O diabetes mellitus tipo 1 (DM1) está associado com condições pró-oxidantes, próinflamatórias e elevado risco cardiovascular, enquanto o exercício físico pode ser considerado um dos melhores instrumentos não farmacológicas para o tratamento do DM1. Nesse contexto, exercícios que propiciem um menor risco hipoglicêmico e diversos benefícios sobre a saúde devem ser estimulados. Um dos objetivos da tese foi verificar a influência da realização de exercícios de força (SE) antes ou depois do exercício intervalado de alta intensidade (HIIE) sobre o comportamento glicêmico durante e logo após uma sessão de esforço (estudo transversal) (manuscrito original 1). Entretanto, o principal objetivo desta tese foi comparar os efeitos do treinamento intervalado de alta intensidade (HIIT), do treinamento de força (ST) e da combinação destes (ST+HIIT), sobre marcadores sanguíneos inflamatórios, de estresse oxidativo (OS) e metabolismo glicêmico em pacientes com DM1 através de um ensaio clínico randomizado (ECR) (manuscrito original 2). Com relação ao estudo transversal (manuscrito 1), em três visitas, adultos fisicamente ativos realizaram 30 min de SE antes de 30 min de HIIE ou realizaram a ordem inversa da sessão (HIIE+SE) ou permaneceram em repouso nesse período (REST). A glicemia capilar foi mensurada a cada 15 min durante e até 60 min da recuperação. Comparando-se com os valores basais, a condição HIIE+SE reduziu a glicemia em 30, 45 e 60 min, enquanto SE+HIIE adiou esta queda glicêmica para a partir de 60 min. HIIE+SE também acarretou uma maior glicemia em 105 min quando comparado a 60 min. A quantidade ingerida de carboidratos durante as sessões, bem como a dose insulínica no mesmo dia antes e depois dos protocolos, além dos episódios noturnos de hipoglicemia, foram similares entre as três condições. Conclui-se que pacientes com DM1 propensos a desenvolver hipoglicemia associada ao exercício devem realizar SE antes do HIIE na mesma sessão. Com relação ao estudo principal (ECR) (manuscrito original 2), após 4 semanas de um período controle, pacientes fisicamente inativos com DM1 foram randomizados para realização de 10 semanas de HIIT, ST ou ST+HIIT, praticados 3x/sem. As sessões de HIIT duraram 25 min, as de ST 40 min, e as de ST+HIIT ~65 min. Os desfechos foram analisados através do modelo de equações de estimativas generalizadas (GEE), com post hoc de Bonferroni. ST, HIIT e ST+HIIT melhoraram parâmetros glicêmicos e antioxidantes, mas não os marcadores plasmáticos de inflamação e de OS. Interessantemente, as intervenções reduziram as concentrações de receptores solúveis para produtos finais da glicação avançada. Entretanto, o conteúdo intracelular das proteínas de choque térmico de 70 kDa aumentou somente depois do HIIT. Enquanto a dose diária de insulina utilizada reduziu apenas no grupo ST+HIIT, todos os protocolos induziram benefícios antropométricos, cardiorrespiratórios e funcionais. Sob uma perspectiva prática, conclui-se que um maior volume (ST+HIIT) de treinamento é necessário para o benefício adicional da redução insulínica diária. Já o HIIT, por exemplo, é diretamente aplicável para pessoas que reclamam da falta de tempo, podendo ser recomendado devido a vantagem extra com relação a proteínas anti-inflamatórios em células imunológicas. / Type 1 diabetes mellitus (DM1) is associated with prooxidant and proinflammatory conditions, besides an increased cardiovascular risk, while exercise may be considered one of the best nonpharmacological tools for DM1 treatment. In this context, exercises linked with a lower hypoglycemic risk and several health benefits should be stimulated. One of the goals of this thesis was to verify the influence of performing strength exercises (SE) before or after highintensity interval exercise (HIIE) on glycaemia during and postexercise (cross-sectional study) (original manuscript 1). However, the main objective of this thesis was to compare the effects of high-intensity interval training (HIIT), strength training (ST) or their combination (ST+HIIT), on blood inflammatory, oxidative stress (OS) and glycemic markers in DM1 patients using a randomized clinical trial (ECR) (original manuscript 2). Regarding the crosssectional study (original manuscript 1), in three visits, physically active adults performed 30 min of SE before 30 min of HIIE or performed the reverse order (HIIE+SE) or rested for 30 min (REST). Capillary glycaemia was measured each 15 min during and 60 min postexercise recovery. HIIE+SE lowered glycaemia at 30, 45 and 60 min compared with baseline concentrations, while SE+HIIE postponed this glucose decayment to 60 min and thereafter. HIIE+SE increased glycaemia at 105 min compared with 60 min. Carbohydrates ingested during exercise, insulin dosage at same day before and after protocols, and nocturnal hypoglycemia episodes were similar among the three conditions. DM1 patients prone to develop exercise-associated hypoglycemia should perform SE before HIIE in a single session. Regarding the main study (ECR) (original manuscript 2), after 4-week control period, physically inactive patients with DM1 were randomly assigned to 10-week HIIT, ST or ST+HIIT protocol, performed 3 x/week. HIIT sessions lasted 25 min, ST lasted 40 min and ST+HIIT sessions lasted ~65 min. Blood biochemical, anthropometric, strength and cardiorespiratory fitness variables were assessed. Outcomes were analyzed via generalized estimating equations (GEE), with Bonferroni post hoc analysis. ST, HIIT and ST+HIIT improved glycemic and antioxidant parameters, but not plasma inflammatory or OS markers. Noteworthy, interventions reduced soluble receptors for advanced glycation end products levels. However, intracellular heat shock protein 70 content increased only after HIIT. While daily insulin dosage decreased only in the ST+HIIT group, all training models induced anthropometric and functional benefits. From a practical clinical perspective, a higher volume (SE+HIIT) of training is required for the additional benefit of daily insulin reduction. The HIIT, for example, is directly applicable for people who claim lack of time, and it may be 13 recommended due to extra advantage concerning anti-inflammatory proteins at immunological cells.

O diabetes mellitus tipo 1 (DM1) está associado com condições pró-oxidantes, próinflamatórias e elevado risco cardiovascular, enquanto o exercício físico pode ser considerado um dos melhores instrumentos não farmacológicas para o tratamento do DM1. Nesse contexto, exercícios que propiciem um menor risco hipoglicêmico e diversos benefícios sobre a saúde devem ser estimulados. Um dos objetivos da tese foi verificar a influência da realização de exercícios de força (SE) antes ou depois do exercício intervalado de alta intensidade (HIIE) sobre o comportamento glicêmico durante e logo após uma sessão de esforço (estudo transversal) (manuscrito original 1). Entretanto, o principal objetivo desta tese foi comparar os efeitos do treinamento intervalado de alta intensidade (HIIT), do treinamento de força (ST) e da combinação destes (ST+HIIT), sobre marcadores sanguíneos inflamatórios, de estresse oxidativo (OS) e metabolismo glicêmico em pacientes com DM1 através de um ensaio clínico randomizado (ECR) (manuscrito original 2). Com relação ao estudo transversal (manuscrito 1), em três visitas, adultos fisicamente ativos realizaram 30 min de SE antes de 30 min de HIIE ou realizaram a ordem inversa da sessão (HIIE+SE) ou permaneceram em repouso nesse período (REST). A glicemia capilar foi mensurada a cada 15 min durante e até 60 min da recuperação. Comparando-se com os valores basais, a condição HIIE+SE reduziu a glicemia em 30, 45 e 60 min, enquanto SE+HIIE adiou esta queda glicêmica para a partir de 60 min. HIIE+SE também acarretou uma maior glicemia em 105 min quando comparado a 60 min. A quantidade ingerida de carboidratos durante as sessões, bem como a dose insulínica no mesmo dia antes e depois dos protocolos, além dos episódios noturnos de hipoglicemia, foram similares entre as três condições. Conclui-se que pacientes com DM1 propensos a desenvolver hipoglicemia associada ao exercício devem realizar SE antes do HIIE na mesma sessão. Com relação ao estudo principal (ECR) (manuscrito original 2), após 4 semanas de um período controle, pacientes fisicamente inativos com DM1 foram randomizados para realização de 10 semanas de HIIT, ST ou ST+HIIT, praticados 3x/sem. As sessões de HIIT duraram 25 min, as de ST 40 min, e as de ST+HIIT ~65 min. Os desfechos foram analisados através do modelo de equações de estimativas generalizadas (GEE), com post hoc de Bonferroni. ST, HIIT e ST+HIIT melhoraram parâmetros glicêmicos e antioxidantes, mas não os marcadores plasmáticos de inflamação e de OS. Interessantemente, as intervenções reduziram as concentrações de receptores solúveis para produtos finais da glicação avançada. Entretanto, o conteúdo intracelular das proteínas de choque térmico de 70 kDa aumentou somente depois do HIIT. Enquanto a dose diária de insulina utilizada reduziu apenas no grupo ST+HIIT, todos os protocolos induziram benefícios antropométricos, cardiorrespiratórios e funcionais. Sob uma perspectiva prática, conclui-se que um maior volume (ST+HIIT) de treinamento é necessário para o benefício adicional da redução insulínica diária. Já o HIIT, por exemplo, é diretamente aplicável para pessoas que reclamam da falta de tempo, podendo ser recomendado devido a vantagem extra com relação a proteínas anti-inflamatórios em células imunológicas. / Type 1 diabetes mellitus (DM1) is associated with prooxidant and proinflammatory conditions, besides an increased cardiovascular risk, while exercise may be considered one of the best nonpharmacological tools for DM1 treatment. In this context, exercises linked with a lower hypoglycemic risk and several health benefits should be stimulated. One of the goals of this thesis was to verify the influence of performing strength exercises (SE) before or after highintensity interval exercise (HIIE) on glycaemia during and postexercise (cross-sectional study) (original manuscript 1). However, the main objective of this thesis was to compare the effects of high-intensity interval training (HIIT), strength training (ST) or their combination (ST+HIIT), on blood inflammatory, oxidative stress (OS) and glycemic markers in DM1 patients using a randomized clinical trial (ECR) (original manuscript 2). Regarding the crosssectional study (original manuscript 1), in three visits, physically active adults performed 30 min of SE before 30 min of HIIE or performed the reverse order (HIIE+SE) or rested for 30 min (REST). Capillary glycaemia was measured each 15 min during and 60 min postexercise recovery. HIIE+SE lowered glycaemia at 30, 45 and 60 min compared with baseline concentrations, while SE+HIIE postponed this glucose decayment to 60 min and thereafter. HIIE+SE increased glycaemia at 105 min compared with 60 min. Carbohydrates ingested during exercise, insulin dosage at same day before and after protocols, and nocturnal hypoglycemia episodes were similar among the three conditions. DM1 patients prone to develop exercise-associated hypoglycemia should perform SE before HIIE in a single session. Regarding the main study (ECR) (original manuscript 2), after 4-week control period, physically inactive patients with DM1 were randomly assigned to 10-week HIIT, ST or ST+HIIT protocol, performed 3 x/week. HIIT sessions lasted 25 min, ST lasted 40 min and ST+HIIT sessions lasted ~65 min. Blood biochemical, anthropometric, strength and cardiorespiratory fitness variables were assessed. Outcomes were analyzed via generalized estimating equations (GEE), with Bonferroni post hoc analysis. ST, HIIT and ST+HIIT improved glycemic and antioxidant parameters, but not plasma inflammatory or OS markers. Noteworthy, interventions reduced soluble receptors for advanced glycation end products levels. However, intracellular heat shock protein 70 content increased only after HIIT. While daily insulin dosage decreased only in the ST+HIIT group, all training models induced anthropometric and functional benefits. From a practical clinical perspective, a higher volume (SE+HIIT) of training is required for the additional benefit of daily insulin reduction. The HIIT, for example, is directly applicable for people who claim lack of time, and it may be 13 recommended due to extra advantage concerning anti-inflammatory proteins at immunological cells.

Diabetes mellitus (DM) é uma das principais causas de doença renal crônica terminal. Na doença renal diabética (DRD) observa-se um curso bifásico no padrão glicêmico, na fase inicial o aumento da resistência insulínica induz a hiperglicemia e, com perda progressiva da taxa de filtração glomerular, há redução na depuração dos medicamentos anti-hiperglicemiantes e insulina, aumentando o risco de hipoglicemias. Portanto, diante da perda da função renal, a reavaliação da terapia hipoglicemiante e ajustes constantes nas doses de insulina são necessários, com intuito de otimizar o controle glicêmico e minimizar seus efeitos colaterais. A revisão da literatura mostra diversos pontos sem resposta, principalmente relacionados à dose, ajuste da terapia insulínica, seguimento e monitoração do controle glicêmico em portadores de DM e DRC. O objetivo deste ensaio randomizado, cruzado, controlado foi comparar o controle glicêmico do tratamento com insulina glargina à insulina NPH em portadores de DM2 e DRD estágios 3 e 4. Pacientes e métodos: Trinta e quatro pacientes foram randomizados para receber insulina glargina uma vez ao dia ou insulina NPH em três aplicações diárias. Insulina lispro foi prescrita três vezes ao dia, em aplicações pré-prandiais nos dois grupos. Após 24 semanas de terapia, os pacientes tiveram seu esquema de insulina trocado para terapia insulínica oposta. Testes laboratoriais foram realizados após 12, 24, 36 e 48 semanas de estudo. O sistema de monitorização continua de glicose (CGMS) foi instalado ao término de cada terapia. Resultados: Dos 34 pacientes incluídos, 29 completaram as 48 semanas propostas no estudo, 2 pacientes perderam seguimento por má adesão e 3 pacientes não completaram o estudo em decorrência a eventos adversos (1 óbito, 1 ingresso em hemodiálise e 1 evento cardiovascular, todos em uso de insulina NPH). Após 24 semanas de tratamento com insulina glargina houve uma redução estatisticamente significante da média da HbA1c de 8,86 ± 1,4% para 7,95 ± 1,1% (p=0,0285), esta diferença não foi observada com a insulina NPH (8,21 ± 1,29% para 8,44 ± 1,32%). Durante o uso de insulina glargina o número de eventos noturnos de hipoglicemia foi menor comparado a insulina NPH (p=0,046); além disso, hipoglicemia grave ocorreu apenas na terapêutica com NPH. Conclusão: O tratamento com insulina glargina foi associado a melhor controle glicêmico e a redução do risco de hipoglicemia noturna quando comparada à insulina NPH,em pacientes portadores de DM e DRC estágios 3 e 4 / Diabetes mellitus is the leading cause of chronic kidney disease (CKD). Kidney disease diagnosis and its progression require re-evaluation of hypoglycemic therapy and constant dosing adjustments, to optimize glycemic control and minimize its side effects. Long acting insulin analogs and its pharmacokinetics have not been studied in different stages of kidney disease, nor is there consensus defining appropriate dose adjustment in patients with type 2 diabetes (T2DM) and CKD. The aim of this randomized, cross-over, open-label controlled clinical trial is to compare the glycemic response to intensive insulin treatment with NPH insulin or insulin glargine in T2DM patients and CKD stages 3 and 4. The primary efficacy end point was change in A1C from baseline. Thirty-four patients were randomized to receive insulin glargine once a day or NPH insulin, three times a day. Insulin lispro was prescribed as prandial insulin to both groups. After six months, patients switched to the other insulin therapy group. Laboratory tests were performed at baseline at 12, 24, 36 and 48 weeks. A continuous glucose monitoring system was implemented after 24 weeks and at the end of protocol. Results: Total of 29 subjects have completed the two branches of study, 2 patients dropped out due to low compliance and other 3 patients as a result of adverse events (1 death, 1 ingress on dialysis program, 1 cardiovascular event; all of them were on NPH therapy). After 24 weeks, average of A1c decreased on glargine group compared to baseline 8,86 ± 1,4% to 7,95 ± 1,1% (p=0,0285), but this difference was not observed on NPH group. There were no differences of insulin doses between both groups. Glargine group showed a tendency of lower risk of nocturnal hypoglycemia compared to NPH group (p=0,046). Conclusion: Insulin glargine improved glycemic control by reducing HbA1c without gain weight and with reduced tendency toward nocturnal hypoglycemic events compared with NPH insulin

<div>The link between volatile organic compounds (VOCs) from breath and various diseases and specific conditions has been identified since long by the researchers. Canine studies and breath sample analysis on Gas chromatography/ Mass Spectroscopy has proven that there are VOCs in the breath that can detect and potentially predict hypoglycemia. This project aims at developing a smart nanosensor system to detect hypoglycemia from human breath. The sensor system comprises of 1-Mercapto-(triethylene glycol) methyl ether functionalized goldnanoparticle (EGNPs) sensors coated with polyetherimide (PEI) and poly(vinylidene fluoride -hexafluoropropylene) (PVDF-HFP) and polymer composite sensor made from PVDF-HFP-Carbon Black (PVDF-HFP/CB), an interface circuit that performs signal conditioning and amplification, and a microcontroller with Bluetooth Low Energy (BLE) to control the interface circuit and communicate with an external personal digital assistant. The sensors were fabricated and tested with 5 VOCs in dry air and simulated breath (mixture of air, small portion of acetone, ethanol at high humidity) to investigate sensitivity and selectivity. The name of the VOCs is not disclosed herein but these VOCs have been identified in breath and are identified as potential biomarkers for other diseases as well. </div><div> </div><div> The sensor hydrophobicity has been studied using contact angle measurement. The GNPs size was verified using Ultra-Violent-Visible (UV-VIS) Spectroscopy. Field Emission Scanning Electron Microscope (FESEM) image is used to show GNPs embedded in the polymer film. The sensors sensitivity increases by more than 400% in an environment with relative humidity (RH) of 93% and the sensors show selectivity towards VOCs of interest. The interface circuit was designed on Eagle PCB and was fabricated using a two-layer PCB. The fabricated interface circuit was simulated with variable resistance and was verified with experiments. The system is also tested at different power source voltages and it was found that the system performance is optimum at more than 5 volts. The sensor fabrication, testing methods, and results are presented and discussed along with interface circuit design, fabrication, and characterization.</div>

L’activité physique (AP) est liée à plusieurs bénéfices pour la santé chez les personnes atteintes de diabète de type 1 (DT1), mais elles sont peu actives dû à la peur des hypoglycémies liée à l’AP. Un apport en glucides est souvent requis pour prévenir les hypoglycémies lors d’une AP, mais il y a un manque de connaissances quant à la quantité à consommer et la distribution temporelle idéales des glucides. Notre objectif est de comparer l’efficacité de 2 stratégies de collation pour maintenir la glycémie dans les cibles (4,0 - 10,0 mmol/L) lors d’une AP chez les adolescents et adultes avec le DT1. Les participants (N=33) ont effectué 2 interventions durant lesquelles une heure d’ergocycle à intensité moyenne a été réalisée. Ils consommaient un apport en glucides de 0,5g/kg du poids corporel et cet apport était aléatoirement consommé en une prise unique (PU) avant l’AP ou en une prise répartie (PR) avant et pendant l’AP. La GC était mesurée toutes les 10 minutes durant l’AP. Quatre participants ont eu une hypoglycémie durant l’AP avec la PU comparativement à 6 participants pour la PR (P=0,42). Il n’y avait pas de différence significative pour le pourcentage de temps passé dans les cibles entre les deux stratégies (PU : 75 ± 35%; PR : 87 ± 26%; P=0,12). Nos résultats suggèrent qu’un apport en glucide de 0.5g/kg du poids corporel est une option raisonnable pour une AP d’intensité moyenne d’une heure. Les deux stratégies sont similaires pour prévenir les hypoglycémies lors de l’AP. / Physical activity (PA) is associated to many health benefits in people living with type 1 diabetes (T1D), but these patients are not very active due to the fear of PA-related hypoglycemia. Carbohydrate intake is often required to prevent hypoglycemia during PA, but there is a lack of knowledge about the ideal amount to consume and the timing distribution of carbohydrates. Our objective is to compare the efficacy of two snack strategies to maintain glucose levels in the target range (4.0 – 10.0 mmol/L) during PA in adolescents and adults living with T1D. The participants (N = 33) took part in 2 interventions during which one hour of moderate intensity ergocycle was performed. They consumed a carbohydrate intake of 0.5g/kg of body weight and this intake was randomly consumed in a single intake (SI) before PA or in a distributed intake (DI) before and during PA. Capillary blood glucose was measured every 10 minutes during PA. Hypoglycemia occurred in 4 participants with SI compared to 6 participants for DI (P = 0.42). There was no significant difference in the percentage of time spent in the target range between the two strategies (SCI: 75 ± 35%; DCI: 87 ± 26%; P = 0.12). Our results suggest that a carbohydrate intake of 0.5g/kg of body weight is a reasonable option for one hour of moderate PA. The two snack strategies are similar to prevent hypoglycemia during PA.

Vivre avec une maladie chronique a des implications multiples sur une personne atteinte et ses proches. Ces implications sont majeures en cas de diabète insulino-traité comme le diabète de type 1 (DT1) et le diabète de type 2 avancé (DT2). Bien qu’un contrôle glycémique optimal soit indispensable pour prévenir et ralentir les complications micro-vasculaires chroniques, l’atteinte d’un tel objectif avec l’intensification de l’insulinothérapie se heurte à un risque important d’hypoglycémie. Les progrès technologiques : pompes à insuline, systèmes de surveillance de la glycémie interstitielle en continu (SSGC) et couplage de ces dispositifs avec un algorithme dans les systèmes de pancréas artificiel (PA) mono-hormonal avec insuline seule, ou bi-hormonal avec ajout de glucagon permettent de plus en plus de rendre le traitement plus simple (automatisation), plus efficace (moins d’hyperglycémies) et plus sûr (moins d’hypoglycémies). Cependant ces technologies apportent de nouveaux défis que nous avons explorés. À travers les projets de cette thèse : 1) Nous avons exploré la gestion de diabète avec le recours à la technologie de point de vue des utilisateurs actuels pour les pompes et les utilisateurs potentiels futurs pour les systèmes PA. Nos questionnaires ont mis l’accent sur l’enthousiasme des patients pour l’adoption de ces technologies et la perception positive de leur rôle dans le contrôle glycémique et la réduction de la glycémie; toutefois, plusieurs problèmes techniques ont été rapportés avec les pompes (nécessitant une amélioration de la technologie, un meilleur recensement ou une meilleure évaluation des effets indésirables) et une préférence d’être capable au besoin d’ignorer les recommandations du PA. 2) Nous avons testé pour la première fois le système PA développé à Montréal pour les patients vivant avec un DT2 insulino-traité et démontré son applicabilité pour cette population avec amélioration du contrôle glycémique en comparaison aux traitements conventionnels ouvrant la porte aux études plus vastes en vie réelle. 3) Trois stratégies en PA ont été aussi testé pour la première fois pour améliorer le contrôle glycémique pendant l’exercice pratiqué dans la période postprandiale (une situation d’hyperinsulinémie et variations rapides de la glycémie). Nous avons comparé : a) un contrôle glycémique exclusivement basé sur les données de la SSCG, b) une annonce avant le repas visant une glycémie plus haute et c) une annonce combinant la réduction du bolus du repas avec la cible glycémique plus haute. L’option qui consiste à annoncer l’exercice avant le repas à l’algorithme en combinant une cible glycémique plus haute avec une réduction de tiers du bolus prandial constituait l’approche la plus pratique pour éviter les hypoglycémies pendant un exercice d’intensité modérée pour 1h débuté 90 minutes post-repas. 4) Le système PA bi-hormonal est avantageux pour la réduction de l’hypoglycémie mais la formulation actuelle du glucagon présente la problématique de la stabilité avec une recommandation d’utilisation immédiate. Nous avons démontré sa stabilité pour 24 heures en contexte de PA ce qui permet de mener des études pour explorer le bénéfice du PA bi-hormonal. 5) Nous avons également exploré la question de sécurité de cette nouvelle utilisation du glucagon en mini-bolus et de façon chronique et nous avons proposé une liste de paramètres à surveiller dans les études prolongées compte tenu l’effet pléiotropique du glucagon sur la majorité des organes. 6) Nous avons démontré que le traitement des épisodes d’hypoglycémie non-sévères résiduels qui surviennent lors du traitement par PA restent difficiles à traiter avec seulement 17% des épisodes corrigés 15 min après l’ingestion des 15 grammes de glucides tel que recommandé. 7) Nous avons finalement exploré si le traitement des épisodes d’hypoglycémies non sévères pourrait être modulé en fonction du seuil glycémique atteint et de la quantité initiale des glucides consommés. Nous avons alors testé l’ingestion de 16 g de glucides (selon les recommandations) contre 32 g de glucides (plus représentatif des pratiques des patients) à deux seuils d’hypoglycémie (3,0 à 3,5 mmol/L et  3,0 mmol/L). Nos résultats confirment la difficulté de traitement de ces épisodes (lenteur de la correction et besoin fréquent de second traitement) quel que soit le seuil de traitement et/ou la dose initiale de glucides consommés. Ainsi, nous avons démontré les avantages et les limites de la technologie pour le diabète insulino-traité, y compris les systèmes PA, en allant de la préférence des patients pour la technologie, à l’utilité du PA dans le DT2 avancé, à la nécessité de annoncer l’exercice à l’algorithme avant le repas pour l'exercice postprandial, à la stabilité de la formulation disponible du glucagon et les paramètres cliniques à surveiller dans les essais à long terme du PA. Cette thèse a finalement montré le manque d’efficacité du traitement de l'hypoglycémie non-sévère par consommation de glucides oraux même dans le cadre du PA. / Living with diabetes, a chronic disease, has multiple implications for a person and their loved ones. These implications are major in the case of insulin-treated diabetes such as type 1 diabetes (T1D) and advanced type 2 diabetes (T2D). Although optimal glycemic control is essential to prevent and slow chronic microvascular complications, achieving such a goal through intensive insulin therapy has the drawback of increased risks of hypoglycemia. Technological advances: insulin pumps, continuous glucose monitoring systems (CGMS) and coupling of these devices with an algorithm in artificial pancreas (AP) systems, mono-hormonal (insulin) or bi-hormonal (with glucagon), can make diabetes treatment simpler (automation), more effective (less hyperglycemia) and safer (less hypoglycemia). However, these technologies bring up new challenges that we have explored through the projects of this thesis: 1) We have examined the use of technology in diabetes management from the perspective of current users for insulin pumps and potential future users for AP systems. Our online surveys highlighted the enthusiasm of patients for technology adoption and the positive perception they hold about its role in glycemic management; nevertheless, several technical problems have been reported with insulin pumps (hence the need to improve the identification of adverse events) and a preference to ignore AP recommendations if necessary. 2) We have tested for the first time the mono-hormonal AP system developed in Montreal for patients living with insulin-treated T2D and demonstrated its applicability for this population with improved glucose management in comparison to conventional treatments opening the door to larger studies in real life settings. 3) Three strategies in AP were also tested for the first time to improve glucose management during exercise practiced in the postprandial period (a situation of hyperinsulinemia and rapid changes in blood sugar). We compared: a) glycemic control based exclusively on CGMS data, b) a pre-meal announcement of exercise to the algorithm that increases target glucose levels, and c) a combination of exercise announcement with meal bolus reduction. The last strategy offered the most practical approach to avoid hypoglycemia during moderate-intensity aerobic exercise of one hour duration that is practiced 90 minutes post-meal. 4) The bi-hormonal AP system is advantageous for the reduction of hypoglycemia but the current commercial glucagon formulation (lyophilized powder) is not stable in liquid form and is only approved for immediate use post reconstitution in an acid solution. We have however demonstrated its stability for 24 hours in the context of AP use (mini-boluses through pumps), which makes it possible to conduct studies to explore the benefit of bi-hormonal AP until new stable formulations are approved. 5) We have also explored the question of the safety of this new use of glucagon in mini-bolus and in chronic way. We have proposed a list of parameters to be monitored in prolonged bi-hormonal AP studies given the pleiotropic effect of glucagon on the majority of organs. 6) We have demonstrated that during AP control (mono-or bi-hormonal), residual non-severe hypoglycaemic episodes remain difficult to treat with a resolution of only 17% of these episodes 15 min after ingestion of the recommended 15 grams of carbohydrates (CHO). 7) We have finally investigated whether non-severe hypoglycaemia treatment with oral CHO could be modulated according to the hypoglycemia threshold reached and the initial amount of CHO consumed. We have thus tested 16 g CHO (recommended by guidelines) versus 32 g CHO (closer to patients’ practices) at two hypoglycemia thresholds (3.0- 3.5 mmol/L and  3.0 mmol/L). Our results confirm the difficulty of treating these episodes (slow correction and frequent need for a second treatment) regardless of the treatment threshold and/or initial CHO dose consumed. Therefore, we have demonstrated the advantages and limits of technology in insulin-treated diabetes including AP systems, by revealing the preferences of patients for technology use, the usefulness of AP in insulin treated T2D, the need of pre-meal announcement to the algorithm during postprandial exercise, the stability of commercial glucagon formulation and the clinical parameters to be monitored in long-term trials. This thesis finally showed the compromised efficacy of non-severe hypoglycaemia treatment with recommended oral CHO even in the context of AP.

Indiana University-Purdue University Indianapolis (IUPUI) / The expression of pyruvate dehydrogenase kinase (PDK) 2 and 4 are increased in the fasted state to inactivate the pyruvate dehydrogenase complex (PDC) by phosphorylation to conserve substrates for glucose production. To assess the importance of PDK2 and PDK4 in regulation of the PDC to maintain glucose homeostasis, PDK2 knockout (KO), PDK4 KO, and PDK2/PDK4 double knockout (DKO) mice were generated. PDK2 deficiency caused higher PDC activity and lower blood glucose levels in the fed state while PDK4 deficiency caused similar effects in the fasting state. DKO intensified these effects in both states. PDK2 deficiency had no effect on glucose tolerance, PDK4 deficiency produced a modest effect, but DKO caused a marked improvement, lowered insulin levels, and increased insulin sensitivity. However, the DKO mice were more sensitive than wild-type mice to long term fasting, succumbing to hypoglycemia, ketoacidosis, and hypothermia. Stable isotope flux analysis indicated that hypoglycemia was due to a reduced rate of gluconeogenesis. We hypothesized that hyperglycemia would be prevented in DKO mice fed a high saturated fat diet for 30 weeks. As expected, DKO mice fed a high fat diet had improved glucose tolerance, decreased adiposity, and were euglycemic due to reduction in the rate of gluconeogenesis. Like chow fed DKO mice, high fat fed DKO mice were unusually sensitive to fasting because of ketoacidosis and hypothermia. PDK deficiency resulted in greater PDC activity which limited the availability of pyruvate for oxaloacetate synthesis. Low oxaloacetate resulted in overproduction of ketone bodies by the liver and inhibition of ketone body and fatty acid oxidation by peripheral tissues, culminating in ketoacidosis and hypothermia. Furthermore, when fed a ketogenic diet consisting of low carbohydrate and high fat, DKO mice also exhibited hypothermia, ketoacidosis, and hypoglycemia. The findings establish that PDK2 is more important in the fed state, PDK4 is more important in the fasted state, survival during long term fasting depends upon regulation of the PDC by both PDK2 and PDK4, and that the PDKs are important for the regulation of glucose and ketone body metabolism.

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.

L’hypoglycémie est une barrière au traitement du diabète de type 1 (DbT1). La collation au coucher est recommandée pour prévenir l’hypoglycémie nocturne (HN), mais son efficacité n’est pas démontrée. Objectif : Déterminer si une prise alimentaire en soirée est associée à la survenue d’HN. Étude observationnelle : 100 DbT1 ont porté un lecteur de glucose en continu et complété un journal alimentaire pendant 72 heures. L’HN est survenue durant 28 % des nuits. Une prise alimentaire en soirée n’était pas associée à l’HN. Toutefois, dans un modèle ajusté, l’apport en glucides en soirée était positivement associé aux HN (avec injection d’insuline rapide) et l’apport en protéines inversement associé aux HN (sans injection d’insuline rapide). Manger en soirée ne semble pas associé à moins d’HN. Des études contrôlées sont nécessaires pour comprendre l’effet de la collation au coucher sur le contrôle glycémique et le rôle de l’insuline rapide injectée en soirée. / Hypoglycemia remains a limiting factor of type 1 diabetes (T1D) treatment. Bedtime snack is often suggested to reduce nocturnal hypoglycemia (NH), but its effectiveness is not supported by evidence-based data. Objective: To determine the association between post-dinner dietary intake and NH occurrence. This is an observational study during which 100 T1D wore a blinded continuous glucose monitoring system and completed a food diary for 72 hours. NH occurred on 28 % of the 282 nights studied. Post-dinner dietary intake was not associated with NH. However, in multivariate models, carbohydrate intake was positively associated with NH (when rapid insulin was injected) and protein intake was inversely associated with NH (without rapid insulin injected). Post-dinner dietary intake does not seem to be associated with a reduce occurrence of NH. Further studies are needed to better understand the impact of bedtime snack on glycemic control and the role of the injection of rapid insulin in the evening.

La plupart des conditions détectées par le dépistage néonatal sont reliées à l'une des enzymes qui dégradent les acyls-CoA mitochondriaux. Le rôle physiopathologique des acyls-CoA dans ces maladies est peu connue, en partie parce que les esters liés au CoA sont intracellulaires et les échantillons tissulaires de patients humains ne sont généralement pas disponibles. Nous avons créé une modèle animal murin de l'une de ces maladies, la déficience en 3-hydroxy-3-methylglutaryl-CoA lyase (HL), dans le foie (souris HLLKO). HL est la dernière enzyme de la cétogenèse et de la dégradation de la leucine. Une déficience chronique en HL et les crises métaboliques aigües, produisent chacune un portrait anormal et distinct d'acyls-CoA hépatiques. Ces profils ne sont pas prévisibles à partir des niveaux d'acides organiques urinaires et d'acylcarnitines plasmatiques. La cétogenèse est indétectable dans les hépatocytes HLLKO. Dans les mitochondries HLLKO isolées, le dégagement de 14CO2 à partir du [2-14C]pyruvate a diminué en présence de 2-ketoisocaproate (KIC), un métabolite de la leucine. Au test de tolérance au pyruvate, une mesure de la gluconéogenèse, les souris HLLKO ne présentent pas la réponse hyperglycémique normale. L'hyperammoniémie et l'hypoglycémie, des signes classiques de plusieurs erreurs innées du métabolisme (EIM) des acyls-CoA, surviennent de façon spontanée chez des souris HLLKO et sont inductibles par l'administration de KIC. Une charge en KIC augmente le niveau d'acyls-CoA reliés à la leucine et diminue le niveau d'acétyl-CoA. Les mitochondries des hépatocytes des souris HLLKO traitées avec KIC présentent un gonflement marqué. L'hyperammoniémie des souris HLLKO répond au traitement par l'acide N-carbamyl-L-glutamique. Ce composé permet de contourner une enzyme acétyl-CoA-dépendante essentielle pour l’uréogenèse, le N-acétylglutamate synthase. Ceci démontre un mécanisme d’hyperammoniémie lié aux acyls-CoA. Dans une deuxième EIM des acyls-CoA, la souris SCADD, déficiente en déshydrogénase des acyls-CoA à chaînes courtes. Le profil des acyls-CoA hépatiques montre un niveau élevé du butyryl-CoA particulièrement après un jeûne et après une charge en triglycérides à chaîne moyenne précurseurs du butyryl-CoA. / Most conditions detected by expanded newborn screening result from deficiency of one of the enzymes that degrade acyl-CoA esters in mitochondria. The role of acyl-CoAs in the pathophysiology of these disorders is poorly understood, in part because CoA esters are intracellular and samples are not generally available from human patients. We created a mouse model of one such condition, deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (HL), in liver (HLLKO mice). HL catalyses a reaction of ketone body synthesis and of leucine degradation. Chronic HL deficiency and acute crises each produced distinct abnormal liver acyl-CoA patterns, which would not be predictable from levels of urine organic acids and plasma acylcarnitines. In HLLKO hepatocytes, ketogenesis was undetectable. Measures of Krebs cycle flux diminished following incubation of HLLKO mitochondria with the leucine metabolite 2-ketoisocaproate (KIC). HLLKO mice also had suppression of the normal hyperglycemic response to a systemic pyruvate load, a measure of gluconeogenesis. Hyperammonemia and hypoglycemia, cardinal features of many inborn errors of acyl-CoA metabolism, occurred spontaneously in some HLLKO mice and were inducible by administering KIC. KIC loading also increased levels of several leucine-related acyl-CoAs and reduced acetyl-CoA levels. Ultrastructurally, hepatocyte mitochondria of KIC-treated HLLKO mice show marked swelling. KIC-induced hyperammonemia improved following administration of carglumate (N-carbamyl-L-glutamic acid), which bypasses an acetyl-CoA-dependent reaction essential for urea cycle function, thus demonstrating an acyl-CoA-related mechanism for this complication. In a second animal model of an inborn error of acyl-CoA metabolism, short chain acyl-CoA dehydrogenase (SCAD)-deficient mice, the main finding in liver acyl-CoAs is increased butyryl-CoA, particularly during fasting or after enteral loading with medium chain triglyceride precursor of butyryl-CoA.