decrease of TG at 12 months after BS. The risk of postoperative VTE after BS is low depending on the individual risk level.