While obesity is a world leading health problem, the most efficient treatment option for severely obese patients is Roux-Y gastric bypass (RYGB) surgery. However, there are large inter-individual differences in weight loss after RYGB surgery. The reasons for this are not yet elucidated and the role of genetics in weight loss-regulation is still not fully understood. The main aim for this thesis was to investigate the effects of common obesity-associated genetic variants and their effect on weight loss and food intake. We examined if the weight loss two years following RYGB surgery depends on the  FTO genotype, as well as pre-surgery vitamin D status. For FTO AA-carriers, the surgery resulted in a 3% per-allele increased excess BMI loss (EBMIL; P=0.02). When split by vitamin D baseline status, the EBMIL of vitamin D deficient patients carrying AA exceeded that of vitamin D deficient patients carrying TT by 14% (P=0.03). No such genotypic differences were found in patients without pre-surgery vitamin D deficiency. As the influence of individual single nucleotide polymorphisms may be small, we identified a novel method to combine SNPs into a genetic risk score (GRS). Using the random forest model, SNPs with high impact on weight loss after RYGB surgery were filtered out. An up to 11% lower EBMIL with higher risk score was estimated for the GRS model (p=0.026) composed of seven BMI-associated SNPs (closest genes: MC4R, TMEM160, PTBP2, NUDT3, TFAP2B, ZNF608 and MAP2K5). Pre-surgical hunger feelings were found to be associated with EBMIL and the SNP rs4846567. Before surgery, patients filled out the Three Factor Eating Questionnaire and were genotyped for known BMI and waist-hip ratio (WHR) associated SNPs. Patients with the lowest hunger scores had up to 32% greater EBMIL compared to the highest scoring patients (P=0.002). TT-allele carriers of rs4846567 showed a 58% lower hunger feelings. TT- carriers also showed a 51% decrease in disinhibition, but no significant impact on cognitive restraint was observed. Due to the association of eating behaviour and weight loss, acute effects on DNA methylation in response to a food intake intervention of a standardized meal were also investigated. After food intake, 1832 CpG sites were differentially methylated compared to the baseline after multiple testing correction. When adjusted for white blood cell fractions, 541 CpG sites remained. This may be interpreted as that the immune system is playing an active role in the response to food intake and highlights the dynamic nature of DNA-methylation. These findings will contribute to a better care for morbidly obese patients. Post-surgical treatment may be optimized so that patients with a less favourable genetic profile may receive additional support for weight loss and weight management. This may be considered as a step in the transition towards personalized medicine.

O presente estudo teve como objetivo avaliar o esvaziamento gástrico e o trânsito intestinal em 31 pacientes (sendo 10 controle e 21 com vômitos) após cirurgia bariátrica de DGYR e a relação das alterações destas duas variáveis entre si e com quadro sintomático e ainda tentar definir o tempo de esvaziamento gástrico desejável. O esvaziamento gástrico e o trânsito gastrintestinal foram avaliados mediante cintilografia, segundo técnicas padronizadas e previamente empregadas em outros estudos. A análise das imagens obtidas e armazenadas foi feita mediante o delineamento de regiões de interesse (ROI, da expressão, em Lingua Inglesa, region of interest) correspondendo ao coto gástrico, para a quantificação do esvaziamento gástrico, e para este segmento e também para as porções proximal e distal do intestino delgado e para a região ileocecal, para o trânsito gastrintestinal. A mesma região de interesse foi utilizada para as contagens de todas as imagens consecutivas, para a mesma projeção e para o mesmo paciente. Para a determinação do esvaziamento gástrico, a atividade em cada momento do estudo foi expressa pela média geométrica das contagens das imagens anteriores e posteriores, para correção do efeito da eventual movimentação intragástrica das partículas do radiotraçador (30, 60, 90 e 120 minutos após ingerir a refeição). Foi feita também correção adicional das contagens para compensar o declínio físico do 99m Tecnécio. Ambas as correções foram feitas automaticamente pelo equipamento. As contagens corrigidas permitiram a construção, para cada sujeito do estudo, da correspondente curva de esvaziamento gástrico, expressa como porcentuais de retenção intragástrica do radiotraçador ingerido, em cada um dos momentos de aquisição das imagens. Foi considerado como tempo inicial o momento em que se deu o término da ingestão da refeição contendo o radioisótopo, que corresponderia idealmente a um estado caracterizado por retenção intragástrica alimentar de todo o ingerido (100%). Após a realização da cintilografia, as imagens permaneceram armazenadas num sistema computadorizado acoplado à gama câmara e, no momento da análise, foram então definidas manualmente as ROI correspondentes ao estômago, ao jejuno, ao íleo e à região ileocecal. Em todos os casos, atentou-se para que as áreas destas ROI fossem semelhantes, o que foi feito levando-se em conta o número de pixels englobado por cada uma das regiões. Foi feita uma subdivisão do grupo com sintomas em 2 subgrupos: 8 pacientes com quadro de vômitos e exames de imagem alterados (EDA e seriografia) e 11 pacientes com quadro de vômitos e exames de imagem normais.O teste de Mann-Whitney bicaudal foi utilizado para comparações entre os dois grupos e entre os dois subgrupos. Os resultados foram apresentados como mediana e percentis, com significância de p < 0,05. Para a verificação das correlações entre esvaziamento gástrico e trânsito intestinal foi utilizado o coeficiente de correlação de Spearman, com significância de p < 0,05: não houve diferença significativa entre os dois grupos nos diversos tempos estudados (30, 60, 90 e 120 minutos) com relação ao esvaziamento gástrico. Também não houve diferença significativa com relação ao trânsito intestinal de acordo com o centro geométrico nos tempos 0, 30, 60, 90 e 120 minutos. Entretanto, houve diferença significativa entre os dois subgrupos extraídos do grupo com sintomas em todos os tempos do esvaziamento gástrico e nos tempos 0, 30, 60 e 90 minutos do trânsito intestinal (centro geométrico). Não houve diferença significativa entre os subgrupos no tempo 120 e na progressão do centro geométrico. Descritores: esvaziamento gástrico, trânsito intestinal, DGYR. / The objective of the present study was to assess gastric emptying and intestinal transit in 31 patients (10 controls and 21 with vomiting as a symptom) after bariatric surgery by RYGB and the relation of the alterations of these two variables between them and with the signs and symptoms, and also to try to define the desirable time of gastric emptying. Gastric emptying and gastrointestinal transit were evaluated by scintigraphy according to standardized techniques previously employed in other studies. The images obtained and stored were analyzed by delineating the regions of interest (ROI) corresponding to the gastric stump for the quantitation of gastric emptying and also for the proximal and distal portions of the small bowel and for the ileocecal region, for the gastrointestinal transit. The same ROI was used to count all the consecutive images for the same projection and for the same patient. For the determination of gastric emptying, the activity at each time point in the study was expressed as the geometric mean of the counts of the anterior and posterior images, for the correction of the effect of eventual intragastric movement of the radiotracer particles (30, 60, 90 and 120 minutes after meal ingestion). The counts were also additionally corrected to compensate for the physical decline of 99m Technetium. Both corrections were automatically made by the equipment. The corrected counts permitted the construction for each subject of the corresponding gastric emptying curve, expressed as percentage of intragastric retention of the ingested radiotracer at each time of image acquisition. The initial time was considered to be the moment when the ingestion of the meal containing the radioisotope occurred, which would ideally correspond to a state characterized by intragastric retention of all the food ingested (100%). After scintigraphy, the images were stored in a computerized system coupled to the gamma camera and, at the time of analysis, the ROI corresponding to the stomach, jejunum, ileum and ileocecal region were defined manually. In all cases, an attempt was made for these ROI to be similar, by taking into account the number of pixels included in each region. The group with symptoms was divided into 2 subgroups: 8 patients with vomiting and altered imaging exams (UDE and seriography) and 11 patients with vomiting and normal imaging exams. The two-tailed Mann-Whitney test was used to compare the two groups and the two subgroups. Data are reported as median and interquartile range, with significance set at p < 0.05. The Spearman correlation coefficient was used to determine the correlations between gastric emptying and intestinal transit, with significance set at p < 0.05. There was no significant difference between the two groups at the various time points studied (30, 60, 90 and 120 minutes) regarding gastric emptying. Also, there was no significant difference regarding intestinal transit according to the geometric center at 0, 30, 60, 90 and 120 minutes. However, there was a significant difference between the two subgroups extracted from the group with symptoms at all times of gastric emptying and at times 0, 30, 60 and 90 minutes of intestinal transit (geometric center). There was no significant difference between subgroups at 120 minutes or in the progression of the geometric center.

O presente estudo teve como objetivo avaliar o esvaziamento gástrico e o trânsito intestinal em 31 pacientes (sendo 10 controle e 21 com vômitos) após cirurgia bariátrica de DGYR e a relação das alterações destas duas variáveis entre si e com quadro sintomático e ainda tentar definir o tempo de esvaziamento gástrico desejável. O esvaziamento gástrico e o trânsito gastrintestinal foram avaliados mediante cintilografia, segundo técnicas padronizadas e previamente empregadas em outros estudos. A análise das imagens obtidas e armazenadas foi feita mediante o delineamento de regiões de interesse (ROI, da expressão, em Lingua Inglesa, region of interest) correspondendo ao coto gástrico, para a quantificação do esvaziamento gástrico, e para este segmento e também para as porções proximal e distal do intestino delgado e para a região ileocecal, para o trânsito gastrintestinal. A mesma região de interesse foi utilizada para as contagens de todas as imagens consecutivas, para a mesma projeção e para o mesmo paciente. Para a determinação do esvaziamento gástrico, a atividade em cada momento do estudo foi expressa pela média geométrica das contagens das imagens anteriores e posteriores, para correção do efeito da eventual movimentação intragástrica das partículas do radiotraçador (30, 60, 90 e 120 minutos após ingerir a refeição). Foi feita também correção adicional das contagens para compensar o declínio físico do 99m Tecnécio. Ambas as correções foram feitas automaticamente pelo equipamento. As contagens corrigidas permitiram a construção, para cada sujeito do estudo, da correspondente curva de esvaziamento gástrico, expressa como porcentuais de retenção intragástrica do radiotraçador ingerido, em cada um dos momentos de aquisição das imagens. Foi considerado como tempo inicial o momento em que se deu o término da ingestão da refeição contendo o radioisótopo, que corresponderia idealmente a um estado caracterizado por retenção intragástrica alimentar de todo o ingerido (100%). Após a realização da cintilografia, as imagens permaneceram armazenadas num sistema computadorizado acoplado à gama câmara e, no momento da análise, foram então definidas manualmente as ROI correspondentes ao estômago, ao jejuno, ao íleo e à região ileocecal. Em todos os casos, atentou-se para que as áreas destas ROI fossem semelhantes, o que foi feito levando-se em conta o número de pixels englobado por cada uma das regiões. Foi feita uma subdivisão do grupo com sintomas em 2 subgrupos: 8 pacientes com quadro de vômitos e exames de imagem alterados (EDA e seriografia) e 11 pacientes com quadro de vômitos e exames de imagem normais.O teste de Mann-Whitney bicaudal foi utilizado para comparações entre os dois grupos e entre os dois subgrupos. Os resultados foram apresentados como mediana e percentis, com significância de p < 0,05. Para a verificação das correlações entre esvaziamento gástrico e trânsito intestinal foi utilizado o coeficiente de correlação de Spearman, com significância de p < 0,05: não houve diferença significativa entre os dois grupos nos diversos tempos estudados (30, 60, 90 e 120 minutos) com relação ao esvaziamento gástrico. Também não houve diferença significativa com relação ao trânsito intestinal de acordo com o centro geométrico nos tempos 0, 30, 60, 90 e 120 minutos. Entretanto, houve diferença significativa entre os dois subgrupos extraídos do grupo com sintomas em todos os tempos do esvaziamento gástrico e nos tempos 0, 30, 60 e 90 minutos do trânsito intestinal (centro geométrico). Não houve diferença significativa entre os subgrupos no tempo 120 e na progressão do centro geométrico. Descritores: esvaziamento gástrico, trânsito intestinal, DGYR. / The objective of the present study was to assess gastric emptying and intestinal transit in 31 patients (10 controls and 21 with vomiting as a symptom) after bariatric surgery by RYGB and the relation of the alterations of these two variables between them and with the signs and symptoms, and also to try to define the desirable time of gastric emptying. Gastric emptying and gastrointestinal transit were evaluated by scintigraphy according to standardized techniques previously employed in other studies. The images obtained and stored were analyzed by delineating the regions of interest (ROI) corresponding to the gastric stump for the quantitation of gastric emptying and also for the proximal and distal portions of the small bowel and for the ileocecal region, for the gastrointestinal transit. The same ROI was used to count all the consecutive images for the same projection and for the same patient. For the determination of gastric emptying, the activity at each time point in the study was expressed as the geometric mean of the counts of the anterior and posterior images, for the correction of the effect of eventual intragastric movement of the radiotracer particles (30, 60, 90 and 120 minutes after meal ingestion). The counts were also additionally corrected to compensate for the physical decline of 99m Technetium. Both corrections were automatically made by the equipment. The corrected counts permitted the construction for each subject of the corresponding gastric emptying curve, expressed as percentage of intragastric retention of the ingested radiotracer at each time of image acquisition. The initial time was considered to be the moment when the ingestion of the meal containing the radioisotope occurred, which would ideally correspond to a state characterized by intragastric retention of all the food ingested (100%). After scintigraphy, the images were stored in a computerized system coupled to the gamma camera and, at the time of analysis, the ROI corresponding to the stomach, jejunum, ileum and ileocecal region were defined manually. In all cases, an attempt was made for these ROI to be similar, by taking into account the number of pixels included in each region. The group with symptoms was divided into 2 subgroups: 8 patients with vomiting and altered imaging exams (UDE and seriography) and 11 patients with vomiting and normal imaging exams. The two-tailed Mann-Whitney test was used to compare the two groups and the two subgroups. Data are reported as median and interquartile range, with significance set at p < 0.05. The Spearman correlation coefficient was used to determine the correlations between gastric emptying and intestinal transit, with significance set at p < 0.05. There was no significant difference between the two groups at the various time points studied (30, 60, 90 and 120 minutes) regarding gastric emptying. Also, there was no significant difference regarding intestinal transit according to the geometric center at 0, 30, 60, 90 and 120 minutes. However, there was a significant difference between the two subgroups extracted from the group with symptoms at all times of gastric emptying and at times 0, 30, 60 and 90 minutes of intestinal transit (geometric center). There was no significant difference between subgroups at 120 minutes or in the progression of the geometric center.

Die vorliegende Arbeit befasst sich mit der Häufigkeit eines postoperativen Dumping-Syndroms (DS) bei Roux-en-Y gastric bypass (RYGB) und Sleeve-Gastrektomie (SG) Patienten. Primärer Endpunkt der Studie war die Häufigkeit der postoperativen Hypoglykämie (Spätdumping, definiert als Blutzucker < 50 mg/dl mit typischen Beschwerden oder < 40 mg/dl mit oder ohne typische Beschwerden) im modifizierten OGTT (mod. OGTT). Vorab wurde dieser mod. OGTT, der sich vom Standard-OGTT bei gleicher absoluter Glucosemenge nur im reduzierten Volumen (100 ml statt 300 ml) unterschied, validiert. Hierzu wurden beide Tests bei 10 gesunden Probanden durchgeführt. Es wurden insgesamt 30 RYGB Patienten und 12 SG Patienten in die Studie eingeschlossen. Insgesamt zeigt die vorliegende Arbeit, dass ein Jahr postoperativ eine relevante Anzahl von RYGB und SG Patienten ein Frühdumping im mod. OGTT aufwies und über Dumpingbeschwerden im Alltag berichtete. Während ein Frühdumping bei RYGB und SG Patienten gleichermaßen vorkam, wurden Hypoglykämien nur bei RYGB Patienten festgestellt. Der mod. OGTT scheint hierbei zur Detektion von DS Patienten, aufgrund seines geringen Volumens, eine gute Alternative zu den bisherigen diagnostischen Verfahren darzustellen. Der 13C-Octanoat-Atemgastest ermöglichte - auf Basis unserer Ergebnisse - keine eindeutige Abgrenzung der Dumping-Patienten von den Non-Dumpern. / Early and late dumping symptoms are a common problem after bariatric surgery. However, data on a standardized evaluation of these patients are still scarce, especially for patients after sleeve gastrectomy (SG). The aim of this prospective study was to get more insight in the frequency and severity of dumping after SG and Roux-en-Y gastric bypass (RYGB). Additonally, we aimed at studying the diagnostic value of a 13C-octanoid acid breath test to objectify dumping symptoms. Early dumping defined by both an increase in hematocrit and symptoms (Sigstad score) was frequent in both SG and RYGB. Late dumping with hypoglycemia only occurred in RYGB. Glucose and insulin peaks were higher in patients with RYGB than in those with SG. Accepted dumping criteria (rise in hematocrit, hypoglycemia) showed no correlation with subjective symptoms measured with the Sigstad score. The 13C-octanoid acid breath test seems to be no useful tool after bariatric surgery. There was an increase in t1/2 within the limits of normal in RYGB patients. This paradox occurs probably due to altered absorption of 13C-Octanoate.

Die Doktorarbeit beschäftigt sich mit der metabolischen Anpassung der Thermogenese-Kapazität auf die Körpergewichtsveränderung nach Roux-en-Y Magenbypasses (RYGB) im DIO Kleintiermodell. Die zugrundeliegenden Mechanismen der operativen Gewichtsreduktion bei Patienten mit morbider Adipositas sind noch unzureichend verstanden. Die Arbeit untersucht im Rattenmodell der Diät-induzierten Adipositas (DIO) den abweichenden Einfluss der operativen versus diätetischen Gewichtsreduktion auf das Genexpressionsmuster der adaptiven Thermogenese in verschiedenen Fettdepots. Die Studienergebnisse deuten darauf hin, dass die operative Gewichtsreduktion via RYGB-Intervention eine Veränderung der peripheren Signalwirkung der Energiereserven an das zentrale Nervensystem bewirkt, wodurch die physiologische Adaptation der Thermogenese-Aktivität im braunen Fettgewebe an die Gewichtsreduktion ausbleibt. Die Untersuchung der hier zugrundeliegenden Mechanismen der veränderten zentralen Adipokinsignalwirkung ist nicht mehr Bestandteil der Doktorarbeit. Die Ergebnisse weisen auf eine veränderte Regulation des Energieumsatzes nach RYGB-Operation hin, deren funktioneller Einfluss auf den nachhaltigen Gewichtseffekt der Intervention noch untersucht werden muss.

No description available.

<p>In our first study, we explored the barriers to complying with iron supplement recommendations using focus groups. We recruited adults, ages 18-75 years, who have had bariatric surgery at least two months previously to participate in one of four 90-minute focus groups. Participants filled out a survey asking for information on demographics and supplement use, and a facilitator asked a set of pre-determined questions to each group. Responses were written, recorded, transcribed using TranscribeMe (San Francisco CA), and analyzed using NVivo (QSR International Pty Ltd, Doncaster, Victoria). The focus groups contained nineteen participants, five of which had sleeve gastrectomy (SG) and fourteen had Roux-en-Y gastric bypass (RYGB). The average age of the participants was 49.3 ± 9.4 years, and they had undergone surgery 3.9 ± 3.6 years previously. The key factors that influenced participants’ adherence to supplement guidelines were cost, tolerability, and palatability of the supplement, level of knowledge and support from healthcare providers, and convenience of the supplementation regime.</p> <p>The second study was a prospective observational study to determine the bioavailability of ASP compared to FS. Iron deficient RYGB patients ages 18-65 years, who had surgery at least 6 months previously, participated in 8-hour iron absorption tests. Participants received a low-iron breakfast with 65 mg ASP (N=7) or FS (N=3). We assessed serum iron every 30 minutes for 8 hours following the supplementation using a colorimetric assay (South Bend Medical Foundation, South Bend, IN). In participants administered FS, serum iron increased 96.0 ± 27.2 µg/dL compared to baseline, whereas with ASP, serum iron increased 5.8 ± 4.7 µg/dL compared to baseline (<i>P</i> = 0.02). These data indicate that ASP is not as bioavailable as FS in RYGB patients.</p>

No description available.

Submitted by Natalia de Souza Gonçalves (natalia.goncalves@ufpe.br) on 2016-10-10T13:09:11Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) GALENO EGYDIO - COLACAO DE GRAU.pdf: 1509311 bytes, checksum: f4dc67e7a0e6a1a9159df433631ba569 (MD5) / Made available in DSpace on 2016-10-10T13:09:12Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) GALENO EGYDIO - COLACAO DE GRAU.pdf: 1509311 bytes, checksum: f4dc67e7a0e6a1a9159df433631ba569 (MD5) Previous issue date: 2014-02-19 / O uso de anel na derivação gástrica em Y de Roux (DGYR) está associado à intolerância alimentar pós-operatória, cujo tratamento clássico tem sido a remoção cirúrgica. Um novo método utilizando prótese plástica autoexpansível (PPAE) induz erosão intragástrica do anel, o qual é removido por via endoscópica de forma minimamente invasiva. Objetiva-se analisar a eficácia e a segurança dessa técnica de remoção de anel após DGYR. Estudo prospectivo longitudinal de série de 41 pacientes com intolerância alimentar associada à presença de anel, que foram, tratados por via endoscópica, entre 2007 e 2013. O grupo apresentava média de idade igual a 44,1 anos, IMC médio de 27,0 Kg/m², e vômitos foram os sintomas mais frequentes (n=37), com ocorrência diária em 46,3%. O sucesso terapêutico foi definido como a melhora dos sintomas após a remoção do anel. O implante de PPAE foi realizado sob anestesia geral e guiado por radioscopia, sendo utilizado endoscópio padrão. Os pacientes receberam alta após 24 horas com dieta líquida e inibidor de bomba de prótons (IBP), que foi prescrito durante o tempo médio de permanência da PPAE, que foi de 15,3 dias. A prótese promoveu erosão completa de anel em 24 (58,5%) pacientes e no grupo restante, a remoção em segundo estágio após 7 dias com pinça de corpo estranho. Houve três casos de migração da prótese com eliminação espontânea por via retal. O efeito adverso mais comum foi vômito (n=7). Não houve complicações graves, nem necessidade de remoção precoce da prótese. Após seguimento médio de 6 meses, não houve mudança significativa no IMC e 78% dos pacientes foram capazes de ingerir carne vermelha. A remoção do anel com uso de prótese endoscópica demonstrou ser um procedimento seguro e eficaz, com100% dos anéis sendo removidos com sucesso e 29,3% de ocorrência de eventos adversos leves (vômitos). Esta técnica é uma alternativa adequada na remoção do anel, evitando a intervenção cirúrgica e reduzindo a possibilidade de reganho de peso. / Ring dysfunction after roux-en-y gastric bypass (RYGB) causing delayed gastric emptying on Fobi pouch is classically treated by surgical ring removal. In a novel way of using selfexpandable stents, intraluminal erosion of the ring is achieved, allowing its removal by endoscopy, with no need of surgery. No study has shown clinical applicability of this principle in RYGB banded with silastic ring. In this case series we analyze endoscopic removal of noneroded dysfunctional rings after RYGB using self-expandable plastic stents (SEPS). This is a prospective case series of 41 patients with delayed gastric emptying secondary to extrinsic compression of the ring after RYGB between 2007 and 2013. Successful ring removal, symptoms improvement, weight control and adverse events were evaluated. Mean age of subjects was 44.1 years, median BMI at treatment was 27.0 Kg/m2. Most common symptom was vomiting (n=37), with daily occurrence in 46.3%. Success was defined as symptoms improvement after stent and ring removal. SEPS placement was done under general anesthesia and fluoroscopic guidance. A standard gastroscope (Pentax Medical, Montvale, NJ), and a PolyflexTM stent (25x21x150mm) (Boston Scientific, Natick, MA) were used in all cases. All patients were discharged after a 2-hour observation period, with liquid diet and proton pump inhibitor. SEPS induced complete erosion in 24 patients, allowing for simultaneous stent and ring removal. The median time of stenting was 15 days. There was one case of stent migration, which was naturally expelled. Most common adverse event was vomiting (n=7). There was no early stent removal, and no serious complications. After a mean follow-up of 6 months, there was no significant change in mean BMI, and 78% of patients are able to ingest solid foods. Endoscopic stents led to ring intraluminal erosion in 100% of subjects, allowing for successful removal of dysfunctional rings. The procedure is technically feasible and safe, with a 29.3% occurrence of mild adverse events (vomiting), and no serious complications. It proved to be a reasonable alternative for ring removal in our casuistic, avoiding surgery, and decreasing the possibility of weight regain.

Bypass or resection of the stomach and oesophagus, has long been recognised to result in profound changes in the handling of ingested nutrients. This results in significant morbidity after radical surgery for oesophago-gastric cancer, in particular post-prandial hypoglycaemia, altered appetite, early satiety and noxious post-prandial symptoms. By profiling and challenging the gut hormone axis in healthy volunteers and patients who had undergone total or subtotal gastrectomy, or oesophagectomy, this thesis explores the possible causative mechanisms for the challenges faced by this patient population. In the surgical groups, an oral glucose tolerance test (OGTT) resulted in enhanced secretion of satiety and incretin gut hormones (GLP-1, GIP, PYY) and insulin, followed by hypoglycaemia in a cohort of patients. Continuous glucose monitoring of gastrectomy participants over two weeks of normal lifestyle identified an increased incidence of day and night time hypoglycaemia. RNAseq and mass spectrometry based peptidomics of human and murine enteroendocrine cells in the pre- and post-operative populations revealed no significant change in the underlying cellular pathways for nutrient sensing and gut hormone secretion, indicating that the altered hormone secretion is primarily driven by accelerated nutrient transit, rather than adaptive changes in the gut. Finally, specific blockade of the GLP-1 receptor in post-gastrectomy patients using Exendin 9-39 normalised insulin secretion and prevented reactive hypoglycaemia after an OGTT. In conclusion, profound changes in gut hormone secretion as a result of enhanced nutrient transit after foregut surgery likely underlie the early and late post-prandial symptoms seen in this group, and therapies specifically targeting the gut hormone axis, and GLP-1 in particular, could be the first targeted treatments for post-gastrectomy syndromes.