La Neuréguline 1 (NRG1) est une cytokine appartenant à la famille des facteurs decroissance. Pouvant être libéré par la contraction musculaire, elle fut récemment décritecomme une myokine. Au-delà de son rôle dans les processus de croissance et de maturation,la NRG1 favorise la régulation du métabolisme du glucose in vitro. L’objectif de ce travailétait d’étudier l’influence des pathologies métaboliques et de l’entrainement sur la voie dela NRG1 ainsi que son rôle physiologique dans la régulation du métabolisme énergétique.Nos résultats ont montré que la voie de la NRG1 n’était pas modifiée chez des rats rendusobèses par un régime enrichi lipides et en glucides. A l’inverse, l’entrainement en endurancecouplé à un régime équilibré favorise l’activation de la voie de la NRG1 dans le musclesquelettique de rats obèses. En effet, une période d’entrainement de huit semaines associéà un régime équilibré permet le clivage de la NRG1 et l’activation de son récepteur ErbB4dans le muscle gastrocnémien de rats obèses via l’activation de la métalloprotéase ADAM17.De plus, un traitement en chronique ou en aigu favorise la captation du glucose chez lasouris obèse et diabétique (db/db). Les mécanismes sous-tendant ce phénomèneimpliquerait l’activation du récepteur ErbB3 et l’activation des protéines FOXO1 et Akt dansle foie. Cependant, le traitement à la NRG1 ne modifie la dépense énergétique, la prisealimentaire et la composition alimentaire des souris db/db. Ainsi, il apparait que la NRG1pourrait jouer un rôle important dans la régulation du métabolisme glucidique in vivo chezen condition de pathologies métaboliques et que l’entrainement pourrait activer cette voiedans le muscle squelettique. / Neuregulin 1 (NRG1) is a cytokine that belongs to the epidermal growth factors family. NRG1can be released during exercise and can be define as a myokine. Initially studied for its rolein growth and maturation, NRG1 can also regulate glucose homeostasis in vitro. Thus, theaim of this work was to investigate the effect of training and metabolic disorders on NRG1pathway and its role in energy metabolism. Results showed that NRG1 pathway was notaltered in skeletal muscle of obese rats. Conversely, endurance training combined with awell-balanced diet improved NRG1 pathway activation in skeletal muscle of obese. Indeed, 8weeks of training and diet increased the cleavage of NRG1 and the activation of its receptorErbB4 through the activation of the metalloprotease ADAM17. Moreover, acute and chronictreatment improved glucose tolerance in diabetic mice (db/db). Acute treatment loweredglycemia by activating ErbB3, Akt and FOXO1 in the livre. Thus, NRG1 might play a key role inthe regulation of glucose homeostasis in people who suffers from metabolic disorders.Training might a good tool to activate this pathway in skeletal muscle.

Aim/Objectives: There were two aims; improving type II diabetes glycaemic control; and enhancing the role of community pharmacists by engaging them in type II diabetes medicine management. Methods: This quantitative study collected data from both community pharmacists and patients. In a premises survey, 426 self-administered questionnaires were distributed to community pharmacies. In a knowledge survey, 125 questionnaires were distributed to community pharmacists. In a clinical trial, 40 community pharmacies were randomly assigned to be control (18) and intervention (22) premises. Each pharmacy recruited 4 or 5 patients with type II diabetes. 225 patients were recruited and assigned to receive usual pharmacist care (n=100) or a pre-defined pharmacist intervention (n=125). Results: Community pharmacists had good knowledge of diabetes with average scores 21/29 (±3.18). The differences between control and intervention groups in patients' HbA1c and FPG changes were not significant. In the intervention group patients' diabetes knowledge was significantly improved (p=0.031). In the intervention group HbA1c and FPG improved significantly and in the control group FPG improved significantly and HbA1c did not. Patients' self-reported self-management activities improved significantly around blood glucose measurements (p < 0.001) and physical exercising (p=0.001). Attitudes around the value of tight control of diabetes improved (p < 0.001). Conclusion: The findings suggest that community pharmacists in Libya may have the ability to improve type II diabetes care. The primary outcomes were not improved in intervention versus control. The before/after analysis showed significant improvement in primary outcomes in the intervention group and also in one of the primary outcomes in the control group. Patients' self-reported self-care activities and attitudes improved significantly in the intervention group.

Metabolic pathways in adipose tissue affect the whole-body energy homeostasis. De novo lipogenesis and futile metabolic cycling based on lipolysis and fatty acid re-esterification which is engaged in regulation of fatty acid level in bloodstream are occuring there. These processes are partly regulated by nuclear receptor PPARγ. Mitochondrial biogenesis and oxidative phosphorylation in adipocytes are controlled by interacting of PPARγ with transcriptional coactivators PGC-1α and PGC-1β. The aims of this thesis were to find out whether PGC-1β is connected with regulation of futile cycling and de novo lipogenesis in white adipose tissue and also how specific inactivation of PGC-1β gene in adipose tissue affects phenotype of mice during short-term cold exposure or treatment based on high fat diet enriched by n-3 polyunsaturated fatty acids in combination with mild calorie restriction. The results show that inactivation of PGC-1β probably does not affect futile cycling based on lipolysis and fatty acid re-esterification. In mice with PGC-1β ablation compensation in weight of brown adipose tissue was observed as well as increase in the gene expresion of nuclear receptors PPAR, transcriptional coactivator PGC-1α and UCP1 during cold exposure. Even though the inactivation of PGC-1β in brown adipose tissue...

Bakgrund: Diabetes mellitus typ II (DMT2) är ett folkhälsoproblem som har ökat i hela värden och cirka 422 miljoner människor är drabbade av sjukdomen. I Sverige har ungefär 500 000 människor DMT2. Egenvård är en viktig del av behandlingen.  Syfte: Att beskriva patienters upplevelser av egenvård vid diabetes mellitus typ II. Metod: En litteraturöversikt baserad på tio kvalitativa vetenskapliga artiklar, från databaserna Cinhal Complete och PubMed. Litteraturöversikten har analyserats med utgångspunkt i Fribergs modell. Resultat: Resultatet presenteras i tre huvudteman: “Nya levnadsvanor”, “Behov av stöd” och “Kunskap och information”. Sammanfattning: Många patienter upplevde att det var en utmaning att utföra egenvård då det innebär mycket uppoffring, kunskap, motivation och stöd vid egenvård. / Background: Diabetes mellitus type II (DMT2) is a public health problem that has increased throughout the world. Around 422 million people worldwide are affected by the disease. In Sweden, there are approximately 500,000 people who have a DMT2 diagnosis. Self-Care is an important part of the treatment. Aim: To describe patients' experiences of self-care in type II diabetes mellitus.Method:A literature review based on ten qualitative scientific articles, retrieved from the databases Cinhal complete and PubMed. The literature review has been analyzed on the basis of Friberg's model.  Results: The results are presented in three main themes: "New lifestyles", "Need for support" and "Knowledge and information".  Summary: Many patients felt that it was a challenge to perform self-care as it involves a lot of sacrifice, knowledge, motivation, and support in self-care.

Background: Type II diabetes is a common disease worldwide and several drug treatments are available. Some of the more recently approved drugs are DPP4-inhibitors, GLP analogues and SGLT2-inhibitors. Most of the Type II diabetes drugs (T2DMD) are prescribed by primary care physicians. To ensure rational drug use it is important to follow up prescribing patterns to design strategies and interventions that can improve drug treatment, since consequences of inappropriate drug use might be poor health outcomes and increased health costs. Aim: To study differences in the prescribing pattern of T2DMD among primary healthcare centres (PHC) at a macro level in Region Uppsala. Method: A cross-sectional study based on data collected from Region Uppsala’s data register. Data consisted of individuals over 25 years of age with at least one prescription of a diabetes drug from the Anatomic Therapeutic Chemical (ATC) group A10 prescribed within the period of January 2018 to June 2020. Results: There is a moderate difference in the prescribing patterns of T2DMD among different PHCs in Region Uppsala. Overall, a larger proportion of oral antidiabetic drugs (OAD) were prescribed compared to Insulins. Most PHC prescribed a larger proportion of long acting insulins than other Insulins. Among OAD, a larger proportion of Biguanide derivative where prescribed. DPP-4 inhibitors, Sulphonylureas and SGLT2-inhibitors were prescribed to almost the same extent. Conclusion: Overall, there is a minor difference in the prescribing patterns of T2DMD among different PHCs in Region Uppsala during the study period. Lately, prescribing of DPP4-inhibitors, SGLT2-inhibitors and long acting insulins have increased. / I detta fördjupningsprojekt studerades förskrivningsmönstren av typ II diabetesläkemedel i Region Uppsala. Studieresultaten vissa skillnader i hur olika vårdcentraler i Region Uppsala förskriver typ II diabetesläkemedel. Från början var hypotesen att icke-insuliner förskrivs i större utsträckning än insuliner. Vilket visade sig stämma överens med resultaten. I studien jämförs också skillnaden mellan förskrivning av icke-insuliner som funnits längre på marknaden och de nyligen godkända (DPP4-hämmare och SGLT2-inhibitorer). Resultaten visar en tydlig ökning i förskrivning av de nya läkemedlen under studieperioden. En anledning till detta kan vara läkemedels positiva farmakologiska effekter. I studien jämförs också skillnaden i förskrivningen av de olika insuliner i Region Uppsala. Resultaten visar att långverkande insuliner förskrivs i större utsträckning i jämförelse med andra insuliner, vilket är inte enligt rekommendationslistan för förskrivning av typ II diabetesläkemedel Studieresultaten kan användas för att fortsätta följa upp och förbättra kvalitén på diabetesvården i Region Uppsala. Ytterligare studier skulle till exempel kunna utgå ifrån hela populationen med en typ 2 diabetesdiagnos för att studera utfall även för andra interventioner än läkemedel. Dessutom behövs fortfarande kunskap om det är kostnadseffektiv att fler nya typ 2 diabetesläkemedel används. Studien ger kunskap om förskrivningen av typ II diabetesläkemedel i Region Uppsala. Studien kan användas som grund för dialog om förskrivningen av typ II diabetesläkemedel i regionen, så att denna optimeras och fler individer får adekvat behandling. Detta arbete är viktigt eftersom typ II diabetes är en mycket vanlig sjukdom där prevalensen ökar.  Denna studie är en tvärsnittsstudie baserat på sekundärdata från Region Uppsalas elektroniska medicinalt register och primärdata från två enkäter skickade till sjuksköterskor och läkare som jobbar på vårdcentraler med patienter med diabetes. Studien inkluderar data från de 26 offentliga vårdcentraler som hör till förvaltningen Nära, Vård och Hälsa i region Uppsala. Förskrivningsdata baseras på recept för ett diabetesläkemedel från Anatomic Therapeutic Chemical (ATC) gruppen A10, förskrivet mellan januari 2018-juni 2020.

Les antidépresseurs figurent parmi les médicaments les plus prescrits dans les pays industrialisés, incluant la France. L’utilisation croissante de ces médicaments dans la population générale suscite de multiples préoccupations quant à leurs effets indésirables sur la santé des populations. Plusieurs travaux de recherche se sont récemment intéressés à l’impact de l’utilisation prolongée de ces médicaments sur le risque cardiométabolique. Toutefois, les résultats produits sont contradictoires, limitées et ne concernaient pas la population Française. L’objectif général de ce travail de thèse consiste donc à étudier, à partir des données de deux grandes cohortes françaises (E3N et D.E.S.I.R.), l’association entre l’utilisation de médicaments antidépresseurs et le risque cardiométabolique, en essayant d’en comprendre les mécanismes sous-jacents. La première étude a montré que l’utilisation d’antidépresseurs était associée à un risque accru de diabète de type II. Cependant, l’association était évidente uniquement chez les femmes qui avaient plus de consultations médicales au cours des douze derniers mois. Les résultats de la seconde étude n’ont montré aucune association entre l’utilisation d’antidépresseurs et les marqueurs physio-biologiques qui caractérisent le diabète tels que : la glycémie à jeun, l’hémoglobine glyquée, la fonction des cellules β et la sensibilité à l’insuline. Enfin la troisième étude de ce travail de thèse a mis en évidence un risque accru de syndrome métabolique chez les utilisateurs d’antidépresseurs même si l’effet semblait se potentialiser chez les hommes uniquement. Les résultats de ces études apportent des éléments en faveur de l’hypothèse d’un biais de détection pour expliquer l’association observée entre utilisation d’antidépresseurs et diabète. Ce travail de thèse a permis de clarifier l’association entre l’utilisation d’antidépresseurs chez l’adulte et le risque cardiométabolique. Les implications scientifiques, cliniques et de santé publique sont discutées. / Antidepressants are among the most frequently prescribed medications in industrialized countries, including France. The increasing use of antidepressants in the general population has led to concerns about their adverse effects on health. Recently, important research work has focused on the impact of the prolonged use of antidepressants on cardiometabolic risk. However, the results produced were conflicting, limited and were not based on French population. The general objective of this thesis is therefore to study, based on data from two large French cohorts (E3N and D.E.S.I.R.), the association between the use of antidepressant drugs and cardiometabolic risk, with the ambition to understand the underlying mechanisms. The first study showed antidepressant medication use to be associated with an increased risk of type II diabetes. However, this association was evident only in women with more medical visits in the last twelve months. The results of the second study shows no association between antidepressant medication use and physio-biological markers that characterize diabetes such as fasting plasma glucose, glycated haemoglobin, β-cell function and insulin sensitivity. Finally, the third study showed an increased risk of metabolic syndrome among users of antidepressants, although the effect was apparent in men only. The results of these studies provide evidence supporting the hypothesis of a detection bias to explain the observed association between antidepressants use and diabetes. This work has helped to clarify the association between the use of antidepressants in adults and cardiometabolic risk. The scientific, clinical and public health implications are discussed.

The biochemical factors affecting post-harvest preservation in apples indicated that well-preserved varieties of apples had increased superoxide dismutase (SOD) activity initially and the activity declined during later storage as apples deteriorated. The SOD link to better preservation correlated with higher phenolic content and free-radical scavenging linked antioxidant activity. Well-preserved varieties were able to maintain a more stable pentose phosphate pathway (PPP) (measured by the activity of glucose-6-phosphate dehydrogenase, G6PDH) throughout the storage period. Proline content increased in all varieties with an increase in proline dehydrogenase (PDH) activity in the initial period indicating proline catabolism supporting potential ATP synthesis. During later storage succinate dehydrogenase (SDH) activity increased while PDH activity declined indicating a shift to tricarboxylic acid cycle and likely NADH generation for ATP synthesis. This shift coupled with the declining SOD activity coincides with rapid deterioration. The guaiacol peroxidase activity (GPX) activity generally declined in late stages indicating post-harvest deterioration. Increasing number of studies have shown that regular intake of fruits and vegetables have clear links to reduced risk of chronic diseases like diabetes and cardiovascular disease. The beneficial effects in many cases have been attributed to the phenolic and antioxidant content of the fruits and vegetables. Apples are a major source of fiber and contain good dietary phenolics with antioxidant function. Previous epidemiological studies have indicated that intake of apples reduces the risk of developing Type II diabetes. Our studies indicate that this reduced risk is potentially due to modulation of postprandial glucose increase by phenolics present in apples via inhibition of a-glucosidase. Phenolic content was evaluated during 3 months of post-harvest storage of four varieties of apples and results indicated positive linkage to enhanced post-harvest preservation and a-glucosidase inhibition. These in vitro results along with existing epidemiological studies provide strong biochemical rationale for further animal or human clinical studies.

Aim/Objectives: There were two aims; improving type II diabetes glycaemic control; and enhancing the role of community pharmacists by engaging them in type II diabetes medicine management. Methods: This quantitative study collected data from both community pharmacists and patients. In a premises survey, 426 self-administered questionnaires were distributed to community pharmacies. In a knowledge survey, 125 questionnaires were distributed to community pharmacists. In a clinical trial, 40 community pharmacies were randomly assigned to be control (18) and intervention (22) premises. Each pharmacy recruited 4 or 5 patients with type II diabetes. 225 patients were recruited and assigned to receive usual pharmacist care (n=100) or a pre-defined pharmacist intervention (n=125). Results: Community pharmacists had good knowledge of diabetes with average scores 21/29 (±3.18). The differences between control and intervention groups in patients' HbA1c and FPG changes were not significant. In the intervention group patients' diabetes knowledge was significantly improved (p=0.031). In the intervention group HbA1c and FPG improved significantly and in the control group FPG improved significantly and HbA1c did not. Patients' self-reported self-management activities improved significantly around blood glucose measurements (p<0.001) and physical exercising (p=0.001). Attitudes around the value of tight control of diabetes improved (p<0.001). Conclusion: The findings suggest that community pharmacists in Libya may have the ability to improve type II diabetes care. The primary outcomes were not improved in intervention versus control. The before/after analysis showed significant improvement in primary outcomes in the intervention group and also in one of the primary outcomes in the control group. Patients' self-reported self-care activities and attitudes improved significantly in the intervention group.

Functional analyses have gained more interest as we have easier access to massive data sets. However, such data sets often contain large heterogeneities, noise, and dimensionalities. When generalizing the analyses from vectors to functions, classical methods might not work directly. This dissertation considers noisy information reduction in functional analyses from two perspectives: functional variable selection to reduce the dimensionality and functional clustering to group similar observations and thus reduce the sample size. The complicated data structures and relations can be easily modeled by a Bayesian hierarchical model, or developed from a more generic one by changing the prior distributions. Hence, this dissertation focuses on the development of Bayesian approaches for functional analyses due to their flexibilities. A nonparametric Bayesian approach, such as the Dirichlet process mixture (DPM) model, has a nonparametric distribution as the prior. This approach provides flexibility and reduces assumptions, especially for functional clustering, because the DPM model has an automatic clustering property, so the number of clusters does not need to be specified in advance. Furthermore, a weighted Dirichlet process mixture (WDPM) model allows for more heterogeneities from the data by assuming more than one unknown prior distribution. It also gathers more information from the data by introducing a weight function that assigns different candidate priors, such that the less similar observations are more separated. Thus, the WDPM model will improve the clustering and model estimation results. In this dissertation, we used an advanced nonparametric Bayesian approach to study functional variable selection and functional clustering methods. We proposed 1) a stochastic search functional selection method with application to 1-M matched case-crossover studies for aseptic meningitis, to examine the time-varying unknown relationship and find out important covariates affecting disease contractions; 2) a functional clustering method via the WDPM model, with application to three pathways related to genetic diabetes data, to identify essential genes distinguishing between normal and disease groups; and 3) a combined functional clustering, with the WDPM model, and variable selection approach with application to high-frequency spectral data, to select wavelengths associated with breast cancer racial disparities. / Doctor of Philosophy / As we have easier access to massive data sets, functional analyses have gained more interest to analyze data providing information about curves, surfaces, or others varying over a continuum. However, such data sets often contain large heterogeneities and noise. When generalizing the analyses from vectors to functions, classical methods might not work directly. This dissertation considers noisy information reduction in functional analyses from two perspectives: functional variable selection to reduce the dimensionality and functional clustering to group similar observations and thus reduce the sample size. The complicated data structures and relations can be easily modeled by a Bayesian hierarchical model due to its flexibility. Hence, this dissertation focuses on the development of nonparametric Bayesian approaches for functional analyses. Our proposed methods can be applied in various applications: the epidemiological studies on aseptic meningitis with clustered binary data, the genetic diabetes data, and breast cancer racial disparities.

In the United States alone, there were 25.8 million people suffering from diabetes in 2010. The prevalence of diabetes is expected to markedly increase worldwide over the next 30 years, an estimated 2.8% in 2000 and 4.4% in 2030. For individuals diagnosed with type 2 diabetes mellitus (T2DM), treatment is essential to control adverse effects such as hypertension and diabetic neuropathy. The focus of this study is to examine various approaches to maintain and improve the lifestyle of individuals suffering from T2DM. A comparative approach has been used to evaluate the differences in the treatment of T2DM with the use of traditional Chinese medicine (TCM) and Western medicine. In Western society, pharmaceuticals are commonly used as a treatment method to manage hyperglycemia, along with life-style modifications. Furthermore, TCM views the human body and its functioning in a holistic way, stating that no single body part or symptom can be understood apart from its relation to a whole. Herbal medications and other treatments in TCM are targeted to treat underlying medical complaints that resulted in symptoms, instead of treating one specific manifestation. Data collection has been gathered through Qualitative over the phone interviews with patients suffering from T2DM, as well as TCM physicians. Interviews were conducted on patients that were diagnosed with T2DM (fasting plasma glucose levels of 126 or greater and HbAlc levels [greater than] 8%), and had continued treatment longer than three months prior to interviews. Collection of chart notes containing glucose levels, levels of pain, lifestyle changes, and vital signs were also used. A total of 21 patients from a family practice were interviewed, answering 23 constructed questions based on treatment of choice (TCM or western) and their personal input on treatment satisfaction. Patients varied in age, ethnicities, and gender, ranging from 39-70 years of age. Two traditional Chinese medicine physicians were also interviewed. Interviews with TCM physicians elaborated on course of treatment and steps taken to diagnose T2DM. Furthermore, prescription medications were also charted and documented to further analyze with secondary data. Upon completing the interviews, the data stated 21 patients (total population questioned) had not experienced alternative medicine and were exposed only to western medicine as treatment. A major concern for most patients were the pharmaceutical side effects, and 85.1% of patients stated they would be interested in an alternative treatment. Due to insufficient sources and knowledge on TCM treatment, 14.2% of patients stated they were satisfied with their western medicine treatment of choice and would not change treatment. The research's objective was to evaluate the differences in treatment of T2DM. Data collected supported the objective and showed the lack of sources to alternative treatments aside from western medicine. The researcher informed and educated interviewees about literature review on traditional Chinese medicine about alternative treatments available to treat T2DM.