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Background: The postnatal failures of expression of the hepatic glucose-6-phosphatase system suggest there are developmental deficiencies in the mechanism to ‘switch-on’ this key enzyme of gluconeogenesis at the time of birth in both preterm and term infants. The evidence for hormonal regulation of this critical enzyme system in animal studies, in adult humans, and studies of cell lines make the possible failure of hormonal control around the time of birth an important hypothesis to test, but before this can be done, further studies of perinatal metabolism and its hormonal control need to be undertaken. Objective: To describe the hormonal and metabolic profiles of ‘unstressed’ term infants delivered by elective caesarean section. Methods: One hundred and fifty three women who had an elective caesarean section for a singleton pregnancy at term in Ninewells Hospital and Medical School, Dundee were recruited between July 2004 and April 2006. Maternal venous blood was taken for glucose and lactate estimations. Umbilical venous cord blood was obtained for the measurement of glucose, lactate, 3-hydroxybutyrate, free fatty acids, amino acids (alanine, arginine, citruline, cystine, GABA, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine ornithine, phenyalanine, serine,taurine, threonine, tyrosine and valine), insulin, glucagon, human growth hormone, cortisol, catechols (EPI, NE, DA, DOPA, DHPG, DOPAC) and their sulfated conjugates (EPI sulfate, NE sulfate, DA sulfate, DOPA sulfate, DHPG sulfate, DOPAC sulfate), and blood gas and acid-base profiles. Results The mean maternal glucose and lactate levels were 4.28 mmol/l and 1.8 mmol/l respectively. Three infants were hypoglycaemic with umbilical blood glucose levels of less than 2.6 mmol/l. The mean infant glucose and lactate levels were as expected for full term infants at 3.3 mmol/l and 2.2 mmol/l respectively. High mean levels of insulin and catechols were noted at birth. There was a significant positive association between umbilical venous cord glucose levels and maternal venous glucose levels (p=<0.001) but no association of umbilical venous cord glucose levels with amino acids, insulin, glucagon, human growth hormone, cortisol and catechols. Conclusions: This extensive data set of levels of metabolites and hormones in infants at birth acts as a reference source and will be valuable for evaluating any effects of antenatal or intrapartum factors on the hormonal and metabolic profiles of infants at birth as well as to investigate the mechanisms to ‘switch-on’ the key enzyme glucose-6-phosphatase. Objective: To describe the hormonal and metabolic profiles of ‘unstressed’ term infants delivered by elective caesarean section. Methods: One hundred and fifty three women who had an elective caesarean section for a singleton pregnancy at term in Ninewells Hospital and Medical School, Dundee were recruited between July 2004 and April 2006. Maternal venous blood was taken for glucose and lactate estimations. Umbilical venous cord blood was obtained for the measurement of glucose, lactate, 3-hydroxybutyrate, free fatty acids, amino acids (alanine, arginine, citruline, cystine, GABA, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine ornithine, phenyalanine, serine, taurine, threonine, tyrosine and valine), insulin, glucagon, human growth hormone, cortisol, catechols (EPI, NE, DA, DOPA, DHPG, DOPAC) and their sulfated conjugates (EPI sulfate, NE sulfate, DA sulfate, DOPA sulfate, DHPG sulfate, DOPAC sulfate), and blood gas and acid-base profiles. Results: The mean maternal glucose and lactate levels were 4.28 mmol/l and 1.8 mmol/l respectively. Three infants were hypoglycaemic with umbilical blood glucose levels of less than 2.6 mmol/l. The mean infant glucose and lactate levels were as expected for full term infants at 3.3 mmol/l and 2.2 mmol/l respectively. High mean levels of insulin and catechols were noted at birth. There was a significant positive association between umbilical venous cord glucose levels and maternal venous glucose levels (p=<0.001) but no association of umbilical venous cord glucose levels with amino acids, insulin, glucagon, human growth hormone, cortisol and catechols.

abstract: Background: Despite the reported improvements in glucose regulation associated with flaxseeds (Linum usitatissimum) few clinical trials have been conducted in diabetic participants. Objective: To evaluate the efficacy of ground flaxseed consumption at attenuating hyperglycemia, dyslipidemia, inflammation, and oxidative stress as compared to a control in adults with non-insulin dependent type 2 diabetes (T2D). Design: In a randomized parallel arm controlled efficacy trial, participants were asked to consume either 28 g/d ground flaxseed or the fiber-matched control (9 g/d ground psyllium husk) for 8 weeks. The study included 17 adults (9 male, 8 females; 46±14 y; BMI: 31.4±5.7 kg/m2) with a diagnosis of T2D ≥ 6 months. Main outcomes measured included: glycemic control (HbA1c, fasting plasma glucose, fasting serum insulin, and HOMA-IR), lipid profile (total cholesterol, LDL-C, HDL-C, total triglycerides, and calculated VLDL-C), markers of inflammation and oxidative stress (TNF-alpha, TBARS, and NOx), and dietary intake (energy, total fat, total fiber, sodium). Absolute net change for measured variables (week 8 values minus baseline values) were compared using Mann-Whitney U non-parametric tests, significance was determined at p ≤ 0.05. Results: There were no significant changes between groups from baseline to week 8 in any outcome measure of nutrient intake, body composition, glucose control, or lipid concentrations. There was a modest decrease in TNF-alpha in the flaxseed group as compared to the control (p = 0.06) as well as a mild decrease in TBARS in the flaxseed as compared to the control group (p = 0.083), though neither were significant. Conclusions: The current study did not detect a measurable association between 28 g/d flaxseed consumption for 8 weeks in T2D participants and improvements in glycemic control or lipid profiles. There was a modest, albeit insignificant, decrease in markers of inflammation and oxidative stress in the flaxseed group as compared to the control, which warrants further study. / Dissertation/Thesis / Doctoral Dissertation Nutrition 2015

abstract: Purpose: The purpose of this study was to examine the acute effects of two novel intermittent exercise prescriptions on glucose regulation and ambulatory blood pressure. Methods: Ten subjects (5 men and 5 women, ages 31.5 &plusmn; 5.42 yr, height 170.38 &plusmn; 9.69 cm and weight 88.59 &plusmn; 18.91 kg) participated in this four-treatment crossover trial. All subjects participated in four trials, each taking place over three days. On the evening of the first day, subjects were fitted with a continuous glucose monitor (CGM). On the second day, subjects were fitted with an ambulatory blood pressure monitor (ABP) and underwent one of the following four conditions in a randomized order: 1) 30-min: 30 minutes of continuous exercise at 60 - 70% VO2peak; 2) Mod 2-min: twenty-one 2-min bouts of walking at 3 mph performed once every 20 minutes; 3) HI 2-min: eight 2-min bouts of walking at maximal incline performed once every hour; 4) Control: a no exercise control condition. On the morning of the third day, the CGM and ABP devices were removed. All meals were standardized during the study visits. Linear mixed models were used to compare mean differences in glucose and blood pressure regulation between the four trials. Results: Glucose concentrations were significantly lower following the 30-min (91.1 &plusmn; 14.9 mg/dl), Mod 2-min (93.7 &plusmn; 19.8 mg/dl) and HI 2-min (96.1 &plusmn; 16.4 mg/dl) trials as compared to the Control (101.1 &plusmn; 20 mg/dl) (P < 0.001 for all three comparisons). The 30-min trial was superior to the Mod 2-min, which was superior to the HI 2-min trial in lowering blood glucose levels (P < 0.001 and P = 0.003 respectively). Only the 30-min trial was effective in lowering systolic ABP (124 &plusmn; 12 mmHg) as compared to the Control trial (127 &plusmn; 14 mmHg; P < 0.001) for up to 11 hours post exercise. Conclusion: Performing frequent short (i.e., 2 minutes) bouts of moderate or high intensity exercise may be a viable alternative to traditional continuous exercise in improving glucose regulation. However, 2-min bouts of exercise are not effective in reducing ambulatory blood pressure in healthy adults. / Dissertation/Thesis / Ph.D. Physical Activity, Nutrition and Wellness 2013

Soft sensors have been suggested as potent tools for on-line estimations of critical bioprocess variables to be able to control the biological process in an as high extent as possible. The formation of inhibitory by-products in the form of organic acids, caused by an overflow of glucose, is a problem in most bioprocesses expressing recombinant proteins.    In this project a new method of controlling the glucose feeding in an Escherichia coli fed-batch cultivation expressing the green fluorescent protein (GFP) was investigated. The new controller system implemented in the software controlled the feed rate based on on-line HPLC measurements of the concentration of organic acids.      The results showed that the controller managed to down-regulate the inhibitory organic acids to a low level as it tried to keep the glucose uptake rate at an optimum for maximum cell growth. The results suggested that the controller could be a powerful tool to create a more secure reproducibility and to generate high product yields in recombinant protein productions.

In type 1 diabetes (T1D), an autoimmune disease, autoantibodies are preferentially directed against proteins associated with Golgi and post-Golgi secretory vesicles, including insulin secretory granules and synaptic-like microvesicles. Thus, the study of beta-cell autoantigens with yet unknown function may provide novel insight into the secretory machinery of beta-cells and led to the discovery of novel pathways. Islet cell autoantigen of 69 kDa (ICA69) is a T1D autoantigen. It is a cytosolic protein of still unknown function. An impairment in neurotransmitter release upon mutation of its homologue in C. elegans suggests, however, an involvement of ICA69 in neurosecretion. Interestingly, ICA69 contains a BAR domain, present in several proteins involved in intracellular transport. The BAR domain functions as a dimerization motif, provides a general binding interface for different types of GTPases, and is a membrane binding/bending module. Its presence in ICA69 is a further hint supporting the putative involvement of ICA69 in intracellular membrane trafficking. The first part of this thesis was concerned with the characterization of ICA69, and the elucidation of its role in membrane traffic in pancreatic beta-cells. ICA69 was shown to be enriched in the perinuclear region, where also markers of the Golgi region are found. ICA69 was shown to interact with several membrane lipids, preferentially with PI(4)P, enriched on the Golgi complex. During the course of this thesis a combination of biochemical and imaging techniques were applied to investigate the interaction between ICA69 and Rab2, a small GTPase associated with the intermediate compartment and involved in the trafficking between the ER and the Golgi complex. ICA69 was shown to co-immunoprecipitate with Rab2 from INS-1 cells extracts. GST-pull down assays demonstrated that this interaction is GTP-dependent. Furthermore, confocal microscopy indicated that ICA69 and Rab2 extensively colocalize in particulate structures throughout the cytoplasm. Immunocytochemistry and subcellular fractionation experiments suggested that Rab2 recruits ICA69 to membranes. Functional studies indicated that ICA69 over-expression in INS-1 cells has effects that resemble, and in some cases amplify those observed upon Rab2 over-expression. Specifically, it impairs the trafficking between ER and Golgi, measured through the appearance and the conversion of the pro-form of ICA512 in the mature form of the protein. Moreover, it correlates with a redistribution of the beta-COP subunit of the coatomer, participating in the early secretory pathway, between membrane-bound compartments and the cytosol and it reduces stimulated insulin secretion. The data reported in this thesis conclusively point to ICA69 as a novel Rab2 effector, and may therefore contribute to the elucidation the yet poorly understood mechanism of action of Rab2 in the secretory pathway. The second part of the thesis was devoted to the study of an ICA69 paralogue gene, called ICA69-RP. Similarly to ICA69, ICA69-RP mRNA was shown to be primarily present in tissues such as brain and pancreatic islets, showing the expression pattern of a gene preferentially expressed in neuroendocrine cells. Unlike ICA69, however, and similar to other genes associated with the secretory machinery of beta-cells, ICA69-RP appeared to be glucose regulated, as shown by a 1.55 fold increase in mRNA levels upon stimulation of the cells with 25 mM glucose for two hours.Glucose stimulation of beta-cells prompts the activation of post-transcripional mechanisms which quickly up-regulate the expression of secretory granule genes and consequently renew granule stores. The increased expression of ICA69-RP upon glucose stimulation of cells may be part of this process. Unfortunately, all attempts to elucidate the intracellular localization of endogenous ICA69-RP failed, and it was not possible to obtain significant insights about its localization by over-expressing a fusion protein between ICA69-RP and GFP. Unlike other paralogues containing the BAR domain, such as amphiphysin 1 and 2 or Rvs167p and Rvs161p, ICA69 and ICA69-RP were shown not to form heterodimers. Furthermore, ICA69-RP did not show any interaction with Rab2 or Rab1, involved in the anterograde transport between ER and Golgi. Thus, its physiological role remains to be investigated.

In type 1 diabetes (T1D), an autoimmune disease, autoantibodies are preferentially directed against proteins associated with Golgi and post-Golgi secretory vesicles, including insulin secretory granules and synaptic-like microvesicles. Thus, the study of beta-cell autoantigens with yet unknown function may provide novel insight into the secretory machinery of beta-cells and led to the discovery of novel pathways. Islet cell autoantigen of 69 kDa (ICA69) is a T1D autoantigen. It is a cytosolic protein of still unknown function. An impairment in neurotransmitter release upon mutation of its homologue in C. elegans suggests, however, an involvement of ICA69 in neurosecretion. Interestingly, ICA69 contains a BAR domain, present in several proteins involved in intracellular transport. The BAR domain functions as a dimerization motif, provides a general binding interface for different types of GTPases, and is a membrane binding/bending module. Its presence in ICA69 is a further hint supporting the putative involvement of ICA69 in intracellular membrane trafficking. The first part of this thesis was concerned with the characterization of ICA69, and the elucidation of its role in membrane traffic in pancreatic beta-cells. ICA69 was shown to be enriched in the perinuclear region, where also markers of the Golgi region are found. ICA69 was shown to interact with several membrane lipids, preferentially with PI(4)P, enriched on the Golgi complex. During the course of this thesis a combination of biochemical and imaging techniques were applied to investigate the interaction between ICA69 and Rab2, a small GTPase associated with the intermediate compartment and involved in the trafficking between the ER and the Golgi complex. ICA69 was shown to co-immunoprecipitate with Rab2 from INS-1 cells extracts. GST-pull down assays demonstrated that this interaction is GTP-dependent. Furthermore, confocal microscopy indicated that ICA69 and Rab2 extensively colocalize in particulate structures throughout the cytoplasm. Immunocytochemistry and subcellular fractionation experiments suggested that Rab2 recruits ICA69 to membranes. Functional studies indicated that ICA69 over-expression in INS-1 cells has effects that resemble, and in some cases amplify those observed upon Rab2 over-expression. Specifically, it impairs the trafficking between ER and Golgi, measured through the appearance and the conversion of the pro-form of ICA512 in the mature form of the protein. Moreover, it correlates with a redistribution of the beta-COP subunit of the coatomer, participating in the early secretory pathway, between membrane-bound compartments and the cytosol and it reduces stimulated insulin secretion. The data reported in this thesis conclusively point to ICA69 as a novel Rab2 effector, and may therefore contribute to the elucidation the yet poorly understood mechanism of action of Rab2 in the secretory pathway. The second part of the thesis was devoted to the study of an ICA69 paralogue gene, called ICA69-RP. Similarly to ICA69, ICA69-RP mRNA was shown to be primarily present in tissues such as brain and pancreatic islets, showing the expression pattern of a gene preferentially expressed in neuroendocrine cells. Unlike ICA69, however, and similar to other genes associated with the secretory machinery of beta-cells, ICA69-RP appeared to be glucose regulated, as shown by a 1.55 fold increase in mRNA levels upon stimulation of the cells with 25 mM glucose for two hours.Glucose stimulation of beta-cells prompts the activation of post-transcripional mechanisms which quickly up-regulate the expression of secretory granule genes and consequently renew granule stores. The increased expression of ICA69-RP upon glucose stimulation of cells may be part of this process. Unfortunately, all attempts to elucidate the intracellular localization of endogenous ICA69-RP failed, and it was not possible to obtain significant insights about its localization by over-expressing a fusion protein between ICA69-RP and GFP. Unlike other paralogues containing the BAR domain, such as amphiphysin 1 and 2 or Rvs167p and Rvs161p, ICA69 and ICA69-RP were shown not to form heterodimers. Furthermore, ICA69-RP did not show any interaction with Rab2 or Rab1, involved in the anterograde transport between ER and Golgi. Thus, its physiological role remains to be investigated.

Le diabète de type 1 (DT1) se caractérise par la destruction auto-immune des cellules ß des îlots de Langerhans du pancréas productrices d’insuline, entraînant un état d’hyperglycémie chronique. Malgré une prise en charge très fine de la maladie, s’appuyant sur l’insulinothérapie fonctionnelle, les personnes vivant avec le DT1 sont fréquemment sujettes à des épisodes hypoglycémiques et hyperglycémiques en raison de difficultés à adapter le traitement insulinique, notamment lors de l’activité physique. L’activité physique procure de nombreux bénéfices pour la santé que l’on ait ou non un diabète. Cependant, dans le cadre du DT1, les excursions glycémiques lors de l’activité physique peuvent conduire à des barrières à l’activité physique dans cette population ou peuvent limiter les performances sportives d’athlètes vivant avec le DT1. L’objectif de cette thèse était triple : 1) Étudier les barrières à l’activité physique chez les enfants et adultes vivant avec le DT1 et à leurs liens avec les excursions glycémiques réellement vécues dans la vie quotidienne et d’autant plus autour de l’activité physique, 2) Chez des enfants vivant avec le DT1, comparer deux types d’exercice (exercice aérobie continu vs. intermittent intense), représentatifs de leur activité physique spontanée, et explorer leurs effets sur les variations glycémiques à l’exercice et à la récupération précoce et tardive et, 3) Mesurer la glycémie en continu, à l’exercice et à la récupération, chez des sportifs en endurance qui n’ont pas de diabète, afin de comprendre les mécanismes impliqués dans la régulation de la glycémie lors d’épreuves d’ultra-endurance et de transposer ces résultats chez des sportifs vivant avec le DT1. Les résultats montrent que : 1) Chez les enfants, plus le temps passé <54 mg.dL-1 les nuits suivant les séances d'activités physiques augmente, plus la peur de l'hypoglycémie est importante. Chez les adultes, étonnamment, ceux qui déclarent le moins l’hypoglycémie comme une barrière à l’activité physique sont ceux qui ont le plus grand pourcentage de séances d’activités physiques entraînant une baisse de glycémie; 2) Le risque hypoglycémique n’est pas supérieur lors d’un exercice continu modéré représentatif de l’activité physique spontanée des enfants et, cet exercice semble efficace pour diminuer l’hyperglycémie retrouvée les jours inactifs sur la même période de temps; 3) Un risque hyperglycémique existe lors des phases intenses de la course et pendant 48 heures de récupération lors d’un ultra-trail réalisé chez des athlètes qui n’ont pas de diabète. Ce risque hyperglycémique à la récupération pourrait être en lien avec les dommages musculaires. / Type 1 diabetes (T1D) is characterized by the autoimmune destruction of the insulin-producing ß-cells of the islets of Langerhans in the pancreas, leading to a state of chronic hyperglycemia. Despite very sophisticated management of the disease, based on functional insulin therapy, people living with T1D are frequently subject to hypoglycemic and hyperglycemic episodes because of difficulties in adapting insulin treatment, particularly during physical activity. Physical activity has many health benefits, whether or not you have diabetes. However, in the context of T1D, glycemic excursions during physical activity may lead to barriers to physical activity in this population or may limit the sporting performance of athletes living with T1D. The aim of this thesis was threefold: 1) Investigate the barriers to physical activity in children and adults living with T1D and their links with the glycemic excursions actually experienced in daily life and all the more so around physical activity, 2) In children living with T1D, compare two exercise modalities (continuous aerobic exercise vs. intense intermittent), representative of their spontaneous physical activity, and explore their effects on glycemic variations during exercise and early and late recovery and, 3) Measure glycemia continuously, during exercise and recovery, in endurance athletes without diabetes in order to understand the mechanisms involved in regulating glycaemia during ultra-endurance events and transpose these results to athletes living with T1D. The results show that: 1) In children, the greater the time spent <54 mg.dL-1 on the nights following physical activity sessions, the greater the fear of hypoglycemia. Surprisingly, among adults, those who least reported hypoglycemia as a barrier to physical activity were those who had the highest percentage of physical activity sessions resulting in a drop in blood glucose levels; 2) The risk of hypoglycemia is no greater during continuous moderate exercise representative of the spontaneous physical activity of children, and this exercise appears to be effective in reducing the hyperglycemia found on inactive days over the same period of time; 3) A hyperglycemic risk exists during the intense phases of the race and during 48 hours of recovery during an ultra-trail run carried out in athletes who do not have diabetes. This hyperglycemic risk during recovery could be related to muscle damage.

[ES] Las infusiones exógenas de insulina son vitales para las personas con diabetes tipo 1 para suplir parcialmente la incapacidad del páncreas de secretar insulina. Sin embargo, las terapias intensivas actuales pueden restringir la calidad de vida de los pacientes. Los pacientes con esta enfermedad tienen que tomar decisiones constantemente sobre las dosis de insulina que lleva a la glucosa a niveles seguros. Si no lo consiguen, pueden sufrir las complicaciones crónicas y agudas derivadas de los niveles anormalmente altos o bajos de glucosa. La regulación automática de glucosa con sistemas de páncreas artificial prometía reducir la carga del autocontrol de la enfermedad al mismo tiempo que se mejoraba el tiempo en normoglucemia y se reducía la variabilidad. Sin embargo, estas promesas sólo se han cumplido parcialmente. Aunque esta tecnología mejora el control glucémico que logran las terapias tradicionales, la ingesta de alimentos y la práctica de ejercicio limitan la eficiencia de los sistemas de páncreas artificial durante el día. De hecho, los sistemas comerciales sólo pueden hacerles frente con la ayuda de los pacientes. Para compensar las ingestas, los pacientes deben anunciar el contenido de carbohidratos al sistema. Para el ejercicio, deben anunciar el inicio de la actividad o tomar medidas preventivas como modificar la referencia de glucosa o reducir la basal con mucha antelación. Estas exigencias no sólo no ayudan a reducir la carga del paciente, sino que pueden comprometer la eficiencia del sistema cuando el paciente se equivoca al estimar los carbohidratos, omite el anuncio de la comida o no puede planificar el ejercicio. Así pues, esta tesis propone nuevos métodos para eliminar el anuncio de ingestas y ejercicio lo que ayudaría a reducir la intervención del paciente en los sistemas de páncreas artificial, y, en consecuencia, mejorar la calidad de vida. Desde un punto de vista de control, las ingestas y el ejercicio pueden considerarse perturbaciones. Esta tesis explota métodos de la literatura de rechazo de perturbaciones y acomodación de fallos para lograr el objetivo de la tesis. En concreto, hay que destacar tres aplicaciones: 1) se ha desarrollado un observador super-twisting para detectar comidas no anunciadas como primer paso para su compensación; 2) se ha diseñado un observador de modos deslizantes de primer orden para la estimación de la ratio de aparición de glucosa, la cual ha sido integrada en un generador de bolos para compensar las comidas; 3) se ha empleado el principio de diseño por modelo interno para mitigar el efecto de las ingestas de alimentos y ejercicio, añadiendo sugerencias de carbohidratos de rescate a la insulina. Como resultado, las contribuciones de esta tesis allanan el camino para el desarrollo de sistemas de páncreas artificial sin anuncios, que liberen al paciente de la carga de la gestión de la diabetes. / [CA] Les infusions exògenes d'insulina són vitals per a les persones amb diabetis tipus 1 per a suplir parcialment l'incapacitat del pàncrees de secretar insulina. No obstant, les teràpies intensives actuals poden restringir la qualitat de vida dels pacients. Les persones amb aquesta malaltia han de prendre decisions contínuament sobre la dosi d'insulina que fa que la glucosa estiga en valors segurs. Si no ho aconsegueixen, poden sofrir les complicacions cròniques i agudes derivades dels nivells anormalment alts o baixos de glucosa. La regulació automàtica de glucosa amb sistemes de pàncrees artificials prometia reduir la càrrega d'autocontrol de la malaltia al mateix temps que es millorava el temps en normoglucèmia i es reduïa la variabilitat. No obstant, aquestes promeses s'han complit només parcialment. Encara que aquesta tecnologia millora el control de la glucosa, la ingesta d'aliments i la pràctica d'exercici limiten l'eficiència dels sistemes de pàncrees artificials durant el dia. De fet, els sistemes comercials només poden fer-les front amb la ajuda dels pacients. Per a compensar les ingestes, el pacients han d'anunciar al sistema la quantitat de carbohidrats. Per al exercici, han d'anunciar l'inici de l'activitat o prendre mesures preventives com modificar la referència de glucosa o reduir la infusió basal d'insulina. Aquestes exigències no només no ajuden a reduir la càrrega al pacient, sinó que poden comprometre l'eficiència del sistema quan el pacient confon la estimació dels carbohidrats, omet l'anunciament de la ingesta o no pot planificar l'exercici. Així doncs, aquesta tesi proposa nous mètodes per a eliminar l'anunciament d'ingestes i exercici permetent reduir així la intervenció del pacient, i, en conseqüència, millorar la qualitat de vida. Des del punt de vista de control, les ingestes i el exercici poden considerar-se pertorbacions. Aquesta tesi explota mètodes de la literatura de rebuig de pertorbacions i acomodament de fallades. En particular, es destaquen tres aplicacions: 1) s'ha desenvolupat un observador super-twisting per a detectar ingestes no anunciades com a primer pas per a la seua compensació; 2) se ha dissenyat un observador de modes lliscants per a estimar el rati d'aparició de glucosa de la ingesta, el qual s'ha integrat en un generador de bols d'insulina per compensar les ingestes; 3) se ha empleat el principi de disseny per model intern per a mitigar l'efecte de les ingestes i exercici, incorporant recomanacions de carbohidrats a la insulina. Com a resultat, les contribucions d'aquesta tesi obren el camí per a desenvolupar sistemes de pàncrees artificial sense anunciaments, que alliberen al pacient de la càrrega de la gestió de la diabetis. / [EN] Exogenous insulin infusions are vital for people with type 1 diabetes to partially make up for the inability of the pancreas to secrete insulin. However, current intensive therapies may restrict patients' quality of life. People with this disease have to constantly make decisions about insulin doses to bring glucose levels to a safe range. If unsuccessful, they may suffer from chronic and acute complications related to abnormally high and low glucose values. The automatic regulation of glucose with artificial pancreas systems promised to reduce patients' self-control burdens while improving time in normoglycemia and decreasing variability. However, these promises are fulfilled only partially. Although this technology outperforms the glycemic outcomes achieved by conventional therapies, meal intake and physical activity limit its daytime performance. Indeed, commercially available systems only can handle them with the support of the patients. For meals, patients must announce the carbohydrate content to the system. For exercise, they must notify the activity or take preventive actions like changing glucose setpoint or decreasing basal well ahead before exercise. These demands do not help reduce the patient's burden. They even can compromise the system performance when the patient misestimates the carbohydrate content, omits the meal announcement, or cannot plan the exercise event. Hence, this thesis proposes new methods to eliminate the need for meal and exercise announcements, thus reducing patient intervention in artificial pancreas systems for a better quality of life. From a control perspective, meals and exercise can be regarded as disturbances; therefore, this thesis exploits methods from the disturbance rejection and fault accommodation literature to achieve the thesis goal. Specifically, the following three applications must be highlighted: 1) a super-twisting-based residual generator has been developed to detect unannounced meals as the first step to their compensations; 2) a sliding-mode disturbance observer has been designed to estimate the glucose meal appearance, which is fed into a bolusing algorithm to compensate the meals; 3) the internal model principle is employed to mitigate the effects of meal intakes and exercise, supplementing insulin infusions with carbohydrate recommendations. As a result, the contributions of this thesis pave the way for the development of announcement-free artificial pancreas systems, releasing patients from the burden of diabetes management. / This work was partially supported by: grant DPI2016-78831-C2-1-R funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”; grant PID2019-107722RB-C21 funded by MCIN/AEI/10.13039/501100011033; and grant ACIF/2017/021 funded by the Generalitat Valenciana through European Social Funds (FSE). Also, the grant BEFPI/2019/077, funded by the Generalitat Valenciana through FSE funds, supported a 7-month research stay at Physiological da University (Óbudai Egyetem, Óbuda, Budapest, Hungary) / Sala Mira, I. (2023). New Contributions Towards Meal and Exercise Announcement-Free Artificial Pancreas Systems [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/192684