Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13450号 / 論医博第2243号 / 新制||医||1054(附属図書館) / (主査)教授 稲垣 暢也, 教授 妹尾 浩, 教授 小濱 和貴 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background. Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity, where gut peptides such as ghrelin, glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) play an instrumental role in reduced appetite after RYGB. This systematic review and meta-analysis aimed to establish the magnitude of change of ghrelin, GLP-1, PYY and appetite sensation following RYGB. Methods. A systematic search was conducted in Medline Ovid, Embase, Scopus, and Cochrane Central Register of Controlled Trials up until March 2021. Two independent reviewers screened articles for studies that evaluated ghrelin, GLP-1, PYY or appetite sensation via visual analogue scales (VAS) before and after RYGB in adults. Risk of bias was assessed with the quality assessment tool for before-after studies with no control group from the National Heart, Lung and Blood Institute (NHLBI). A multilevel model with random effects for study and follow-up time points nested in study was fit to the data. The model included kilocalorie consumption as a covariate and time points as moderators. Results. Among the 2,559 articles identified, 47 met the inclusion criteria, among which k=19 evaluated ghrelin, k=40 GLP-1, k=22 PYY and k=8 appetite sensation via VAS. Our results indicate that fasting ghrelin levels are decreased 2 weeks post-RYGB (p = .005) but do not differ from baseline from 6 weeks to 1-year post-RYGB. Postprandial ghrelin levels at 6 months and 1-year post-RYGB were not different from pre-surgical values (p = .51). Fasting GLP-1 levels were not different from pre-surgical levels up to 2 years post-RYGB. Postprandial levels of GLP-1 increased significantly from 1 week (p < .001) to 2 years post-RYGB (p < .01) compared to before surgery. Compared to pre-RYGB levels, fasting PYY increased at 6 months (p = .034) and 1 year (p = .0299) post-surgery and postprandial levels were increased up to 1 year (p < .01). Heterogeneity was significant in most analyses. Insufficient data on appetite sensation was available to be meta-analyzed. Conclusion. Our analyses illustrate the magnitude of change of ghrelin, GLP-1 and PYY before and after RYGB surgery. Importantly, between study heterogeneity within the current literature warrants more standardized protocols and studies with longer follow-up periods for better comprehension of changes in gut peptides following RYGB surgery.

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Prediabetes is a condition affecting 35% of US adults and about 50% of US adults age 65+. Foods rich in polyphenols, including flavanols and other flavonoids, have been studied for their putative beneficial effects on many different health conditions including type 2 diabetes mellitus and prediabetes. Studies have shown that some flavanols increase glucagon-like peptide 1 (GLP- 1) levels. GLP-1 is a feeding hormone that increases insulin secretion after carbohydrate consumption and increased GLP-1 levels may be responsible for some of the beneficial effects on glycemic control after flavanol consumption. The present study explored the effects of grape powder consumption on metrics of glycemic health in normoglycemic and prediabetic C57BL/6J mice; additionally, the mechanism of action of grape powder was investigated. Grape powder significantly reduced (p<0.01) blood glucose levels following oral glucose gavage after GLP-1 receptor antagonism by exendin-3 (9-39) compared to sugar-matched control; indicating that it was able to attenuate the hyperglycemic effects of GLP-1 receptor antagonism. Grape powder was employed in acute (1.6 g grape powder/kg bodyweight) and long-term high fat diet (grape powder incorporated into treatment diets at 5% w/w) feeding studies in normoglycemic and prediabetic (diet-induced obesity) mice; grape powder did not improve glycemic control in these studies versus sugar-matched control. The mechanisms by which grape powder ameliorates the deleterious effects of GLP-1 receptor antagonism warrants further study. / Master of Science in Life Sciences

Introdução: O gene TCF7L2 (Transcription Factor 7-Like 2) codifica o fator de transcrição de mesmo nome que, tem importante papel na via Wnt de sinalização intra celular. A via Wnt é constituída por proteínas de integração e ligação dos processos de diferenciação e multiplicação celulares, interagindo com os fatores TCF, e ativando a expressão de genes relacionados ao TCF7L2, sendo este amplamente expresso em vários tecidos. Dados epidemiológicos atuais não deixam dúvidas quanto à forte associação de polimorfismos do gene TCF7L2 com o diabetes tipo 2 (DM2) em diferentes etnias. Apesar de serem pouco conhecidos os mecanismos que envolvem o gene TCF7L2 no DM2, tem sido bem demonstrada a associação do alelo T no rs7903146 com redução da secreção de insulina, redução do efeito das incretinas, principalmente do GLP-1, aumento na secreção de glucagon e a longo prazo, redução da meia vida da célula beta. Em vista destas evidências, aventamos a hipótese de que pacientes com DM2 portadores da variante rs7903146 do gene TCF7L2, ao ser tratados com GLP-1 mimético, poderiam responder de forma peculiar. Objetivos: Avaliar a resposta hormonal pancreática antes e após tratamento com GLP-1 mimético em indivíduos com DM2 portadores da variante rs7903146 do gene TCF7L2. Pacientes e Métodos: Foram genotipados162 indivíduos com DM2 portadores da variante rs7903146 do gene TCF7L2: idade (57,0 &#177; 7,6) anos, IMC (30,5 &#177; 5,1) kg/m2. Dessa amostra, 56 pacientes foram divididos em dois grupos conforme o genótipo, sendo 26 CC x 30 CT/TT, e a seguir tratados com Exenatide durante oito semanas. Os testes de refeição foram realizados antes e após o tratamento, para avaliação das concentrações plasmáticas de: Glicose (mg/dl), Insulina (&#956;U/dl), Pró-insulina (pmol/L), Peptideo-c (ng/ml); Glucagon (pg/ml) e GLP-1(pmol/L). Foram comparadas as áreas sob as curvas e os pontos das curvas durante o teste. Análise estatística por ANOVA com dois fatores e medidas repetidas, nível de significância maior que 5%. Resultados: A distribuição genotípica CC x CT x TT foi 41,4% x 47,5% x 11,1% respectivamente. A influência do alelo T na resposta pancreática durante o teste da refeição mostrou que as concentrações plasmáticas de insulina, pró-insulina e peptídeo-c foram maiores no grupo CT/TT do que no CC (p<0,05) mas, não houve diferença na secreção do glucagon, GLP-1 e na glicemia entre os grupos (NS).Com relação à influência do alelo T na resposta ao tratamento verificou-se que o grupo CT/TT apresentou maior redução da secreção de insulina (p<0,005), peptídeo-c (p<0,05) e pró-insulina (p<0,001) do que o grupo CC durante o teste da refeição após o tratamento. Observou-se diminuição da glicemia, do glucagon e do GLP-1 de forma semelhante em ambos os grupos. Além disso, houve diminuição semelhante do peso e da hemoglobina glicosilada em ambos os grupos. Discussão: Os resultados do presente estudo mostraram que a presença do alelo T em indivíduos com DM2 esteve associada à maior secreção de insulina, pró-insulina e peptídeo-c em relação aos não portadores, com semelhantes concentrações séricas de glucagon e glicose em resposta ao teste da refeição. Este dado demonstra que a função da célula &#946; dos portadores da variante rs7903146 apresenta características diferentes dos não portadores. Após o tratamento com Exenatide, os indivíduos com DM2 e genótipo CT/TT, apresentaram valores estatisticamente menores de insulina, pró-insulina e peptídeo-c do que o grupo CC. Os efeitos do GLP-1 na glicemia pós-prandial são atribuídos a mecanismos de supressão do glucagon, lentificação do esvaziamento gástrico e também a efeitos insulinotrópicos e decorrentes de aumento na sensibilidade periférica à insulina. Além disso, já foi demonstrado que o Exenatide aumenta a captação de glicose de forma insulino-independente em músculo esquelético, pelo estímulo dos transportadores de glicose. Portanto, acredita-se que as características da resposta observada após o tratamento nos portadores do alelo T correspondem ao efeito do Exenatide na célula &#946; melhorando o processamento da pró-insulina, peptídeo-c e insulina e ao aumento da captação periférica da glicose. Sugere-se que esse processo seja resultante da melhor interação com os receptores de GLP-1, tanto em fígado, músculo esquelético e pâncreas. Conclusões: Os dados sugerem que indivíduos com DM2 portadores do alelo T no rs7903146 do gene TCF7L2 apresentam mais benefícios do tratamento com Exenatide, pois a secreção de insulina, pró-insulina e peptídeo-c foram condizentes com maior qualidade na função de célula &#946; nesse grupo após o tratamento. Além disso, o presente estudo proporcionou adicionais evidências clínicas de que os problemas que associam o TCF7L2 ao DM2 estão relacionados à tolerância periférica a glicose. / Introduction:The TCF7L2 gene (Transcription Factor 7-Like 2) encodes the transcription factor of the same name that has an important role in the intracellular Wnt signaling. The Wnt pathway is composed of connecting and integrating proteins of cell proliferation and differentiation process by interacting with TCF factors, and activating the expression of genes related to TCF7L2, which is widely expressed in several tissues. Current epidemiological data leave no doubt as to the strong association of polymorphisms of the TCF7L2 gene with type 2 diabetes (T2DM) in different ethnic groups. Although they are poorly known mechanisms involving TCF7L2 gene in DM2 the association of the T allele of rs7903146 with reduced insulin secretion, reducing effect of incretins, mainly GLP-1, increase in glucagon secretion and long-term reduction in the half-life of the beta cell, have been well demonstrated. In view of this evidences, we hypothesized that patients with DM2 carriers of the variant rs7903146 of the TCF7L2 gene, being treated with GLP-1 mimetic, could respond in a peculiar way. Objectives: Evaluating the pancreatic hormone response before and after treatment with GLP-1 mimetic in individuals with T2DM carriers of rs7903146 variant of TCF7L2 gene. Patients and Methods: We genotyped 162 individuals with T2DM patients with the variant rs7903146 gene TCF7L2: age ( 57.0 &#177; 7.6 ) years old, BMI ( 30.5 &#177; 5.1 ) kg/m2. From this sample, 56 patients were divided into two groups according to the genotype, 26 x 30 CC CT / TT, and then treated with exenatide for eight weeks. Meal tests were conducted before and after treatment to evaluate plasma concentrations of: Glucose ( mg / dl) Insulin ( U / dL ) Proinsulin (pmol / L), C-peptide (ng / ml) , Glucagon (pg / ml) and GLP-1 (pmol / L). The areas under the curves and the points of the curves were compared during the test. Statistical analysis by ANOVA with two factors and repeated measures, significance level greater than 5%. Results: The genotype distribution CC x CT x TT was 41.4% vs. 47.5% vs. 11.1 % respectively. The influence of the T allele in the pancreatic response during the test meal showed that plasma insulin concentrations, pro-insulin and c-peptide were higher in the CT / TT than in CC (p <0.05) but no difference in the glucagon secretion, GLP-1 and glucose in both groups (NS). Regarding to the influence of the T allele in response to treatment has been found that the group CT / TT presented greater reduction in insulin secretion (p <0.005) c-peptide (p <0.05) and proinsulin (p <0.001) than in CC group during the test meal after treatment. There was a decrease in blood glucose, glucagon and GLP-1 similarly in both groups. In addition, there was a similar decrease in weight and glycosylated hemoglobin in both groups. Discussion: The results of this study showed that the presence of the T allele in individuals with T2DM was associated with higher insulin secretion, proinsulin and c-peptide compared to non-carriers, with similar serum concentrations of glucagon and glucose in response to the test meal. This data demonstrates that the function of &#946; cells of carriers of the variant rs7903146 shows different features from non-carriers. After treatment with Exenatide, individuals with T2DM and genotype CT / TT, showed statistically lower values of insulin, proinsulin and c-peptide than the CC group. The effects of GLP-1 on postprandial glycemia mechanisms are attributed to suppression of glucagon, retardation of gastric emptying and also the insulinotropic effects and resulting increase in peripheral sensitivity to insulina. In addition, it was demonstrated that the Exenatide increases glucose uptake independent of insulin in skeletal muscle, the stimulation of glucose transporters way. Therefore, it is believed that the characteristics of the response observed after treatment in patients with the T allele corresponds to the effect of Exenatide in &#946; cell improving the processing of proinsulin, insulin and c-peptide and increasing peripheral glucose uptake. It is suggested that this process is best resulting from the interaction with the GLP-1 receptor in both liver, skeletal muscle and pancreas. Conclusions: These data suggest that individuals with T2DM patients with T allele in rs7903146 of TCF7L2 presents more benefits of treatment with Exenatide, because the secretion of insulin, proinsulin and c-peptide were consistent with higher quality in &#946; cell function in that group after treatment. Moreover, this study provided further evidence that the clinical problems associated with T2DM and TCF7L2 are related to peripheral glucose tolerance.

Introdução: O gene TCF7L2 (Transcription Factor 7-Like 2) codifica o fator de transcrição de mesmo nome que, tem importante papel na via Wnt de sinalização intra celular. A via Wnt é constituída por proteínas de integração e ligação dos processos de diferenciação e multiplicação celulares, interagindo com os fatores TCF, e ativando a expressão de genes relacionados ao TCF7L2, sendo este amplamente expresso em vários tecidos. Dados epidemiológicos atuais não deixam dúvidas quanto à forte associação de polimorfismos do gene TCF7L2 com o diabetes tipo 2 (DM2) em diferentes etnias. Apesar de serem pouco conhecidos os mecanismos que envolvem o gene TCF7L2 no DM2, tem sido bem demonstrada a associação do alelo T no rs7903146 com redução da secreção de insulina, redução do efeito das incretinas, principalmente do GLP-1, aumento na secreção de glucagon e a longo prazo, redução da meia vida da célula beta. Em vista destas evidências, aventamos a hipótese de que pacientes com DM2 portadores da variante rs7903146 do gene TCF7L2, ao ser tratados com GLP-1 mimético, poderiam responder de forma peculiar. Objetivos: Avaliar a resposta hormonal pancreática antes e após tratamento com GLP-1 mimético em indivíduos com DM2 portadores da variante rs7903146 do gene TCF7L2. Pacientes e Métodos: Foram genotipados162 indivíduos com DM2 portadores da variante rs7903146 do gene TCF7L2: idade (57,0 &#177; 7,6) anos, IMC (30,5 &#177; 5,1) kg/m2. Dessa amostra, 56 pacientes foram divididos em dois grupos conforme o genótipo, sendo 26 CC x 30 CT/TT, e a seguir tratados com Exenatide durante oito semanas. Os testes de refeição foram realizados antes e após o tratamento, para avaliação das concentrações plasmáticas de: Glicose (mg/dl), Insulina (&#956;U/dl), Pró-insulina (pmol/L), Peptideo-c (ng/ml); Glucagon (pg/ml) e GLP-1(pmol/L). Foram comparadas as áreas sob as curvas e os pontos das curvas durante o teste. Análise estatística por ANOVA com dois fatores e medidas repetidas, nível de significância maior que 5%. Resultados: A distribuição genotípica CC x CT x TT foi 41,4% x 47,5% x 11,1% respectivamente. A influência do alelo T na resposta pancreática durante o teste da refeição mostrou que as concentrações plasmáticas de insulina, pró-insulina e peptídeo-c foram maiores no grupo CT/TT do que no CC (p<0,05) mas, não houve diferença na secreção do glucagon, GLP-1 e na glicemia entre os grupos (NS).Com relação à influência do alelo T na resposta ao tratamento verificou-se que o grupo CT/TT apresentou maior redução da secreção de insulina (p<0,005), peptídeo-c (p<0,05) e pró-insulina (p<0,001) do que o grupo CC durante o teste da refeição após o tratamento. Observou-se diminuição da glicemia, do glucagon e do GLP-1 de forma semelhante em ambos os grupos. Além disso, houve diminuição semelhante do peso e da hemoglobina glicosilada em ambos os grupos. Discussão: Os resultados do presente estudo mostraram que a presença do alelo T em indivíduos com DM2 esteve associada à maior secreção de insulina, pró-insulina e peptídeo-c em relação aos não portadores, com semelhantes concentrações séricas de glucagon e glicose em resposta ao teste da refeição. Este dado demonstra que a função da célula &#946; dos portadores da variante rs7903146 apresenta características diferentes dos não portadores. Após o tratamento com Exenatide, os indivíduos com DM2 e genótipo CT/TT, apresentaram valores estatisticamente menores de insulina, pró-insulina e peptídeo-c do que o grupo CC. Os efeitos do GLP-1 na glicemia pós-prandial são atribuídos a mecanismos de supressão do glucagon, lentificação do esvaziamento gástrico e também a efeitos insulinotrópicos e decorrentes de aumento na sensibilidade periférica à insulina. Além disso, já foi demonstrado que o Exenatide aumenta a captação de glicose de forma insulino-independente em músculo esquelético, pelo estímulo dos transportadores de glicose. Portanto, acredita-se que as características da resposta observada após o tratamento nos portadores do alelo T correspondem ao efeito do Exenatide na célula &#946; melhorando o processamento da pró-insulina, peptídeo-c e insulina e ao aumento da captação periférica da glicose. Sugere-se que esse processo seja resultante da melhor interação com os receptores de GLP-1, tanto em fígado, músculo esquelético e pâncreas. Conclusões: Os dados sugerem que indivíduos com DM2 portadores do alelo T no rs7903146 do gene TCF7L2 apresentam mais benefícios do tratamento com Exenatide, pois a secreção de insulina, pró-insulina e peptídeo-c foram condizentes com maior qualidade na função de célula &#946; nesse grupo após o tratamento. Além disso, o presente estudo proporcionou adicionais evidências clínicas de que os problemas que associam o TCF7L2 ao DM2 estão relacionados à tolerância periférica a glicose. / Introduction:The TCF7L2 gene (Transcription Factor 7-Like 2) encodes the transcription factor of the same name that has an important role in the intracellular Wnt signaling. The Wnt pathway is composed of connecting and integrating proteins of cell proliferation and differentiation process by interacting with TCF factors, and activating the expression of genes related to TCF7L2, which is widely expressed in several tissues. Current epidemiological data leave no doubt as to the strong association of polymorphisms of the TCF7L2 gene with type 2 diabetes (T2DM) in different ethnic groups. Although they are poorly known mechanisms involving TCF7L2 gene in DM2 the association of the T allele of rs7903146 with reduced insulin secretion, reducing effect of incretins, mainly GLP-1, increase in glucagon secretion and long-term reduction in the half-life of the beta cell, have been well demonstrated. In view of this evidences, we hypothesized that patients with DM2 carriers of the variant rs7903146 of the TCF7L2 gene, being treated with GLP-1 mimetic, could respond in a peculiar way. Objectives: Evaluating the pancreatic hormone response before and after treatment with GLP-1 mimetic in individuals with T2DM carriers of rs7903146 variant of TCF7L2 gene. Patients and Methods: We genotyped 162 individuals with T2DM patients with the variant rs7903146 gene TCF7L2: age ( 57.0 &#177; 7.6 ) years old, BMI ( 30.5 &#177; 5.1 ) kg/m2. From this sample, 56 patients were divided into two groups according to the genotype, 26 x 30 CC CT / TT, and then treated with exenatide for eight weeks. Meal tests were conducted before and after treatment to evaluate plasma concentrations of: Glucose ( mg / dl) Insulin ( U / dL ) Proinsulin (pmol / L), C-peptide (ng / ml) , Glucagon (pg / ml) and GLP-1 (pmol / L). The areas under the curves and the points of the curves were compared during the test. Statistical analysis by ANOVA with two factors and repeated measures, significance level greater than 5%. Results: The genotype distribution CC x CT x TT was 41.4% vs. 47.5% vs. 11.1 % respectively. The influence of the T allele in the pancreatic response during the test meal showed that plasma insulin concentrations, pro-insulin and c-peptide were higher in the CT / TT than in CC (p <0.05) but no difference in the glucagon secretion, GLP-1 and glucose in both groups (NS). Regarding to the influence of the T allele in response to treatment has been found that the group CT / TT presented greater reduction in insulin secretion (p <0.005) c-peptide (p <0.05) and proinsulin (p <0.001) than in CC group during the test meal after treatment. There was a decrease in blood glucose, glucagon and GLP-1 similarly in both groups. In addition, there was a similar decrease in weight and glycosylated hemoglobin in both groups. Discussion: The results of this study showed that the presence of the T allele in individuals with T2DM was associated with higher insulin secretion, proinsulin and c-peptide compared to non-carriers, with similar serum concentrations of glucagon and glucose in response to the test meal. This data demonstrates that the function of &#946; cells of carriers of the variant rs7903146 shows different features from non-carriers. After treatment with Exenatide, individuals with T2DM and genotype CT / TT, showed statistically lower values of insulin, proinsulin and c-peptide than the CC group. The effects of GLP-1 on postprandial glycemia mechanisms are attributed to suppression of glucagon, retardation of gastric emptying and also the insulinotropic effects and resulting increase in peripheral sensitivity to insulina. In addition, it was demonstrated that the Exenatide increases glucose uptake independent of insulin in skeletal muscle, the stimulation of glucose transporters way. Therefore, it is believed that the characteristics of the response observed after treatment in patients with the T allele corresponds to the effect of Exenatide in &#946; cell improving the processing of proinsulin, insulin and c-peptide and increasing peripheral glucose uptake. It is suggested that this process is best resulting from the interaction with the GLP-1 receptor in both liver, skeletal muscle and pancreas. Conclusions: These data suggest that individuals with T2DM patients with T allele in rs7903146 of TCF7L2 presents more benefits of treatment with Exenatide, because the secretion of insulin, proinsulin and c-peptide were consistent with higher quality in &#946; cell function in that group after treatment. Moreover, this study provided further evidence that the clinical problems associated with T2DM and TCF7L2 are related to peripheral glucose tolerance.