Дисертації з теми "Diabetes Iran"
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White, Desley Louise. "Non-transferrin-bound iron and protein glycation in type 2 diabetes." Thesis, University of Plymouth, 2012. http://hdl.handle.net/10026.1/1181.
Повний текст джерелаAljwaid, Husam O. Dakhil. "Relationships between iron, oxidative stress, glycated proteins and the development of atherosclerosis in Type 2 diabetes." Thesis, University of Plymouth, 2015. http://hdl.handle.net/10026.1/3222.
Повний текст джерелаFernández, Cao José Cándido. "Iron excess and risk of type 2 diabetes mellitus in a prospective cohort of mediterranean population." Doctoral thesis, Universitat Rovira i Virgili, 2016. http://hdl.handle.net/10803/378354.
Повний текст джерелаAntecedentes:El consumo de hierro hemo y los depósitos de hierro se han asociado con el riesgo de diabetes mellitus tipo 2 (DMT2) en cohortes estadounidenses, chinas, y del norte de Europa, sin embargo estas relaciones no han sido estudiadas en poblaciones del sur de Europa. Objetivos:Evaluar, prospectivamente, el efecto de la ingesta elevada de hierro y el estado elevado de hierro en la aparición de la DMT2 en población mediterránea adulta, y estudiar la relación entre el estado del hierro y la osteocalcina. Métodos:Los participantes fueron hombres y mujeres de 55 a 80 años del estudio PREDIMED. La DMT2 fue diagnosticada utilizando los criterios de la ADA. Se recogieron datos sociodemográficos, antropométricos, de estilo de vida, estado de hierro, perfil lipídico, metabolismo de la glucosa e inflamación. En un estudio observacional en 1.073 personas, 131 diabéticos incidentes, se evaluó la asociación entre la ingesta de hierro y la DMT2. Se analizó transversalmente en 423 sujetos la relación entre el estado de hierro y la osteocalcina. Finalmente, un estudio casos-control anidado fue diseñado para evaluar la asociación entre el estado de hierro, medido mediante la ferritina sérica (FS) y el receptor soluble de transferrina (sTfR),y el riesgo de DMT2 en 459 participantes, 153 diabéticos incidentes. Resultados:Se encontró que una ingesta elevada de hierro hemo aumenta el riesgo de DMT2 en un 30%. Además, los valores de FS>257μg/L en varones y >139μg/L en mujeres se asociaron con DMT2. También se encontró asociación entre el ratio sTfR:ferritina y la DMT2, pero no con el sTfR. Tanto SF como el sTfR se relacionan con la osteocalcina. Conclusiones:En una población mediterránea adulta de alto riesgo cardiovascular, una ingesta elevada de hierro hemo y unos depósitos elevados de hierro aumentan el riesgo de DMT2. La relación entre el estado de hierro y la osteocalcina es controvertida.
Background: The intake of haem iron intake as well as body iron stores have been associated with the risk of developing type 2 diabetes mellitus (T2DM) in U.S., Chinese, and northern European cohorts, however these relationships have not been studied in southern European populations. Objectives: To assess, prospectively, the effect of elevated dietary iron intake and body iron status on the onset of T2DM in an adult Mediterranean population, and to evaluate the relationship between iron status and osteocalcin as a potential mechanism for explaining iron-induced T2DM. Methods: Participants were men and women aged 55 to 80 years from the PREDIMED study. New-onset T2DM during follow-up was diagnosed using the criteria of the American Diabetes Association. Socio-demographic, anthropometric, lifestyle, dietary intake, iron status, lipid profile, glucose metabolism, inflammation variables were collected at baseline. An observational cohort study was conducted in 1,073 individuals, 131 incident diabetics, to assess the association between iron intake and T2DM. A cross-sectional study was carried out in 423 subjects to evaluate the relationship between iron status and osteocalcin. Finally, a prospective nested case-control study was design to assess the association between body iron status, measured as serum ferritin (SF) and soluble transferrin receptor (sTfR) and its ratio, with T2DM in 459 participants, 153 incident diabetics. Results: We found that a high haem iron intake increases the risk of T2DM by 30%. In addition, SF values >257µg/L in males and >139µg/L in females were associated with T2DM. We also found association between sTfR:ferritin ratio and T2DM, but not with sTfR. Both SF and sTfR were related to osteocalcin. Conclusions: In an adult Mediterranean population at high cardiovascular risk, high dietary haem iron and body iron stores increase the risk of T2DM after adjustment for potential confounding variables. The relationship between iron status and serum osteocalcin levels is controversial.
Dubreil, Chloé. "Nanoparticules tolérogènes pour l’administration d’un auto-antigène des cellules bêta dans le diabète auto-immun Tolerogenic iron oxide nanoparticles in type 1 diabetes: biodistribution and pharmacokinetics studies in nonobese diabetic mice Tolerogenic nanoparticles boost regulatory B cells to reverse autoimmune diabetes." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB141.
Повний текст джерелаChronic autoimmune diseases are the consequence of self-antigens recognition as foreign by the adaptive immune system, resulting in inflammation and potential destruction of targeted tissues and organs. Type 1 diabetes (T1D) is one of the most common chronic autoimmune diseases. It is characterized by insulin deficiency due to selective destruction of insulin-producing beta-cells. At clinical onset, more than 70% of beta-cell mass can be destroyed. Consequently, early diagnosis is a major objective in order to avoid, limit or reverse autoimmune aggression, and to create opportunities for strategies enhancing beta-cell survival or regeneration. Antigen (Ag)-specific approaches are appealing because their effects are expected to be limited to cells expressing the chosen antigen, ideally the target organ. However, while treatment with beta -cell Ags can prevent disease in the model of the Non-Obese Diabetic (NOD) mouse, clinical trials in humans have produced disappointing results. Consequently, combinatorial approaches may be required for reversal and prevention of T1D. A potential strategy is to associate self-antigens with signals inducing a tolerogenic phenotype. Co-delivery ensures that both compounds get delivered at the same time and presented in the same cellular environment to auto-reactive immune cells. The first part of this work consisted in undertaking a thorough physicochemical characterization of a new drug vector, aiming to establish quantitative methods to optimize drug loading while maintaining biocompatibility and stability of the delivery vehicle. In this work, 9nm Ultra-small superparamagnetic iron-oxide (USPIO) nanoparticles were surface functionalized with phosphonate polyethylene glycol molecules (USPIO-PEG). Carboxylic acid functions were used to covalently bind a T1D autoantigen. PEG brush allows for the co-packaging of hydrophobic tolerogenic drug molecules, trapped between PEG chains through hydrophobic interactions. We carefully characterized protein and tolerogenic drug loading, and studied cell labeling, toxicity, integrity of loaded protein and tolerogenic drug, and activity of our nanoplatform on murine Bone Marrow Derived Dendritic Cells (BMDCs). We undertook biodistribution and pharmacokinetics studies using the NOD model that shares numerous features with human T1D. Biokinetic studies were performed both qualitatively using MRI 7T and histological Perls staining analyses and quantitatively using magnetometry for NP quantification. USPIO accumulate preferentially in NOD mice pancreas via Enhanced Permeability retention (EPR) effect thus, allowing us to distinguish pre-diabetic mice from non-diabetic controls. This result suggests that vascular leakage could be exploited for NP bioaccumulation, for therapeutic agent delivery and for imaging using MRI agents to monitor treatment. The second part of the work consisted in evaluating the therapeutic effect of such tolerogenic nanoparticles (NPS) on NOD diabetic mice. Diabetic mice were injected intravenously at diabetes onset. USPIO-PEG and vehicle treated mice reached 600mg/dL blood glucose level, considered limit for sacrificing mice, within a couple of days. NPs carrying either the tolerogenic drug or the autoantigen delayed diabetes progression up to 40 days. Complete NPs showed synergistic effects. In fact, 50% of treated mice were still alive 65 days after disease onset, and two mice reverted to stable normoglycemia for more than 300 days. To identify the underlying mechanism, the immune response to NPs in lymphoid organs was investigated. It was found that tolerogenic NPs induce splenomegaly mainly due to B cell proliferation. NP-stimulated B cells secrete anti-inflammatory cytokines namely IL-10 and TGF-beta. Similar B cells could be produced in vitro upon incubation of with NPs. Our strategy has promising therapeutic potential and could be applied, using relevant antigens, to a wider range of autoimmune diseases
Olivatto, Gabriela Marsola. "Caracterização sociodemográfica e clínica de pacientes com talassemia maior e diabetes mellitus de um centro de referência no interior de São Paulo." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/22/22132/tde-28112017-150253/.
Повний текст джерелаThe longer life expectancy of patients with thalassemia major, repeated red blood cell transfusions as part of the treatment, may lead to increased iron deposition in the organs, and consequently, comorbidities. Thus, among the endocrine comorbidities, we have diabetes mellitus as one of the main ones, being necessary to know the panorama in our reality. The aim of the study was to determine the prevalence of diabetes in patients with thalassemia major and to characterize and compare patients with thalassemia major, and diabetes mellitus, according to sociodemographic and clinical variables.This is a descriptive and cross-sectional study, carried out in a reference center in thalassemia treatment of São Paulo countryside. The sample consisted of 31 patients with thalassemia major. For data collection, an instrument was divided into two parts. Sociodemographic and clinical data were obtained by means of a directed interview and the laboratory tests results by the patient\'s electronic record, from June to August 2015. Data were loaded into SPSS for Windows software, version 17.0 and submitted to descriptive statistical analysis. The project was approved by the Research Ethics Committee of the University of São Paulo at Ribeirão Preto College of Nursing (CEP / EERP-USP) under Protocol No. 41912415.3.0000.5393. Of the 31 patients with thalassemia major, 5 (16,1%) had diabetes mellitus. Regarding the sociodemographic variables, there were no differences in the distribution of the patients between the sexes, most of them were single and enrolled in high school. The age ranged from five to 48 years, with a mean of 24,9 years of age, the majority received up to 10 minimum wages, were students and had a work contract. Regarding the clinical variables, we have that the predominant treatment was the oral chelator deferasirox, and in those patients with diabetes, in addition to deferasirox, the majority used insulin. The predominant transfusion regimen was 15 to 22 days. Body mass index was classified as eutrophic and blood pressure was considered optimal for most patients. Regarding the laboratory findings, patients with diabetes and thalassemia had altered values of fasting glycemia and transaminase, whereas patients without diabetes had altered values of serum ferritin. Regarding imaging exams findings, no patient with diabetes and major thalassemia presented adequate bone mass, which reinforces the importance of their monitoring. The increase in cardiac overload for patients with diabetes and thalassemia stands out. For patients with thalassemia and without diabetes, the majority had severe hepatic iron overload in the magnetic resonance imaging of the liver, while for most patients with diabetes it was considered normal. Thus, knowing the clinical characteristics of patients with thalassemia major and diabetes allows subsidizing qualified nursing care and contributing to the health of patients with chronic conditions. However, our findings corroborate the prevalence rates of diabetes in patients with thalassemia major found in the national and international literature
Steed, Kevin Sage. "Alzheimer's Disease and Diabetes: A Transgenic Mouse Model in Behavior, MRI, and Cells." BYU ScholarsArchive, 2018. https://scholarsarchive.byu.edu/etd/7460.
Повний текст джерелаSuarez, Ortegon Milton Fabian. "Markers of iron status and cardiometabolic disease risk : an exploration of the association based on cross-sectional and prospective studies in multiple populations." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/31470.
Повний текст джерелаVirasith, Helene. "Long-chain polyunsaturated fatty acids and iron status in infants of gestational diabetic mothers." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86758.
Повний текст джерелаL'acide arachidonique (AA), l'acide docosahexaénoïque (DHA) et le fer sont d'importants nutriments pour le nouveau-né. Il semblerait que leurs niveaux sont compromis chez les enfants de mères diabétiques (EMD). L'objectif de cette étude est de comparer les niveaux d'AA, de DHA et de fer chez les EMD avec ceux mesurés chez les enfants de mères non diabétiques qui sont nés avec un poids moyen ou gros pour l'âge gestationnelle pour déterminer si les niveaux de gras insaturés à longues chaînes et de fer sont tous les deux amoindris chez l'enfant. L'analyse de covariance entre le fer et les gras insaturés a montré que le niveau de fer est positivement corrélé avec le niveau d'AA mais pas avec celui de DHA. Chez les EDM, le lien entre le fer et l'AA est encore plus marquant. Ces résultats suggèrent que le niveau de fer est relié avec le niveau d'AA chez tous les nouveau-nés et qu'il y a un plus grand risque chez les EDM d'avoir un niveau d'AA amoindri et par conséquent de souffrir de problèmes de croissance.
Kuek, Conchita Maria. "Hereditary haemochromatosis and the C282Y genotype : implications in diagnosis and disease." University of Western Australia. School of Surgery and Pathology, 2003. http://theses.library.uwa.edu.au/adt-WU2004.0024.
Повний текст джерелаGONÇALVES, RODOLFO D. M. R. "Avaliação de micronutrientes e sua influência no metabolismo secundário de Bidens pilosa e Salvia officinalis, plantas usadas no tratamento de diabetes." reponame:Repositório Institucional do IPEN, 2015. http://repositorio.ipen.br:8080/xmlui/handle/123456789/26385.
Повний текст джерелаMade available in DSpace on 2016-06-22T13:06:23Z (GMT). No. of bitstreams: 0
Dissertação (Mestrado em Tecnologia Nuclear)
IPEN/D
Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP
Engelman, Corinne Denise. "Effects of vitamin D genes on measures of insulin secretion, insulin sensitivity and adiposity : an ancillary study to the insulin resistance atherosclerosis study (IRAS) family study /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2006.
Знайти повний текст джерелаTypescript. Includes bibliographical references (leaves 168-182). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
Hangel, Christoph [Verfasser], and Markus [Akademischer Betreuer] Hecker. "Leptin-mediated downregulation of glutathione peroxidase 4 and iron overload contributing to podocyte ferroptosis in diabetic nephropathy / Christoph Hangel ; Betreuer: Markus Hecker." Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1199196096/34.
Повний текст джерелаZhang-Sun, Wei. "Relation structure-activité des lipopolysaccharides isolés des bactéries sulfato-réductrices de la flore intestinale chez le sujet sain et diabétique." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T082.
Повний текст джерелаRecent studies have highlighted the role of lipopolysaccharide (LPS) in the intestinal flora (gut microbiota) which could contribute to the inflammation process leading to obesity and type 2 diabetes. This thesis is part of a collaborative project between the laboratories of Dr. Caroff (U. Paris -Sud, Orsay, France) and Prof. Zhao (U. Jiao Tong , Shanghai, China). It has been shown by Pr.Zhao’s team in 2010 that the Sulfate -Reducing Bacteria (SRB) were presented in greater proportion in the intestinal mice flora following a fat diet compared to mice following a normal diet. The same results were observed in humans. The starting hypothesis was that SRB could produce a large amount of endotoxin in obese and diabetic patients and play a role in the development of metabolic diseases. Several SRB strains isolated from the human intestinal flora of a healthy subject and of a diabetic subject were grown in the Chinese laboratory. Studies of their LPS structure / activity relationships were carried out in the French laboratory. The aim of this study was to determine their roles in the development of metabolic diseases.Strains isolated from the two subjects could be classified in the Desulfovibrio genus. The corresponding LPS were extracted and purified by the methods developed in the French laboratory. The chemical structure was elucidated by the following methods: Electrophoresis, Thin layer chromatography, Gas chromatography and MALDI mass spectrometry. The mass spectra were obtained and the structure of lipid A, the active part of LPS isolated from SRB was described here for the first time. The biological activities test (TNFα, IL-6) vary depending on the number of fatty acids present in their lipid A structure. The LPS of SRB isolated from the healthy patient had a variable structure (Smooth versus Rough) depending on the amount of iron present in the medium, and those isolated from diabetic patients had atypical structures are not all inflamogenic .An unknown membrane molecule, which we named "Glycosyl'X" was co-extracted with the LPS. It apparently plays an important role in the growth of SRB was investigated after complex purification steps. The structures and the inflammatory power of these molecules variying with strains chelating iron were studied. They are mainly of glycosidic nature and linked to the bacterial membrane.The proportion of these molecules relatively to LPS varies with the amount of iron in the medium. An environment rich in iron promotes the growth of Desulfovibrio Glycosyl'X, molecules but competes with LPS and indirectly modulates the activity of the latter. The increase number of Desulfovibrio leading to increased Glycosyl'X molecules may also modulate positively (by presentation) or negatively (by killing bacteria) the absorption of iron in the intestines which balance is essential for metabolic homeostasis.Furthermore, the growth of Desulfovibrio increasing the production of Hydrogen Sulfide is known for its deleterious effects on the cells. We favor the hypothesis that its action on the separation of epithelial cells favors the passage of different LPS released by the Gram- negative of intestinal flora and even whole cell bacteria into the bloodstream
"Iron depletion therapy and chromium supplementation for improving insulin." Master's thesis, 2015. http://hdl.handle.net/2286/R.I.29912.
Повний текст джерелаDissertation/Thesis
Masters Thesis Nutrition 2015
MacKay, Meredith. "Evaluating Alternate Anthropometric Measures as Predictors of Incident Type 2 Diabetes Mellitus (T2DM). The Insulin Resistance Atherosclerosis Study (IRAS)." Thesis, 2008. http://hdl.handle.net/1807/17197.
Повний текст джерелаCarrêlo, Ana Catarina Lourenço. "Alterações da motilidade gástrica na diabetes mellitus tipo II : o efeito dos agonistas do recetor do glucagon-like peptide I (GLP-IRA)." Master's thesis, 2016. http://hdl.handle.net/10316/40664.
Повний текст джерелаO glucagon-like peptide I (GLP-1) corresponde a um dos principais, e mais recentes, alvos terapêuticos para o tratamento da Diabetes Mellitus tipo II, pois desempenha várias funções metabólicas benéficas para o tratamento desta patologia, tais como, a potenciação da secreção de insulina induzida pela entrada de nutrientes no organismo (“efeito incretina”), a estimulação da biossíntese de insulina, a inibição da secreção de glucagina e a melhoria da função das células beta-pancreáticas. O GLP-1 é também caraterizado por promover cardioproteção, induzir a saciedade, inibir o esvaziamento gástrico e a secreção ácida gástrica, e ainda, inibir a motilidade gastrintestinal através da ativação de recetores (GLP-1R) presentes em neurónios entéricos e por via da libertação de óxido nítrico. Têm sido desenvolvidos novos fármacos agonistas do recetor do GLP-1 (GLP-1RA) que mimetizam os efeitos do agonista endógeno e que são resistentes à degradação enzimática pela DPP-IV. Os GLP-1RA também têm sido aplicados na terapêutica da obesidade devido ao efeito significativo desta classe farmacológica na inibição do apetite e consequente perda de peso. O objetivo deste projeto consistiu no estudo do efeito dos GLP-1RA, GLP-1 e Liraglutido, sobre a motilidade gástrica e de que forma esta está alterada na presença da diabetes tipo II. Para esse fim, foram usadas tiras de fundo de estômago isolado de ratos Wistar (grupo controlo) e Goto-Kakizaki (rato GK, modelo animal diabético do tipo II não obeso), com dezasseis semanas de idade, para a realização de estudos funcionais de registo da contração isométrica de curvas cumulativas concentração-resposta (CR) dos GLP-1RA (0,05 nM - 111,1 nM) após pré-contração com carbacol 5 μM. Ambos os GLP-1RA induziram contração tónica, não colinérgica e dependente da concentração, sendo que o GLP-1 foi mais eficaz na indução da contração de fundo gástrico isolado de rato GK comparativamente ao rato Wistar, enquanto os dois GLP-1RA foram equivalentes no rato Wistar. Por outro lado, o Liraglutido foi o mais potente nos animais controlo, sendo que ambos os GLP-1RA foram equipotentes nos animais diabéticos. Comparando ambos os modelos animais, o GLP-1 foi mais eficaz em rato diabético (comparado com rato Wistar). Este aumento de eficácia da resposta contrátil ao agonista endógeno pode relacionar-se com a tendência para o aumento da expressão do GLP-1R observada por Western Blotting em lisados de fundo de estômago isolado de rato GK. O aumento da expressão do recetor pode ser promovido pela patologia como mecanismo compensatório, uma vez que foi comprovada anteriormente por outro grupo de investigadores a diminuição dos níveis plasmáticos e pós-prandiais de GLP-1 em rato GK (comparado com o rato Wistar). Para a caracterização farmacológica da resposta contrátil aos GLP-1RA, realizaram-se segundas curvas CR ao GLP-1 em tiras de estômago de ratos Wistar, na presença e na ausência de 300 nM de Exendin-3 (antagonista seletivo do recetor do GLP-1) e curvas cumulativas CR ao Liraglutido na presença e na ausência de 250 M de NG-nitro-L-arginina (L-NNA, inibidor não seletivo da sintase do óxido nítrico), ambos adicionados ao banho de órgãos trinta minutos antes da execução das curvas. Na presença do antagonista Exendin-3, foi observada uma redução estatisticamente significativa (p <0,05) de 55% do efeito máximo de contração induzida pelo GLP-1, sem alteração da potência, concluindo-se que a resposta contrátil aos GLP-1RA é mediada parcialmente pelo seu recetor específico. Na presença do inibidor L-NNA, não foram observadas alterações estatisticamente significativas na resposta contrátil ao Liraglutido, e portanto, esta não parece ser dependente da sintase do óxido nítrico. Procurando compreender melhor o observável efeito contráctil dos GLP-1RA na nossa preparação, procedeu-se à avaliação do efeito do Liraglutido no relaxamento induzido por um dador de óxido nítrico, o nitroprussiato de sódio e pela noradrenalina, em tiras de fundo de estômago isoladas a partir de ratos Wistar e ratos GK tratados com o fármaco. Para tal, animais com catorze semanas de idade foram divididos em quatro grupos: ratos Wistar e ratos GK administrados com Liraglutido (200 μg/kg s.c.), duas vezes por dia e durante catorze dias; paralelamente ratos Wistar e ratos GK foram administrados com soro fisiológico NaCl 0,9% (grupo controlo). Foram realizadas medições diárias do peso corporal e a ingestão calórica foi avaliada semanalmente. Os parâmetros bioquímicos, glicemia em jejum (de seis horas), triglicerídeos e colesterol total, e a sensibilidade periférica à insulina foram avaliados no primeiro e no último dia de tratamento com Liraglutido. Após o tratamento e sacrifício dos animais, foram realizadas curvas cumulativas CR de relaxamento isométrico ao SNP e à NA (0,01 μM - 631 μM) em tiras de fundo de estômago isolado de ratos Wistar e GK tratados e não tratados com Liraglutido e pré-contraídas com carbacol 5 μM. Comprovámos que este GLP-1RA induziu melhorias no perfil glicémico e lipídico e na sensibilidade periférica à insulina nos animais diabéticos sujeitos ao fármaco, e também, redução da ingestão calórica e perda de peso nos ratos tratados. Portanto, estes resultados são bons indicadores dos efeitos benéficos dos GLP-1RA para o tratamento da diabetes tipo II e da obesidade. Quanto à resposta contrátil do órgão isolado, uma diminuição no relaxamento induzido pelo SNP foi observada em ratos Wistar e GK tratados com Liraglutido (este efeito foi mais acentuado nos animais controlo). A perda de eficácia do efeito do SNP com o tratamento pode resultar de um possível efeito do Liraglutido na diminuição da libertação ou na degradação do óxido nítrico, sendo que um efeito direto do GLP-1RA sobre a síntese deste neurotransmissor é improvável, uma vez que não foram observadas alterações significativas na expressão da nNOS e da p-nNOS em lisados de fundo gástrico isolado de ratos controlo e diabéticos, tratados e não tratados com Liraglutido. Além disso, é possível que os GLP-1RA atuem por via da ativação da eNOS, em detrimento da nNOS. Deste modo, a redução da expressão do GLP-1R, como foi demonstrada em ratos Wistar e GK tratados com Liraglutido, pode resultar numa redução da ativação da eNOS, o que por sua vez, resultaria numa diminuição da síntese e da libertação de óxido nítrico e na consequente inibição do relaxamento do músculo liso gástrico. De fato observou-se imunomarcação do GLP-1R em células endoteliais de vasos sanguíneos co-localizados no plexo nervoso deste órgão. Contudo, há que salientar que não foram observadas alterações significativas na curva CR ao Liraglutido na presença de L-NNA, um inibidor não seletivo da NOS. Sobre a redução da expressão do GLP-1R em fundo gástrico isolado de ratos tratados com Liraglutido, esta pode ser consequência de uma possível internalização do GLP1-1R induzida por uma estimulação prolongada por parte do GLP-1RA. Além disso, também é possível que a perda de peso e a inibição do apetite observada nos ratos tratados com Liraglutido resulte num aumento da secreção de GLP-1 e consequente diminuição da expressão de GLP-1R (mecanismo de feedback negativo). O efeito do SNP é equipotente em ratos Wistar tratados e não tratados com Liraglutido, no entanto, foi observada perda de potência do efeito relaxante do SNP em animais diabéticos tratados com o GLP-1RA, sendo que esta pode ser explicada pela perda de neurónios nitrérgicos, como consequência da diabetes tipo II, e deste modo, diminui o relaxamento por diminuição da síntese e libertação de óxido nítrico endógeno. De facto no nosso estudo observou-se uma tendência para diminuição da expressão da nNOS e/ou p-nNOS no rato GK, relativamente ao rato Wistar. No caso da noradrenalina, foi observada uma perda significativa de potência relativamente à situação controlo, determinada quer pela patologia, quer pelo tratamento. Sendo que a perda de potência da noradrenalina com o tratamento pode relacionar-se com a sub-regulação da expressão do GLP-1R observada nos ratos tratados com Liraglutido, o que por sua vez, pode resultar numa redução da ativação de vias nervosas adrenérgicas. Enquanto a perda de potência da noradrenalina com a patologia pode ser explicada por uma possível sub-regulação da expressão de recetores beta-adrenérgicos em fundo gástrico isolado de rato diabético. Em ambos os casos, a ação da NA estaria diminuída, assim como, o relaxamento induzido por esta. Por fim, a imunomarcação do GLP-1R foi detetada nas células parietais das glândulas gástricas, nas células musculares lisas, nas células ganglionares do plexo nervoso e nas células endoteliais dos vasos sanguíneos, em fundo gástrico isolado de rato. Finalmente, a realização de novos estudos é necessária para compreender melhor a real contribuição do óxido nítrico no mecanismo de ação subjacente ao efeito dos GLP1-RA sobre a motilidade gástrica. E além disso, o uso de animais diabéticos com uma idade mais avançada, ou até mesmo o uso de um outro modelo animal de diabetes tipo II, poderia ajudar a entender melhor as alterações promovidas pela patologia na motilidade gástrica.
Glucagon-like peptide I (GLP-1) has been studied in the development of new therapeutic strategies for the treatment of type II diabetes because of its metabolic effects, like stimulation of insulin secretion induced by nutrients (incretin effect), stimulation of insulin biosynthesis, inhibition of glucagon secretion and improvement of beta-cell function. GLP-1 also promotes cardioprotection, induces satiety, delays gastric emptying, inhibits acid gastric secretion and inhibits gut motility through activation of GLP-1R on enteric neurons and via nitric oxide release. GLP-1R agonists (GLP-1RA) are drugs that mimic the effects of GLP-1 and they are resistant to enzymatic degradation by DPP-IV. GLP-1RA have also been used in the treatment of obesity because of its significant effects in inhibition of appetite and weight loss. The main aim of this project was to study the effects of GLP-1RA, GLP-1 and Liraglutide, in gastric motility and its alterations in the presence of type II diabetes. To this end, gastric fundus strips from Wistar rats (control group) and Goto-Kakizaki rats (GK rat, animal model of spontaneous type II diabetes and non-obese), with sixteen weeks of age, were used in functional studies. Isometric contractile cumulative concentration-response (CR) curves for GLP-1RA were performed (0,05 nM - 111,1 nM) and all gastric fundus strips were pre-contracted with carbachol 5 μM. Both GLP1-RA induced concentration-dependent, non-cholinergic and tonic contraction of isolated rat gastric fundus. GLP-1 was the most effective in GK rat (compared to Wistar rat) and both GLP-1RA were equivalent in Wistar rat. Inversely, Liraglutide was the most potent in the control group and both agonists were equipotent in diabetic rats. Comparing both animal models, GLP-1 was more effective in diabetic rats than in control rats. This increased efficacy of GLP-1 in diabetic rats can be explained, in part, by the tendency of up-regulation of the GLP-1R expression determined, by Western Blotting, in lysates from isolated gastric fundus from GK rat (compared to Wistar rat). This increased GLP-1R expression can be promoted by type II diabetes and can result from a compensation mechanism since a reduction in plasma and post-prandial levels of GLP-1 was reported in GK rat (compared to Wistar rat). xvi For pharmacological characterization of the contractile response to GLP-1RA, second cumulative CR curves for GLP-1 in gastric fundus strips from Wistar rats were performed in the absence and in the presence of Exendin-3, 300 nM (selective GLP-1R antagonist) and cumulative CR curves for Liraglutide were performed in the absence and in the presence of NG-nitro-L-Arginine, 250 μM (L-NNA, non-selective inhibitor of nitric oxide synthase). Both (Exendin-3 and L-NNA) were added to the organ bath thirty minutes before the CR curves. The GLP-1R antagonist, Exendin-3, caused a statistically significant (p <0,05) reduction of the contractile response induced by GLP-1, without changes in potency, so we can conclude that contraction of gastric fundus induced by GLP-1RA is partially mediated by its specific receptor. No significant alterations in contractile response to Liraglutide were observed in the absence and in the presence of inhibitor L-NNA, therefore gastric fundus contraction induced by GLP-1RA is independent of nitric oxide synthase. To better understand the contractile response to GLP-1RA, the effect of the treatment with Liraglutide in isometric relaxation induced by a nitric oxide donor, sodium nitroprusside (SNP) and by noradrenaline, in isolated gastric fundus from Wistar and GK rats was evaluated. To this end, Wistar and GK rats with fourteen weeks of age were divided into four groups: Wistar and GK rats treated with Liraglutide (200 μg/kg s.c.) twice daily and for fourteen days; and Wistar and GK rats treated with saline (NaCl 0,9% s.c.) during the same period. Body weight and caloric intake were evaluated daily and weekly, respectively. Biochemical analyses (fasting glycaemia, triglycerides and total cholesterol) and insulin tolerance evaluation were performed on the first and on the last day of the treatment. After treatment with Liraglutide, cumulative CR curves for SNP and NA were performed (0,01 μM - 631 μM) and all gastric fundus strips from Wistar and GK, treated and non-treated, rats were pre-contracted with carbachol 5 μM. We proved that Liraglutide induced an improvement of biochemical profile and peripheral insulin tolerance in diabetic rats, and also, a significant decrease in caloric intake and body weight in treated-rats. Therefore, we can conclude that GLP-1RA are beneficial for the treatment of type II diabetes and obesity. xvii A decrease in relaxation induced by SNP was observed in Wistar and GK rats treated with Liraglutide and this effect was more significant in Wistar rats. The loss of efficacy of SNP effect determined by the treatment with Liraglutide can be explained by a possible effect of this GLP-1RA in reduction of release or in degradation of nitric oxide. A direct effect in nitric oxide synthesis is unlikely to occur because no significant alterations were observed in nNOS and p-nNOS expression in isolated gastric fundus from treated and non-treated rats. Besides that, if GLP1-RA could act through eNOS activation, instead of nNOS, a reduction in GLP-1R expression (demonstrated, in this study, in Wistar and GK rats treated with Liraglutide) could result in a reduction of eNOS activation and consequently, in a reduction of nitric oxide release and relaxation of gastric smooth muscle. In fact GLP-1R was detected (by immunohistochemical studies) in endothelial cells of blood vessels co-localized in nervous plexus of gastric fundus. But no significant alterations were observed in CR curves to Liraglutide in the presence of L-NNA (a non-selective inhibitor of NOS). About the significant reduction of GLP-1R expression in isolated gastric fundus from rats treated with Liraglutide (compared to non-treated rats), it can be explained by a compensation mechanism between a probable increase of plasmatic levels of GLP-1 induced by weight loss and inhibition of appetite and the reduction of GLP-1R expression in treated-rats (negative feedback mechanism). Besides that, it’s possible that Liraglutide could promote GLP-1R internalization induced by a prolonged stimulation to this GLP1-RA. SNP was equipotent in Wistar treated and non-treated rats, but a loss of potency of SNP effect was observed in diabetic and treated-rats and it can be explained by the fact that diabetes promotes loss of nitrergic neurons and subsequent reduction of nitric oxide synthesis and release, so relaxation of gastric smooth muscle is inhibited. In fact, in our study, a tendency to decreased nNOS and p-nNOS expression in lysates from gastric fundus was observed in GK rat (compared to Wistar rat). Noradrenaline was less potent in Wistar and GK rats treated with Liraglutide, indicating loss of potency with the treatment. Comparing control and diabetic rats, NA was significantly less potent in GK rat, suggesting loss of potency determined by type II diabetes. Loss of potency of noradrenaline with the treatment can be related to the down-regulation of GLP-1R expression in gastric fundus from treated-rats, since GLP1-1RA can act xviii through GLP-1R and subsequent sympathetic adrenergic pathways activation. In this case, a decrease in GLP-1R expression could result in a decrease in activation of sympathetic adrenergic pathways and consequently, in inhibition of noradrenaline action. Loss of potency of NA with the pathology can be explained by a possible down-regulation of beta-adrenergic receptors in gastric fundus induced by type II diabetes and therefore, noradrenaline action would be reduced and also relaxation induced by NA. Finally, GLP-1R immunoreactivity was observed in parietal cells of gastric glands, in smooth muscle cells, in ganglion cells of nervous plexus and in endothelial cells of blood vessels, in isolated rat gastric fundus. To conclude, new studies are necessary to better understand the real contribution of nitric oxide in the action mechanism of GLP-1RA effect in gastric motility. And the use of older diabetic animals or even using another animal model of type II diabetes could help understanding gut motility alterations caused by diabetes.