L'épithélium intestinal, en constant renouvellement, assure de nombreuses fonctions vitales comme l'absorption des nutriments et le maintien d'une barrière entre le milieu extérieur et l'organisme. L'absorption intestinale des sucres est assurée par de nombreux transporteurs au niveau de l'intestin proximal. Parmi eux, GLUT2, localisé dans les entérocytes et les cellules endocrines de l'intestin, transporte le glucose, le fructose et le galactose. Les cellules L entéroendocrines produisent le GLP-1, un puissant stimulateur de la sécrétion d'insuline en réponse au glucose. L'objectif de ma thèse a été d'élucider le rôle de GLUT2 intestinal dans l'absorption des sucres et la fonction entéroendocrine grâce à l'étude d'un modèle murin spécifiquement invalidé pour ce transporteur dans les cellules épithéliales intestinales. La délétion intestinale de GLUT2 entraîne une malabsorption intestinale modérée des sucres associée à une distribution retardée du glucose aux tissus périphériques. Le retard spatial et temporel de l'absorption des sucres provoque une dysbiose intestinale au profit de bactéries ayant un rôle protecteur de l'homéostasie intestinale. De façon surprenante, l'invalidation de GLUT2 intestinal s'accompagne d'une chute de la densité de cellules L entéroendocrines, sans modification des niveaux plasmatiques de GLP-1. Cette étude met en exergue le rôle primordial de GLUT2 intestinal dans l'absorption des sucres et la fonction endocrine de l'intestin. Elle permet d'envisager le criblage de molécules capables d'inhiber l'activité de GLUT2 intestinal, pour atténuer la prise de poids et limiter les perturbations métaboliques induites par des régimes riches en sucres. / The constantly renewing intestinal epithelium handles various essential functions including nutrient absorption and persistence of a barrier between our internal and external environments. Several transporters mediate sugar absorption in the proximal intestine. Among them, GLUT2, a very efficient glucose, fructose and galactose transporter and receptor, is located at the membranes of enterocytes and enteroendocrine cells. The enteroendocrine L-cells produce GLP-1, a strong activator of glucose-induced insulin secretion. This thesis aimed to further decipher the role of intestinal GLUT2 in sugar absorption and enteroendocrine cell function. To address this question, mice lacking GLUT2 specifically in intestinal epithelial cells have been generated and studied. Intestinal GLUT2 invalidation alters intestinal glucose absorption and delays glucose biodistribution to peripheral tissues. This spatial and temporal sugar absorption delay provokes intestinal dysbiosis, favoring gut microbiota having a protective impact on gut homeostasis. Surprisingly, intestinal GLUT2 deletion leads to a strong loss in enteroendocrine L cell density, with no impact on GLP-1 plasma levels. This study highlights critical roles for GLUT2 in sugar absorption and enteroendocrine cell function management. The use of specific GLUT2 inhibitors could be considered to limit body weight gain and metabolic disorders induced by sugar rich diets.

<p>As obesity has become one of the most prevalent metabolic diseases, and diabetes mellitus has become the seventh leading causes of death in the United States, alternative food/nutrition-based approaches to tackle obesity that are both efficacious and cost effective are in high demand. Since starch and its derived products are the principal dietary supply of glucose, strategies of using slowly digestible starch to achieve moderated glycemic response and prolonged glucose delivery, as well as to locationally digest starch into the ileum, have shown successful results such as moderation of insulinemia and reducing food intake in obese animals. An important regulator of appetite suppression is the neuroendocrine system of the gut-brain axis. Glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are the main anorexigenic peptide products of the intestinal enterendocrine L-cells that regulate postprandial insulin levels as well as satiety signals. The stimulation of the enteroendocrine L-cells throughout the gastrointestinal tract through glucose, fatty acids and proteins has been extensively studied and confirmed. However, the stimulatory effect of complex dietary carbohydrates on L-cells is not described. In this dissertation, we investigated the <i>in vitro</i> intestinal cell chemosensation of L-cells to α-amylase starch digestion products, named maltooligosaccharides (MOS), and in the possible application of using slowly digestible starch delivery of MOS <i>in vivo</i>.</p> <p>In Chapter II of this dissertation, we reported a significantly higher stimulatory effect of MOS on GLP-1 and OXM secretion compared to glucose in mouse and human L-cells, respectively. Additionally, maltotriose enhanced the relative expression of the gastrointestinal peptide, cholecystokinin. Moreover, MOS exhibited protective effects on barrier function and monolayer integrity of intestinal epithelial cells. </p> <p>In Chapters III and IV, we performed a multiomics approach where transcriptomic analysis and global protein profiling of mouse L-cells treated with different types of MOS showed that the carbohydrates exhibit their effects through the induction of exocytosis of GLP-1- or OXM-containing vesicles and not through a positive regulation of the proglucagon gene expression. It is suggested that MOS induce higher secretion, but not higher synthesis, of the proglucagon gene products. In addition, maltotriose treatment downregulated the relative expression of the glucotoxicity marker, thioredoxin-interacting protein, and upregulated the relative expression of tight junction proteins supporting a role of MOS in barrier function integrity.</p> <p>Translating the <i>in vitro</i> findings into an <i>in vivo</i> application that is beneficial for human health required the use of controllable tool for the delivery of MOS throughout the small intestine for sensing by a higher number of L-cells. Slowly digestible starch (SDS), compared to rapidly digestible starch, provided such a tool. For this purpose, we used alginate-entrapped SDS microspheres that digest distally into the ileum to examine the role of SDS in the intervention and prevention of obesity in C57BL/6J diet-induced obese (DIO) and lean mice models.</p> <p>Results showed that 20% SDS in low-fat diets significantly improved weight loss and food intake reduction in DIO mice converted to low-fat diet for 12 weeks. Similarly, 15% SDS in high-fat diets showed significant reduction in body fat percent and significant increase in lean body mass as well as considerable reduction in weight gain rate and food intake in lean mice fed on 45% of calories high-fat diet. Immunohistochemistry of small intestine of mice in both the intervention and prevention studies revealed an even and thorough distribution of GLP-1 positive L-cells.</p> <p>Overall, this dissertation proposes several insights into L-cell sensation of dietary starch-degraded MOS delivered by the consumption of slowly digestible starch. MOS exhibit unique influences on L-cell sensitivity and gut hormone productivity. Future research investigating the mechanisms of intestinal sensing of MOS, as well as the development of bioactive carbohydrate structures that could preserve body weight and modulate glucose tolerance <i>in vivo</i> is needed to translate these findings into nutritional recommendations and food products beneficial for human health. The intricate role of dietary carbohydrates on gut physiological response, related to satiety and food intake could be a new approach for design of foods for health applications.</p>

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22358号 / 医博第4599号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 岩田 想, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Bakgrund: Fetma klassificeras som en sjukdom, medan övervikt klassificeras som en riskfaktor för andra sjukdomar såsom typ 2-diabetes (T2D). Genom att beräkna ”body mass index” (BMI) kan vikten klassificieras. Ett BMI &gt;25 kg/m2 klassificieras som övervikt medan BMI &gt;30 kg/m2 klassificieras som fetma. Övervikt hos asiater klassificieras vid BMI &gt;24 kg/m2 och fetma vid BMI &gt; 28 kg/m2 . Orsaken bakom övervikt och fetma kan vara negativa levnadsvanor, ärftlighet och läkemedelsbehandlingar. Fetma är förknippad med flera komplikationer som bland annat metabola syndromet, typ 2-diabetes (T2D) och hjärtkärlsjukdomar. Fetma kan behandlas genom kostintervention och ökad fysisk aktivitet men även genom läkemedel. Orlistat, liraglutid och bupropion i kombination med naltrexon är registrerade i Sverige för behandling av övervikt och fetma. Liraglutid är en GLP-1-analog som används vid behandling av T2D och där viktminskning upptäckts som en biverkan. Syfte: Syftet med detta examensarbete var att genom litteraturstudier undersöka ifall liraglutid har en viktminskningseffekt hos patienter med eller utan T2D. Metod: Detta examensarbete är en undersökning baserad på litteraturstudier. Genom att använda sökorden ”Liraglutide, weight loss, diabetes, BMI” samt ”Efficacy of liraglutide weight loss with type 2 diabetes SCALE” inkluderades 5 kliniska studier som analyserades. Resultat: Den största viktminskningen sågs hos patienter som behandlades med liraglutid 3,0 mg. Patienterna utan T2D som behandlades med 3,0 mg fick en viktminskning på 8,4±7,3 kg standardavviklese (SD) efter 56 veckors behandling. Patienter utan T2D som behandlades med lliraglutid 3,0 mg fick en viktminskning på 9,2 kg i samband med GI biverkningar och de som inte upplevde GI biverkningar fick en viktminskning på 6,3 kg. Patienter med T2D som behandlades med liraglutid 3,0 mg fick en genomsnittlig viktminskning på 6,4 kg efter 56 veckors behandling. Liraglutid 1,8 mg gav en genomsnittlig viktminskning på 6,0 kg och liraglutid 1,2 mg gav en genomsnittlig viktminskning på 5,1 kg. Slutsats: Liraglutids viktminskningseffekt var dosberoende hos patienter med övervikt eller fetma. Viktminskningseffekten påverkades av både BMI och GI biverkningar. Ju högre BMI patienten hade desto större viktminskning fick patienterna. Även ju längre tid som GI biverkningar såsom illamående, kräkningar och diarré varade desto mer gick patienterna ner i vikt. Viktminskningen redovisades i både procent och kilogram beroende på studierna.

Obesity is a health problem that is increasing worldwide and has high socioeconomic impact. In Sweden, obesity costs the society 70 billion SEK every year. For the year 2030, the Institute for Health and Medical Care Economics predicts that obesity can cost the society up to 17 billion SEK more than in 2018. In Sweden, 52% of the citizens 16-84 years of age are either overweight or obese.  The main factor behind obesity is still unidentified. What is known, and almost self-evident, is that weight gain occurs when energy consumption is lower than energy intake. The calorie intake during a day should be 1600-3000 calories and physical activity is important. For weight loss, the focus is mostly on calorie intake, but it is also important to consider the metabolic homeostasis which is regulated by hormones. Obesity can occur when there is a disturbance in the homeostatic mechanisms. One of the most important regulatory hormones is glucagon-like-peptide-1 (GLP-1) which stimulates satiety. Liraglutide and semaglutide are both GLP-1-analogues and are used in the treatment of type 2 diabetes. Liraglutide is also indicated in obesity and semaglutide as an anti-obesity drug has just undergone a phase 3 study. The mechanism of action of GLP-1-analogues in obesity is to stimulate a feeling of satiety, which leads to a lower energy intake and thus weight loss.  The aim of this thesis was to evaluate whether semaglutide can be used as an anti-obesity drug and the effect and safety of the substance compared with the already approved drug liraglutide.  The thesis is a literature study that uses five randomized clinical trials from the database PubMed. Of the six scientific articles, two examine liraglutide for 56 weeks, two semaglutide for 68 weeks and one both drugs for 52 weeks.  All studies demonstrate that semaglutide has a better effect on reducing body weight and waist measurement than liraglutide. In study 5, semaglutide above 1,4 mg per week is shown to have a statistically significantly better weight loss effect compared to liraglutide. Gastrointestinal side effects were the most common side effects in all included studies. The majority of these were of mild or moderate intensity. Of the gastrointestinal side effects, nausea was most common. In the semaglutide groups, the total side effects were slightly more frequent than in the liraglutide groups, which is mainly shown in study 5. Possible factors affecting the results is whether the participants receive IBT or lifestyle advice in combination with the treatment.  Conclusions that can be drawn from the studies is that semaglutide is more effective in terms of weight loss and reduction of waist measurements compared to liraglutide. The adverse reactions were generally similar between semaglutide and liraglutide. Semaglutide should currently be administered with caution and under supervision. More studies need to be conducted to control the dosage and safety.

This review details the manner in which the central nervous system regulates metabolic homeostasis in normal weight and obese rodents and humans. It includes a review of the homeostatic contributions of neurons located in the hypothalamus, the midbrain and limbic structures, the pons and the medullary area postrema, nucleus tractus solitarius, and vagus nucleus, and details how these brain regions respond to circulating levels of orexigenic hormones, such as ghrelin, and anorexigenic hormones, such as glucagon-like peptide 1 and leptin. It provides an insight as to how high intensity exercise may improve homeostatic control in overweight and obese subjects. Finally, it provides suggestions as to how further progress can be made in controlling the current pandemic of obesity and diabetes.

Introduction: Overweight and obesity are among the most serious public health problems in the world. Today, about half of adult men, one third of adult women and one in five children are estimated to be overweight or obese. Being overweight is not considered as a disease, but it can lead to obesity, which puts the individual at high risk of suffering from several diseases such as diabetes type 2, high blood pressure. To define whether an individual is overweight, normal weight, obese or underweight, BMI value is used. Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects women in fertitlity age. The syndrome is associated with several of risk factors such as insulin resistance, obesity, cardiovascular problems, and infertility. Imbalances in the hormones produced by ovaries can be a cause of PCOS.Currently, there are three prescription drugs in Sweden to treat obesity such as liraglutide (Saxenda®), bupropion/naltrexone (Mysimba®) and orlistat (Xenical®).Objectives: The purpose of this study was to investigate the effectiveness of using liraglutide as monotherapy or in combination with metformin to treat women who were overweight or obese and affected by polycystic ovarian syndrome.Method: This study is based on four randomized controlled clinical trials studies, which are taken from the PubMed database. Using these keywords “liraglutide, obesity, weight loss, BMI, treatment, metformin, PCOS”.Results: The greatest weight loss was observed in study 4 in obese women with PCOS, whichwere treated with the combination of both liraglutide 1.2 mg/day and metformin 1000 BID/day. A weight reduction of -9.23 ±1.23 after 12 weeks of treatment was observed. While less weight loss of -3.0 ± 0.6 kg was observed in study two, where obese women with PCOS were treated with liraglutide 1.2 mg/day and metformin 1000 mg BID/day as a monotherapy. In study 1, obese women with PCOS treated with the combination of both liraglutide 1.2-± mg/day and metformin 1000 BID/day had a weight loss of -6.5 ± 2.8 kg. The obese women with PCOS in study 3 were treated with liraglutide 3 mg/day and had a weight loss of -6.3 ± 3.7 kg butexperienced more severe GI adverse events.Conclusion: The four studies showed that short-term treatment with liraglutide, which is a GLP-1 receptor agonist, 1.2 mg/day together with metformin 1000 mg BID/day as a combination therapy is associated with significantly greater weight loss, BMI changes and with changes in waist circumference compared to when treated with liraglutide or metformin as a monotherapy

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