Dissertations / Theses on the topic 'Beta-cell secretion'
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Flax, Helene. "Regulation of beta-cell secretion in man." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291075.
Full textStokesberry, Susan Anne. "Functional effects of temperature on pancreatic beta-cell insulin secretion and integrity." Thesis, University of Ulster, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422895.
Full textOwen, R. A. "The role of transglutaminase in stimulus-secretion coupling in the pancreatic #beta#-cell." Thesis, Nottingham Trent University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384731.
Full textEagle, Laurence Alfanso. "Regulation of Beta-cell tropin secretion from intermediate pituitary of lean and obese mice." Thesis, University of Buckingham, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.601360.
Full textHeister, Paula Maria. "The role of two pore channels (TPCs) in pancreatic beta cell stimulus-secretion coupling." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:4bed27d2-e7e4-49ff-8168-aa02b6f9b613.
Full textCastell, Auví Anna. "The effects of grape seed procyanidin extract on insulin synthesis and secretion." Doctoral thesis, Universitat Rovira i Virgili, 2012. http://hdl.handle.net/10803/79133.
Full textLes procianidines són compostos bioactius presents en fruites i vegetals. Tot i que es coneixen els efectes beneficiosos d’aquests compostos en l’homeòstasi de la glucosa, la seva acció en la funcionalitat de la cèl•lulaβ no és clara. La present tesi doctoral s’ha centrat en descriureels efectes de les procianidines en la síntesi i secreció d’insulina. Els nostres resultats mostren la capacitat de les procianidines de modificar la funcionalitat de la cèl•lula β augmentant la relació insulina plasmàtica/mRNA, tot i que l’efectivitat del tractamentdepèn de la situaciófisiològica. En situacions no patològiques, les procianidines afecten la insulinèmia modificant la síntesi, secreciói/o degradació d’insulina. En situacions de resistència a la insulina, el tractamentcrònicamb procianidines disminueix la síntesi i secreció d’insulina gràcies a la seva acció limitant l’acumulació de lípids. En canvi, en un model més danyat (obesitat genètica), les procianidines exerceixen efectes similars però no son capaces de millorar la hiperinsulinèmia. En conclusió, les procianidines, en les dosis assajades, podenutilitzar-seúnicament coma compostos bioactiuslimitant la disfuncionalitat de la cèl•lula β en els seus estats inicials.
Procyanidins are bioactive compounds found in fruits and vegetables widely consumed. It has been reported that procyanidins show some beneficial effects on glucose homeostasis, although their effects on β-cell functionality remain unresolved. This doctoral thesis is focus on describing the effects of procyanidins on insulin synthesis and secretion. Our results showed that procyanidins modify β-cell functionality through increasing the plasma insulin/mRNA ratio, although the effectiveness of the treatment depends on the physiological situation. Under non-pathological situation, procyanidins affected insulinaemia by modifying insulin synthesis, secretion and/or degradation activity. Under insulin-resistance situation, chronic procyanidins administration decreased insulin synthesis and secretion, thanks to its lipid-lowering effect. Otherwise in a more damaged model, Zucker fatty rat, procyanidins treatment is not able to reduce insulin plasma levels although they repress insulin expression. In conclusion, procyanidins could be used as bioactive compound to limit β-cell dysfunctions under high-palatable diets, but at the assayed doses, it is not enough to counteract a strong metabolic disruption.
Barutcu, Seda. "Role of JIP1-JNK Signaling in Beta-Cell Function and Autophagy." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/954.
Full textTurbitt, Julie Michelle. "The role of taurine in the regulation of insulin secretion and pancreatic beta-cell function." Thesis, University of Ulster, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422896.
Full textIdevall, Hagren Olof. "Oscillatory Signaling and Insulin Secretion from Single ß-cells." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-113686.
Full textHerrero, Rodríguez Laura. "Implication of Long-Chain Fatty Acids in Glucose-Induced Insulin Secretion in the Pancreatic Beta-Cell." Doctoral thesis, Universitat de Barcelona, 2004. http://hdl.handle.net/10803/2999.
Full textOBJECTIVES 1) Study of the malonyl-CoA/CPTI interaction in the pancreatic Beta-cell and its involvement in glucose-stimulated insulin secretion (GSIS). 2) Construction of an INS stable cell line overexpressing LCPTI wt and LCPTI M593S. 3) Determine the effect of C75 on the CPTI activity and palmitate oxidation in pancreatic Beta-cells.
RESULTS. In Ad-LCPTI M593S infected INS(832/13) cells LCPTI activity increased six-fold. This was associated with enhanced fatty acid oxidation, at any glucose concentration, and a 60% suppression of GSIS. In isolated rat islets in which LCPTI M593S was overexpressed, GSIS decreased 40%. At high glucose concentration, overexpression of LCPTI M593S reduced partitioning of exogenous palmitate into lipid esterification products, and decreased PKC activation. Moreover, LCPTI M593S expression impaired KATP channel-independent GSIS in INS(832/13) cells.
INS-1 stable clones of LCPTIwt and LCPTImut were constructed, however none of them resulted in an increase in LCPTI protein expression compared to endogenous LCPTI nor in CPTI activity. Therefore, slight basal overexpression of LCPTI could probably be toxic for the cells, as a result of which only those cells that do not contain the LCPTI plasmids survived throughout cell passages.
When INS(823/13) cells are incubated with C75, CPTI activity is inhibited, as is fatty acid oxidation. In vivo, a single intraperitoneal injection of C75 to mice produces a short-term inhibition of CPTI activity in mitochondria from liver and pancreas.
DISCUSSION. The results with LCPTImut provide direct support for the hypothesis proposing that the malonyl-CoA/CPTI interaction is a component of a metabolic signalling network that controls insulin secretion. Overall, the findings with C75 provide compelling evidence that the drug is a potent inhibitor of CPTI.
Ng, Ming Tak. "Effects of prominsulin C-peptide and other islet peptides on beta-cell function and insulin secretion." Thesis, University of Ulster, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.554231.
Full textPatterson, Steven. "Homocysteine and the effects of other amino thiols on pancreatic beta cell function and insulin secretion." Thesis, University of Ulster, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398994.
Full textWang, Xuan. "Study of the Proliferation, Function and Death of Insulin-Producing Beta-Cells in vitro: Role of the Transcription Factor ZBED6." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-223616.
Full textBando, Mika. "Studies on pathophysiological significance of intraislet ghrelin using transgenic animal model." 京都大学 (Kyoto University), 2014. http://hdl.handle.net/2433/188712.
Full textGRANCINI, VALERIA. "RUOLO CENTRALE DELLA BETA-CELLULA NEL PROMUOVERE LA REGRESSIONE DEL DIABETE DOPO TRAPIANTO DI FEGATO IN PAZIENTI CON CIRROSI EPATICA." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/658515.
Full textOtter, Silke [Verfasser], Eckhard [Akademischer Betreuer] Lammert, and Philipp A. [Gutachter] Lang. "Regulation of insulin secretion - Role of pancreatic NMDA receptors in beta cell function / Silke Otter. Betreuer: Eckhard Lammert. Gutachter: Philipp A. Lang." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2016. http://d-nb.info/1106380991/34.
Full textSantos, Gustavo Jorge 1986. "Memória metabólica de células beta pancreática controla a secreção de insulina e é mediada pela CaMKII = Metabolic memory of pancreatic beta cell controls insulin secretion and is mediated by CaMKII." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/313954.
Full textTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: Introdução: A Cálcio-Calmodulina quinase II (CaMKII) atua tanto na regulação da secreção de insulina com de neurotransmissores pela mesma via de sinalização. Além disso, a CaMKII é conhecida por ser a "molécula da memória", pois sua atividade é fundamental em sua formação. Portanto, hipotetizamos que células ß pancreática tem a capacidade de adquirir e estocar informações contidas em pulsos de cálcio, formando uma memória metabólica. Métodos: Para comprovar nossa hipótese, desenvolvemos um novo paradigma de exposição de células ? a pulsos de 30 mM de glicose, seguido de uma período de consolidação (24 hrs) para excluir qualquer efeito agudo do metabolismo da glicose. Após esse período analizamos a secreção de insulina (RIA), expressão proteica (Western blot), a resposta secretória frente a uma "rampa de glicose" e o Ca2+ citoplasmático induzido por glicose. Resultados: Células ß expostas a pulsos de glicose (30 mM) mostraram maior secreção de insulina estimulada por glucose, evidenciando a memória metabólica a qual foi totalmente dependente a CaMKII. Esse fenômeno foi refletido na expressão proteica de proteínas importantes na sinalização do cálcio e na secreção de insulina. Além disso, células expostas ao regime de pulsos de glucose apresentaram maior expressão do MAFA, um fator de transcrição chave para a função da célula ß. Conclusão: Em suma, assim como neurônios, células ß tumorais (MIN6), ilhotas de camundongos e de humanos são capazes de adquirir, estocar e evocar informações
Abstract: Backgroun: Ca2+/calmodulin-dependent protein kinase II (CaMKII) functions both in regulation of insulin secretion and neurotransmitter release through common downstream mediators. Memory is the ability to acquire, to store and to evocate any kind of information. In CNS, the process behind this phenomenon in the Long-Term Potentiation (LTP) and is known that it requires Ca2+ to occur. In additional, CaMKII is necessary to store information during LTP. In pancreatic ß-cells, CaMKII plays pivotal role during GSIS process. Therefore, we hypothesized that pancreatic ß-cells acquire and store the information contained in Ca2+ pulses as a form of "metabolic memory", just as neurons store cognitive information. Methods: To test this hypothesis, we developed a novel paradigm of pulsed exposure of mice and human ß-cells to intervals of high glucose, followed by a 24-hour consolidation period to eliminate any acute metabolic effects. After this period, we analyzed insulin secretion (by RIA), protein expression (by Western blot), response to a glucose-ramp and the glucose-induced Ca2+ influx. Results: Strikingly, ß-cells exposed to this high-glucose pulse paradigm exhibited significantly stronger insulin secretion. This metabolic memory was entirely dependent on CaMKII. We also observed, in pulse group, an increase in Ca2+ influx induced by glucose. In additional, metabolic memory was reflected on the protein level by increased expression of proteins involved in GSIS and Ca2+-dependent vesicle secretion, such as GCK, Cav1.2, SNAP25, pCaMKII and pSynapsin. Finally, we observed in human islet elevated levels of the key ß cell transcription factor MAFA. Discussion: Based on or findings we conclude that pancreatic ß cells, either from mice or humans, have the ability to acquire, store and retrieve information. This process is CaMKII-dependent and is due to modifications in the glucose-sensing machinery of the cell, since we observed an increase in GSIS and Ca2+ influx together with an increase in several proteins involved in this process. Our findings suggests that MAFA is the key effector in this memory, since (a) it is a potent activator of insulin gene, (b)is activated by CaMKII and (c) its expression is increased even 24 hours after the last pulse. Conclusion: In summary, like neurons, human and mouse ß-cells are able to acquire and retrieve information
Doutorado
Fisiologia
Doutor em Biologia Funcional e Molecular
Micheletto, Francesco. "A model of beta-cell response to GLP-1 to quantify incretin effect in healthy and prediabetic subjects." Doctoral thesis, Università degli studi di Padova, 2013. http://hdl.handle.net/11577/3422996.
Full textLa regolazione della glicemia in soggetti sani, si basa su un complesso sistema di controllo che permette di mantenere il livello di glucosio nel sangue all’interno di un range ristretto che oscilla attorno al suo valore basale. Il mal funzionamento di tale sistema è la causa di patologie metaboliche, ad esempio il diabete. Questa patologia è caratterizzata da iperglicemia cronica che, se non curata, a lungo termine comporta gravi complicanze micro e marco vascolari. Il diabete è comunemente classificato in tipo 1 e tipo 2. Entrambi derivano da complesse interazioni tra ambente e geni, e sono caratterizzati da una totale mancanza di produzione di insulina, nel tipo 1, o da una carenza da parte del pancreas nel produrre insulina in quantità sufficiente per soddisfare le necessità dell’organismo, nel tipo 2. La prevalenza del diabete è in costante aumento in tutto il mondo, così come la sua incidenza è in costante crescita negli ultimi anni. I farmaci tradizionali per la terapia del diabete di tipo 2, come l’insulina, sulfaniluree, metformina e tiazolidinedioni, riducono la glicemia attraverso diversi meccanismi di azione. Tuttavia, molti degli agenti ipoglicemizzanti assunti per via orale, perdono di efficacia con il tempo causando un progressivo deterioramento della funzionalità e riduzione della massa delle β-cellule con conseguente riduzione del controllo glicemico. Di conseguenza vi è un crescente interesse nello sviluppo di nuovi agenti terapeutici che preservino la massa e ripristino la funzionalità delle β-cellule. Uno di questi è l’ormone Glucagon-Like Peptide-1 (GLP-1), che non solo riduce la glicemia aumentando la secrezione di insulina, ma agisce anche nel signaling nelle isole di Langherans stimolando la proliferazione e la neo-genesi delle β-cellule e inibendone l’apoptosi. La ridotta secrezione di insulina e la mancata soppressione del glucagone inducono ad ipotizzare che la diminuita risposata delle β-cellule al GLP-1 possa essere parte della patogenesi del diabete di tipo 2. Pertanto la capacità di misurare l’effetto del GLP-1 sulla secrezione dell’insulina è utile per studiare la patogenesi della malattia ed ottimizzare valutare l’efficacia delle terapie basate sul GLP-1. Infatti è cruciale determinare quali soggetti possono beneficiare maggiormente di tale terapia per ottimizzare le risorse. Tuttavia, non è ancora disponibile un modello che descriva l’azione del GLP-1 sulla secrezione di insulina e permetta di quantificarne l’entità. In questo lavoro viene proposto un modello matematico che descrive i meccanismi di azione del GLP-1 sulla secrezione di insulina, fornendo una misura diretta dell’aumento della secrezione dell’insulina dovuto all’effetto del GLP-1. Sono stati utilizzati tre database per sviluppare, testare e validare i modelli proposti. I dati di 88 soggetti sani sottoposti ad un clamp iperglicemico con contemporanea infusione intravenosa di GLP-1, sono stati utilizzati per lo sviluppo del modello. Sono stati testati una serie di modelli dell’azione del GLP-1 sulla secrezione di insulina di complessità crescente. Tutti i modelli si basano sulla comune assunzione che la secrezione di insulina è costituita da due componenti, una proporzionale alla concentrazione ed una alla velocità di variazione del glucosio plasmatico, modulate rispettivamente dalla responsività statica Φs e dalla responsività dinamica Φd. Ogni modello differisce dagli altri nella descrizione della modalità di azione del GLP-1. Per ciascun modello è stato derivato un indice di potenziamento, П, che rappresenta l’aumento percentuale della secrezione di insulina dovuta ad 1 pmol/l di GLP-1. I modelli predicono bene i dati (infatti il run test conferma la casualità dei residui nel 70% dei soggetti) e forniscono stime precise dei parametri . La selezione del modello ottimo è stata affrontata confrontando le prestazioni dei modelli sulla base di criteri standard (capacità di descrivere i dati, la precisione della stima dei parametri, la parsimonia, la casualità dei residui). Il modello più parsimonioso ipotizza che la secrezione sopra basale di insulina dipenda linearmente sia dalla concentrazione di GLP-1 sia dalla sua variazione. Tuttavia le condizioni sperimentali di tale protocollo non sono fisiologiche e applicabili su larga scala. Pertanto, i dati di 22 soggetti IFG (Impaired Fasting Glucose), studiati due volte con un pasto misto, sono stati utilizzati per testare il modello in una condizione sperimentale più vicina alla fisiologia. I risultati dimostrano che per descrivere i dati di un test orale, è sufficiente un modello più semplice. La validazione del modello è stata effettuata sia in simulazione sia utilizzando i dati reali di 10 soggetti, studiati due volte: una prima volta utilizzando un test orale di tolleranza al glucosio (OGTT) e successivamente un test intravenoso di tolleranza al glucosio durante il quale il glucosio è stato infuso in modo tale da riprodurre la glicemia osservata durante l’OGTT. Questo protocollo permette di calcolare un indice di potenziamento (PI) modello-indipendente dal confronto tra la secrezione di insulina stimata nelle due occasioni. Il confronto tra il potenziamento stimato con il modello, П, e l’indice di potenziamento PI mostra che i due indici sono molto simili (П = 6.55, CV = 65%; PI = 6.15 % per pmol/l). Inoltre nel 93 ± 1% delle simulazioni effettuate il modello è in grado di quantificare correttamente l’effetto del GLP-1 sulla secrezione di insulina.
Cohrs, Christian M., Julia K. Panzer, Denise M. Drotar, Stephen J. Enos, Nicole Kipke, Chunguang Chen, Robert Bozsak, et al. "Dysfunction of Persisting β Cells Is a Key Feature of Early Type 2 Diabetes Pathogenesis." Elsevier, 2020. https://tud.qucosa.de/id/qucosa%3A73294.
Full textXie, Lanyi. "Population pharmacokinetic/pharmacodynamic modeling of insulin kinetics." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/2791.
Full textOliveira, Ricardo Beltrame de. "Proliferação e disfunção da célula beta pancreática em modelo animal de Diabetes Melito tipo 2. Envolvimento da via de sinalização WNT/Beta-Catenina." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317134.
Full textDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: Tem havido um grande interesse na determinação das vias envolvidas na proliferação e função/disfunção da célula beta e a aplicação deste conhecimento em terapias moleculares e celulares da diabetes. A patogênese da diabetes melito tipo 2 (T2DM) é complexa, mas frequentemente está associada com obesidade e distúrbios do metabolismo de lipídios (hipercolesterolemia e hipertrigliceridemia). A T2DM envolve o desenvolvimento de um quadro de resistência periférica à insulina parcialmente compensada por hiperinsulinemia e hiperplasia da célula beta pancreática, resultando em intolerância à glicose e hiperglicemia. Os mecanismos interligando os estados de obesidade/hipercolesterolemia e resistência à insulina ao fenômeno da hiperplasia da célula beta não são completamente conhecidos. A presente dissertação teve como objetivos: 1) caracterizar um modelo animal adequado para se estudar a proliferação e disfunção da célula beta pancreática, e 2) avaliar, no pâncreas endócrino desses animais, a possível ativação da via de sinalização Wnt/beta-catenina, conhecida por estar envolvida no processo de proliferação celular em outros tecidos/órgãos. Para tal, foram empregados camundongos C57BL/6, wild-type (WT) e knockout para receptor de lipoproteína LDL (LDLr-/-), os quais foram submetidos à dieta hiperlipídica (HF) por 60 dias. Após a dieta HF, os animais WT tornaram-se obesos e hipercolesterolêmicos, bem como moderadamente hiperglicêmicos, hiperinsulinêmicos, intolerantes à glicose e resistentes à insulina, caracterizando-os como pré-diabéticos. Além disso, os animais alimentados com dieta HF apresentaram uma diminuição significativa na resposta secretora das células beta à glicose. De modo geral, os animais LDLr-/- apresentaram uma susceptibilidade relativamente mais alta à dieta HF, sugerida pela acentuada hipercolesterolemia, intolerância à glicose, e reduzida secreção de insulina estimulada por glicose observadas nestes animais. No entanto, a dieta HF induziu, de forma semelhante em animais WT e LDLr-/-, uma diminuição significativa no conteúdo celular de Cx36, uma proteína associada à junção comunicante e um marcador de diferenciação terminal da célula beta. Ambos os grupos WT e LDLr-/- alimentados com dieta HF mostraram aumento na proliferação de células beta, como avaliada pela imunomarcação das ilhotas para a proteína Ki67, mas apenas os animais WT exibiram alterações morfométricas indicativas de hiperplasia do pâncreas endócrino, tais como aumento na massa total de ilhotas e de células beta. Uma vez estabelecido que camundongos WT alimentados com dieta HF por 60 dias consistiam em um modelo adequado para a segunda etapa deste estudo, fomos investigar a possível ativação da via Wnt/beta-catenina nas ilhotas pancreáticas desses animais, avaliando-se a distribuição e expressão celular das proteínas beta-catenina total, beta-catenina ativada, c-Myc e ciclina D. A análise por imunofluorescência para beta-catenina não mostrou acúmulo citoplasmático ou translocação para o núcleo desta proteína em ilhotas pancreáticas, que poderia indicar ativação da via Wnt/beta-catenina no nosso modelo de hiperplasia do pâncreas endócrino. No entanto, a análise por Western Blot revelou um aumento significativo na expressão de beta-catenina ativada e ciclina D em ilhotas de animais alimentados com dieta HF em relação ao grupo controle. Concluindo, a dieta HF por 60 dias induz alterações metabólicas típicas da pré-diabetes em animais WT e LDLr-/-. O estado de pré-diabetes está associado a uma diminuição da expressão de Cx36 nas células beta pancreáticas, sugerindo um possível papel da comunicação intercelular mediada pelas junções comunicantes na patogênese da T2DM. A maior susceptibilidade metabólica à dieta HF apresentada por camundongos LDLr-/-, em relação aos WT, pode ser explicada pela maior deficiência na secreção de insulina em resposta à glicose e ausência de hiperplasia compensatória do pâncreas endócrino. Ainda, a análise preliminar de expressão protéica de algumas proteínas da via Wnt/beta-catenina sugere que esta via parece estar ativada durante o processo de hiperplasia do pâncreas endócrino observada no nosso modelo animal
Abstract: The pathogenesis of type 2 diabetes mellitus (T2DM) is often associated with obesity and dyslipidemia (hypercholesterolemia and hypertriglyceridemia). T2DM involves intolerance to glucose and insulin resistance partially compensated by hyperinsulinemia and pancreatic beta cell hyperplasia. The mechanisms linking obesity/hypercholesterolemia and insulin resistance to beta cell hyperplasia are not fully known. The Wnt/beta-catenin signaling pathway has been reported to be involved in cell growth and differentiation in several tissues/organs but its role in endocrine pancreas development and function is still unclear. This work aimed at: 1) establishing an appropriate animal model of T2DM to study pancreatic beta cell proliferation and dysfunction and, 2) investigating a putative involvement of the Wnt/beta-catenin signaling pathway in the beta cell hyperplasia in this model. To this end, we employed C57BL/6 wild-type (WT) and LDL lipoprotein receptor knockout (LDLr-/-) mice, fed a high fat (HF) diet for 60 days. After feeding a HF diet, WT mice became obese, hypercholesterolemic and moderately hyperglycemic, hyperinsulinemic, glucose intolerant and insulin resistant, characterizing them as pre-diabetics. Moreover, animals fed a HF diet showed a significant decrease in beta-cell secretory response to glucose. In general, LDLr-/- animals showed a relatively higher susceptibility to HF diet, as suggested by a marked hypercholesterolemia, glucose intolerance and reduced insulin secretion stimulated by glucose observed in these animals as compared to the control ones. However, HF diet induced similarly in both WT and LDLr-/- mice a significant decrease in cellular content of Cx36, a gap junctional protein and marker of terminally differentiated beta cell. Both WT and LDLr-/- fed a HF diet showed increased proliferation of beta cells, as assessed by Ki67 immunostaining, but only WT mice exhibited morphometric changes indicative of endocrine pancreas hyperplasia, such as increased total islet and beta cell masses. After we investigated a possible activation of Wnt/beta-catenin signaling pathway in these hyperplasic pancreatic islets of WT animals fed a HF diet. This was done by assessing the distribution and cellular protein expression of some proteins associated to this pathway (i.e., total and activated beta-catenin, c-Myc and cyclin D) in islets of our animal model. Beta-catenin immunofluorescence showed no cytoplasmic accumulation or translocation into the nucleus of beta cells in HF-fed mice. However, immunoblotting revealed a significant increase of unphosphorylated beta-catenin (activated) and cyclin D expression in islets of HF diet-fed animals when compared to its control group. In conclusion, a HF diet for 60d induced pre-diabetes state in both WT and LDLr-/- mice. The pre-diabetes state is associated with a decreased expression of Cx36 in pancreatic beta cells, suggesting a possible role of intercellular communication mediated by gap junctions in the pathogenesis of T2DM. The relatively high metabolic susceptibility to the HF diet showed by LDLr-/- mice, as compared to WT, may be explained by a marked impairment of glucosestimulated insulin secretion and a lack of compensatory hyperplasia of the endocrine pancreas. In addition, the protein expression analysis suggests that the Wnt/beta-catenin pathway may be activated during the islet hyperplasia process in our animal model
Mestrado
Histologia
Mestre em Biologia Celular e Estrutural
Solimena, Michele, Anke M. Schulte, Lorella Marselli, Florian Ehehalt, Daniela Richter, Manuela Kleeberg, Hassan Mziaut, et al. "Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes." Springer, 2017. https://tud.qucosa.de/id/qucosa%3A33350.
Full textTomita, Tsutomu. "Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumours in humans : evidence for GPR40 expression in pancreatic beta cells and implications for insulin secretion." Kyoto University, 2006. http://hdl.handle.net/2433/135624.
Full textSantos-Silva, Junia Carolina Rebelo 1983. "Expressão e distribuição celular de proteínas associadas às junções intercelulares no pâncreas endócrino durante o desenvolvimento animal e na diabetes tipo 2." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317145.
Full textDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: As junções intercelulares são especializações da membrana plasmática através das quais células dentro de um tecido podem interagir e aderirem-se umas às outras. Nas ilhotas pancreáticas, as diferentes células endócrinas se interconectam por meio das junções de oclusão, comunicante, aderente e desmossomos. Tais contatos intercelulares parecem ser cruciais para o perfeito funcionamento deste órgão, porém, pouco se sabe sobre a função fisiopatológica e composição das junções intercelulares no pâncreas endócrino. O objetivo geral desta dissertação foi estudar a importância funcional da adesão e reconhecimento celular mediados pelas junções de oclusão (JO) e de adesão (JA) nos processos de maturação e disfunção da célula beta do pâncreas endócrino, ao longo do desenvolvimento do animal e na patogênese da diabetes tipo 2, respectivamente. Nossos dados mostram que as ilhotas de fetos e recém-nascidos de ratos Wistar, cuja resposta secretora de insulina à glicose é significativamente menor, apresentam uma morfologia menos organizada, caracterizada por um formato menos definido e uma associação mais freqüente com ductos, quando comparadas às ilhotas de jovens e adultos, que são responsivas à esse secretagogo. Na ausência de contato intercelular, quando as células das ilhotas de adultos foram dispersas, a resposta secretora de insulina foi completamente inibida, porém parcialmente restabelecida quando as células foram reagregadas. Quando comparado às ilhotas de adultos, o impacto da ausência de contatos intercelulares sobre a resposta secretora de insulina à glicose foi consideravelmente menor no caso das ilhotas de ratos recém-nascidos. A imunofluorescência para NCAM e pan-caderina revelou uma distribuição diferencial destas moléculas de adesão somente nas células das ilhotas pancreáticas de jovens e adultos, o que pode estar relacionada com a citoarquitetura típica (células beta, ocupando a região central e os outros tipos celulares na periferia da ilhota) adquirida no período pré-natal. Das proteínas associadas à JA e JO estudadas, ?- e ?-cateninas e ZO-1 (mas não a ocludina) foram expressas nas células endócrinas das ilhotas de todos os grupos experimentais. De forma geral, a imunofluorescência para tais proteínas revelou uma marcação intercelular menos definida nas células beta de ilhotas de recém-nascidos e fetos em comparação com os animais jovens e adultos. Isto pode indicar uma menor interação/adesão celular, que por sua vez, pode estar relacionada com a resposta secretora deficitária de insulina das ilhotas pancreáticas verificada na fase perinatal. Como modelo de diabetes do tipo 2, utilizamos camundongos C57, machos, alimentados com dieta hiperlipídica por 8 meses desde os 21 dias de idade. Após este período em dieta, os animais tornaram-se obesos e pré-diabéticos, apresentando moderada hiperglicemia e significativa hiperinsulinemia ao final desta dieta. Não observamos diferenças morfológicas marcantes entre os grupos e nem alterações significativas na distribuição intercelular da ZO-1, ?- e ?-cateninas nas ilhotas do grupo tratado em comparação ao grupo controle. Entretanto, verificou-se uma maior marcação intercelular para Ecaderina e uma maior associação de F-actina à membrana na região de contato intercelular nas células endócrinas das ilhotas do grupo pré-diabético em relação ao controle. Em conclusão, os contatos intercelulares mediados pelas proteínas associadas à JA e à JO parecem desempenhar um papel no processo de maturação do pâncreas do endócrino durante o desenvolvimento animal e na patogênese da diabetes do tipo 2
Abstract: Intercellular junctions are specializations of the plasma membrane that allow cells within a tissue to interact and adhere to each other. In endocrine pancreas, the different endocrine cells are interconnected by tight, gap and adherens-type junctions. Such intercellular contacts seem to be crucial for the function of this organ, however, little is known about the pathophysiological role and biochemistry of intercellular junctions in the endocrine pancreas. The aim of this thesis was to study the importance of cell-cell recognition and adhesion mediated by proteins associated to tight and adherens junctions in pancreatic islets, with emphasis on the process of insulin secretion, along the animal development and in pathogenesis of type 2 diabetes. Pancreatic islets of foetuses (F) and newborn (N) Wistar rats, that display a relatively poor insulin secretory response to glucose, present an immature morphology and a less defined cytoarchitecture when compared to islets from young (Y) and adult (A) rats, that are responsive to glucose. The immunofluorescence for N-CAM and pan-cadherin, adhesion molecules that are important in cell segregation, revealed a differential distribution of these proteins only in cells of the islets from Y and A. A lower junctional content of ?-and ?-catenins and ZO-1 in islet cells was seen in F and N in comparison with Y and A. In addition, we found that in the absence of intercellular contact, the glucose-stimulated insulin secretion was completely blocked in A islets. In contrast, the impact of the disruption of cell-cell adhesion on insulin secretory response of N islets was relatively small. As a model of type 2 diabetes, we employed male C57 mice, fed on high-fat (HF) diet for 8 months since they were 21 days old. After HF diet, these mice became obese and pre-diabetic (displaying moderate hyperglycemia and marked hyperinsulinaemia). We did not observe marked differences either in morphology either in the intercellular distribution of ZO-1, ?- and ?-catenins in islets between the HF-treated and control groups. However, there was a stronger immunoreaction for Ecadherin at the cell-cell contact site and an increased association of F-actin to the plasma membrane of islet endocrine cells from pre-diabetic mice as compared to control ones. In conclusion, the intercellular contacts mediated by adherens and tight junction and their constitutive proteins seem to play a role in the developmental maturation of the endocrine pancreas and in the pathogenesis of type 2 diabetes
Mestrado
Histologia
Mestre em Biologia Celular e Estrutural
Bardy, Guillaume. "Effets insulino-sécrétoires et protecteurs de la quercétine au niveau de la cellule beta pancréatique : implication du calcium intracellulaire et de ERK1/2." Thesis, Montpellier 1, 2012. http://www.theses.fr/2012MON13515/document.
Full textIn type 2 diabetes, chronic hyperglycaemia, elevated free fatty acids and inflammation induce oxidative stress (OS) in pancreatic β cell. SO, which appears at the stage of pre-diabetes, may induce early dysfunction of this cell. Thus, the β cell protection by antioxidant molecules could slow the progression of pre-diabetes to diabetes.Quercetin, a flavonoid, has shown antidiabetic properties in several in vivo studies. However, very few data address its mechanism of action directly at the β cell. In this context, we studied the effects of quercetin at the β cell under physiological conditions and conditions of OS.Our results show that in the presence of stimulating concentrations of secretagogue, quercetin potentiates insulin secretion by a mechanism involving increased intracellular calcium and potentiation of ERK1 / 2 via activation of the PKA and the CaMK II pathways. In addition, quercetin protects beta cell from OS via a suractivation of ERK1/2. Resveratrol and NAC, two antioxidants of reference are inactive under these experimental conditions.In the absence of stimulating concentration of secretagogue, quercetin induced moderate insulin secretion by increasing the intracellular calcium via a direct activation of L-type CaV Under these conditions, the activation of ERK1/2 induced by quercetin, which is independent of the activation pathways of PKA and CaMK II to, would not be involved in the secretory mechanism.Our results indicate that the mechanism of action of quercetin at the β cell not only based on its antioxidant capacity but involves pharmacological targets and the regulation of intracellular signaling pathways
Amouyal, Chloé. "Restaurer la fonction bêta pancréatique de la souris leptine déficiente par la chirurgie bariatrique." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS010.
Full textEGA (entero-gastro-anastomosis) is a gastric bypass procedure adapted to rodent. EGA in leptin deficient ob/ob mice improves glucose tolerance by increasing pancreatic insulin content and glucose stimulated insulin secretion in vivo without persistent body weight loss dietary restriction, modification of body composition / energy expenditure. We do not observe differences in islets ‘number or size after EGA. Insulin gene expression, beta-cell proliferation (Ki67 index) and insular immune infiltration are also unchanged. Transcriptomic analysis of pancreatic islets showed that bariatric surgery differentially regulated 193 genes and 27 miRs. Interestingly, the surgery normalized molecular defects (down regulation of TRPM5, GLUT2, GCK, connexin 36) and functional alteration (high sensitivity of islets to low glucose levels) observed in diabetic ob pancreatic islets. In addition, the surgery promoted the enrichment of 227 biological process, composed of genes with known or undetermined beta cell function, especially 21 genes are involved in the hormone transport and 20 genes in the hormone secretion biological process. Computational analysis predicted that 7 of 27 miRs (324-3p, 380-3p, 671-5p, 1927, 6904-5p, 6918-5p and 7682-3p) are hubs in the miRs-gene interaction network. Altogether, our data highlighted novel molecular mechanisms in the resolution of diabetes after bariatric surgery. Overall, diabetes resolution in our model appears to be totally independent of body weight
Papas, Klearchos Kyriacos. "Bioenergetics, metabolism, and secretion of immunoisolated endocrine cell preparations." Thesis, Georgia Institute of Technology, 1996. http://hdl.handle.net/1853/11001.
Full textMezghenna, Karima. "No synthase neuronale pancréatique et musculaire dans la pathogénie des états prédiabétiques." Thesis, Montpellier 1, 2010. http://www.theses.fr/2010MON13503.
Full textType 2 diabetes is a chronic disorder defined by chronic hyperglycemia resulting from a deficiency of insulin secretion and an insulin resistance in peripheral tissues and liver. A long lasting silent phase, called prediabetes, precedes the disease and in which pancreatic ß cell is able to improve insulin secretion to compensate for the insulin resistance. The pancreatic and muscular neuronal nitric oxide synthases (nNOS) control respectively glucose-induced insulin secretion in pancreatic ß cell and glucose uptake and utilization in myocytes. In the genetic model of obese Zucker fa/fa rat mimicking the prediabetic state characterized by hyperinsulinemia and insulin resistance, we found a high increase in the amount of the complex between nNOS and its endogenous inhibitor PIN (Protein Inhibitor of Neuronal NOS) at the level of insulin secretory granules within the ß cell. This complex, through an increased interaction with myosin V, participates in the secretory hyperactivity of the pancreatic ß cell, observed in this model of prediabetes. Indeed, molecules that specifically inhibit nNOS-PIN interaction allow to restore a normal insulin secretion in fa/fa rat. In skeletal muscle of this model, we observed a decreased expression of nNOS protein with no change in mRNA levels, suggesting an increased proteolysis of the protein. Inhibition of proteasomal degradation restores the expression and the catalytic activity of nNOS in skeletal muscle. Thus, this loss of functionality of the enzyme could participate in the installation of insulin resistance. This work therefore validated nNOS as a potential target for the prevention of type 2 diabetes
Debuyser, Anne. "Etude du controle noradrenergique de la cellule beta du pancreas de souris par des techniques electrophysiologique, radioimmunologique et radioisotopiques." Poitiers, 1988. http://www.theses.fr/1988POIT2324.
Full textLOCATELLI, LUIGI. "Expression of aVB6 integrin by Pkhd1-defective cholangiocytes links enhanced ductal secretion of Macrophage chemokines to progressive portal fibrosis in Congenital Hepatic Fibrosis." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/41733.
Full textSchisler, Jonathan Cummings. "New roles of the transcription factor NKX6.1 in beta cell biology." Access to abstract only; dissertation is embargoed until after 5/15/2007, 2006. http://www4.utsouthwestern.edu/library/ETD/etdDetails.cfm?etdID=164.
Full textHolmberg, Hanna. "Autoantibodies as markers of beta-cell autoimmunity in children." Doctoral thesis, Linköping : Univ, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-7092.
Full textMasserini, B. "ANALISI DEL METABOLISMO GLUCIDICO IN PAZIENTI CIRROTICI SOTTOPOSTI A TRAPIANTO EPATICO: RUOLO DELLA SECREZIONE BETA CELLULARE E DELL'INSULINORESISTENZA." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/246332.
Full textMakeeva, Natalia. "Role of MAP Kinases in the Life and Death of Beta-cells." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6317.
Full textGuo, Hong. "Investigation of the cellular and molecular characteristics of four novel human insulin-secreting beta cell lines in vitro and in vivo." Thesis, University of Ulster, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.494356.
Full textLiu, Hui-Kang. "Modification of the function of insulin-secreting cells by beta-cell toxins, differentiation drugs, insulin mimetics, steroids, and incretic hormones and their stable analogues." Thesis, University of Ulster, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399055.
Full textO'Sullivan-Murphy, Bryan M. "Contribution of WFS1 to Pancreatic Beta Cell Survival and Adaptive Alterations in WFS1 Deficiency: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/590.
Full textSelander, Lars. "In vivo and in vitro approaches to induce beta cells from stem and progenitor cells." Doctoral thesis, Umeå : Umeå University, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-25813.
Full textSchubert, Sandra. "The Role of [beta]2-Syntrophin Phosphorylation in Secretory Granule Exocytosis." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2006. http://nbn-resolving.de/urn:nbn:de:swb:14-1146851994562-42414.
Full textDer Transport Insulin-gefüllter sekretorische Granula(SG) ist ein streng kontrollierter komplexer Prozess.Es gibt vermehrt Beweise,dass das kortikale Actinzytoskelett die Ausschüttung der SGs beeinflusst.Bisher ist der Mechanismus der Verankerung von SGs am Zytoskelett noch nicht vollständig aufgeklärt.Ort et al.(2000,2001) haben gezeigt,daß der zytosoplasmatische Teil des trans-membranen SG-Proteins ICA512 mit der PDZ-Domäne von b2-Syntrophin interagiert.Dieses Protein bindet das F-Actin-Bindeprotein Utrophin.Die Ergebnisse zeigen außerdem,daß durch Stimulation der SG-Exozytose der Phosphorilierungsstatus von b2-Syntrophin beeinflusst wird,woraus ein verändertes Bindungsvermögen zu ICA512 resultiert.Es wurde ein Funktionsmodel vorgestellt,in dem sich SGs durch die Interaktion des ICA512/b2-Syntrophin Komplexes an das Actinzytoskelett binden.Dabei wird die Bindedynamik durch Phosphorilierung reguliert.Um dieses Model zu etablieren,wurden stabile GFP-b2-Syntrophin produzierende INS-1-Zellklone erzeugt.Die zelluläre Lokalisation und das Expressionsmuster von GFP-b2-Syntrophin stimmen mit dem des endogenen Proteins überein.Elektronenmikroskopie zeigte eine größe Anzahl oval-verformter SGs in GFP-b2-Syntrophin INS-1-Zellen im Vergleich zu Kontrollzellen.Verglichen mit nicht-transfizierten INS-1 Zellen waren in drei GFP-b2-Syntrophin INS-1-Zellklonen der Insulingehalt der Zellen und die stimulierte Insulinsekretion erhöht.Die Werte korrelierten mit den unterschiedlichen GFP-b2-Syntrophin Expressionsmengen der Klone.Diese Ergebnisse untermauern die Hypothese,daß b2-Syntrophin den Transport und die Sekretion der SGs durch Modulation ihres Bindevermögens an Actin reguliert.Um das postulierte Model genauer zu prüfen,wurde die Phosphorilierung von b2-Syntrophin detaillierter untersucht.Das GFP-Protein wurde,ähnlich dem endogenen b2-Syntrophin,durch Stimulation der Insulinausschüttung dephosphoriliert.Diese Dephosphorilierung ist Ca2+-abhängig und Okadeinsäuresensitiv.Die stimulationsabhängige Dephosphorilierung wurde durch Immunoprezipitation von 32P-markiertem GFP-b2-Syntrophin bestätigt.Massenspektrometrie des präzipitierten Proteins ermöglichte die Identifikation von vier Serin-Phosphorilierungsstellen(S75,S90,S213,S373),welche die Bindung zu ICA512 beeinflussen könnten.Mutanten,in denen die vier Phosphoserine durch Asp beziehungsweise Ala ersetzt wurden,um entweder eine Phosphorilierung(S/D) oder Dephosphorilierung(S/A) nachzuahmen,wurden in INS-1-Zellen exprimiert.Alle S/D Mutanten blieben kortikal lokalisiert.Das Expressionsmuster des S75D Allels unterschied sich jedoch von denen des Wild-Typs(wt).Im Gegensatz dazu waren alle S/A Allele zytosolisch verteilt.Eine Ausnahme bildete S213A,das an der Zellkortex lokalisiert blieb.Im Vergleich zu wt b2-Syntrophin zeigten PullDown-Assays eine erhöhte Bindung von ICA512 zu den S75A und S90D Allelen.Das Gegenteil konnte für die S75D und S90A Mutanten nachgewiesen werden.S75,S90 und S213 sind in einer Konsensussequenz für Cdk5-Phosphorilierung enthalten.Diese Kinase kann die Insulinsekretion regulieren.Die Phosphorilierung von b2-Syntrophin,insbesondere des S75 Allels durch Cdk5 wurde durch pharmakologische Inhibitoren,in vitro-Phosphorilierung und RNAi demonstriert.Zusammenfassend stimmen diese Erkenntnisse mit dem Model überein,daß die Phosphorilierung von b2-Syntrophin die Vernetzung von SGs mit Actin und dadurch deren Mobilität und Exozytose moduliert.Im Speziellen postulieren die Ergebnisse dieser Arbeit eine Cdk5-abhängige Phosphorilierung der S75 Stelle des b2-Syntrophins.Durch eine verminderte Interaktion von b2-Syntrophin und ICA512 erleichtert diese Mutante vermutlich die Insulinsekretion,da der Einfluss des Actinzytoskeletts auf die Granulamobilität vermindert ist.Dieser Prozess ereignet sich möglicherweise in Kombination mit einer Dephosphorilierung des b2-Syntrophins.in Kombination mit einer Dephosphorilierung des b2-Syntrophins
Schubert, Sandra. "The Role of [beta]2-Syntrophin Phosphorylation in Secretory Granule Exocytosis." Doctoral thesis, Technische Universität Dresden, 2005. https://tud.qucosa.de/id/qucosa%3A23710.
Full textDer Transport Insulin-gefüllter sekretorische Granula(SG) ist ein streng kontrollierter komplexer Prozess.Es gibt vermehrt Beweise,dass das kortikale Actinzytoskelett die Ausschüttung der SGs beeinflusst.Bisher ist der Mechanismus der Verankerung von SGs am Zytoskelett noch nicht vollständig aufgeklärt.Ort et al.(2000,2001) haben gezeigt,daß der zytosoplasmatische Teil des trans-membranen SG-Proteins ICA512 mit der PDZ-Domäne von b2-Syntrophin interagiert.Dieses Protein bindet das F-Actin-Bindeprotein Utrophin.Die Ergebnisse zeigen außerdem,daß durch Stimulation der SG-Exozytose der Phosphorilierungsstatus von b2-Syntrophin beeinflusst wird,woraus ein verändertes Bindungsvermögen zu ICA512 resultiert.Es wurde ein Funktionsmodel vorgestellt,in dem sich SGs durch die Interaktion des ICA512/b2-Syntrophin Komplexes an das Actinzytoskelett binden.Dabei wird die Bindedynamik durch Phosphorilierung reguliert.Um dieses Model zu etablieren,wurden stabile GFP-b2-Syntrophin produzierende INS-1-Zellklone erzeugt.Die zelluläre Lokalisation und das Expressionsmuster von GFP-b2-Syntrophin stimmen mit dem des endogenen Proteins überein.Elektronenmikroskopie zeigte eine größe Anzahl oval-verformter SGs in GFP-b2-Syntrophin INS-1-Zellen im Vergleich zu Kontrollzellen.Verglichen mit nicht-transfizierten INS-1 Zellen waren in drei GFP-b2-Syntrophin INS-1-Zellklonen der Insulingehalt der Zellen und die stimulierte Insulinsekretion erhöht.Die Werte korrelierten mit den unterschiedlichen GFP-b2-Syntrophin Expressionsmengen der Klone.Diese Ergebnisse untermauern die Hypothese,daß b2-Syntrophin den Transport und die Sekretion der SGs durch Modulation ihres Bindevermögens an Actin reguliert.Um das postulierte Model genauer zu prüfen,wurde die Phosphorilierung von b2-Syntrophin detaillierter untersucht.Das GFP-Protein wurde,ähnlich dem endogenen b2-Syntrophin,durch Stimulation der Insulinausschüttung dephosphoriliert.Diese Dephosphorilierung ist Ca2+-abhängig und Okadeinsäuresensitiv.Die stimulationsabhängige Dephosphorilierung wurde durch Immunoprezipitation von 32P-markiertem GFP-b2-Syntrophin bestätigt.Massenspektrometrie des präzipitierten Proteins ermöglichte die Identifikation von vier Serin-Phosphorilierungsstellen(S75,S90,S213,S373),welche die Bindung zu ICA512 beeinflussen könnten.Mutanten,in denen die vier Phosphoserine durch Asp beziehungsweise Ala ersetzt wurden,um entweder eine Phosphorilierung(S/D) oder Dephosphorilierung(S/A) nachzuahmen,wurden in INS-1-Zellen exprimiert.Alle S/D Mutanten blieben kortikal lokalisiert.Das Expressionsmuster des S75D Allels unterschied sich jedoch von denen des Wild-Typs(wt).Im Gegensatz dazu waren alle S/A Allele zytosolisch verteilt.Eine Ausnahme bildete S213A,das an der Zellkortex lokalisiert blieb.Im Vergleich zu wt b2-Syntrophin zeigten PullDown-Assays eine erhöhte Bindung von ICA512 zu den S75A und S90D Allelen.Das Gegenteil konnte für die S75D und S90A Mutanten nachgewiesen werden.S75,S90 und S213 sind in einer Konsensussequenz für Cdk5-Phosphorilierung enthalten.Diese Kinase kann die Insulinsekretion regulieren.Die Phosphorilierung von b2-Syntrophin,insbesondere des S75 Allels durch Cdk5 wurde durch pharmakologische Inhibitoren,in vitro-Phosphorilierung und RNAi demonstriert.Zusammenfassend stimmen diese Erkenntnisse mit dem Model überein,daß die Phosphorilierung von b2-Syntrophin die Vernetzung von SGs mit Actin und dadurch deren Mobilität und Exozytose moduliert.Im Speziellen postulieren die Ergebnisse dieser Arbeit eine Cdk5-abhängige Phosphorilierung der S75 Stelle des b2-Syntrophins.Durch eine verminderte Interaktion von b2-Syntrophin und ICA512 erleichtert diese Mutante vermutlich die Insulinsekretion,da der Einfluss des Actinzytoskeletts auf die Granulamobilität vermindert ist.Dieser Prozess ereignet sich möglicherweise in Kombination mit einer Dephosphorilierung des b2-Syntrophins.in Kombination mit einer Dephosphorilierung des b2-Syntrophins.
Aslamy, Arianne. "DOC2B enhancement of beta cell function and survival." Diss., 2018. https://doi.org/10.7912/C25W7M.
Full textDiabetes mellitus is a complex metabolic disease that currently affects an estimated 422 million people worldwide, with incidence rates rising annually. Type 1 diabetes (T1D) accounts for 5-10% of these cases. Its complications remain a major cause of global deaths. T1D is characterized by autoimmune destruction of β-cell mass. Efforts to preserve and protect β-cell mass in the preclinical stages of T1D are limited by few blood-borne biomarkers of β-cell destruction. In healthy β-cells, insulin secretion requires soluble n-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE) complexes and associated accessory regulatory proteins to promote the docking and fusion of insulin vesicles at the plasma membrane. Two target membrane (t)-SNARE proteins, Syntaxin 1/4 and SNAP25/23, and one vesicle-associated (v)-SNARE protein, VAMP2, constitute the SNARE core complex. SNARE complex assembly is also facilitated by the regulatory protein, Double C2-domain protein β (DOC2B). I hypothesized that DOC2B deficiency may underlie β-cell susceptibility to T1D damage; conversely , overexpression of DOC2B may protect β-cell mass. Indeed, with regard to DOC2B abundance, my studies show reduced levels of DOC2B in platelets and islets of prediabetic rodents and new-onset T1D humans. Remarkably, clinical islet transplantation in T1D humans restores platelet DOC2B levels, indicating a correlation With regard to protection/functional effects, DOC2B deficiency enhances susceptibility to T1D in mice, while overexpression of DOC2B selectively in β-cells protects mice from chemically induced T1D; this correlates with preservation of functional β-cell mass. Mechanistically, overexpression of DOC2B and the DOC2B peptide, C2AB, protects clonal β-cell against cytokine or thapsigargin-induced apoptosis and reduces ER stress; this is dependent on C2AB’s calcium binding capacity. C2AB is sufficient to enhance glucose stimulated insulin secretion (GSIS) and SNARE activation in clonal β-cells to the same extent as full-length DOC2B. In summary, these studies identify DOC2B as a potential biomarker and novel therapeutic target for prevention/management of T1D.
Joseph, Jamie W. "Beta-cell stimulus-secretion coupling : a role for uncoupling protein 2." 2004. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=94794&T=F.
Full textXia, Fuzhen. "Lipid Rafts in Pancreatic Beta- and Alpha-cell Stimulus-secretion Coupling." Thesis, 2008. http://hdl.handle.net/1807/17314.
Full textKoo, Ellen. "Syntaxin-3 Regulates Biphasic Glucose Stimulated Insulin Secretion in the Pancreatic Beta Cell." Thesis, 2010. http://hdl.handle.net/1807/25732.
Full textErion, Karel Arnt. "Nutrient regulation of insulin secretion: implications for hyperinsulinemia." Thesis, 2016. https://hdl.handle.net/2144/16726.
Full text2018-06-15T00:00:00Z
Allen, Ronald Wayne. "Fatty acid required for glucose-induced change in beta cell plasma membrane potential leading to insulin secretion." Thesis, 2019. https://hdl.handle.net/2144/34890.
Full textRonnebaum, Sarah Marie. "Pyruvate Cycling Pathways and Glucose-Stimulated Insulin Secretion in Pancreatic Beta Cells." Diss., 2008. http://hdl.handle.net/10161/603.
Full textYang, Wei-Ti, and 楊惟蒂. "The Effects of Momordica charantia Linn. Water Extracts and Fractions on Glucose Uptake of Hepatic Cell Line and Insulin Secretion of Islet Beta Cell Line." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/55625661937437677029.
Full text國立臺灣大學
微生物與生化學研究所
98
Metabolic syndromes predict a high risk of cardiovascular diseases and type 2 diabetes. Insulin resistance and abnormal regulation of glucose homeostasis are major part of metabolic syndromes. Tissue-specific knockouts of the insulin receptor in liver and islet beta cells in mice resulted in impaired plasma glucose control, indicating that both liver and islet beta cells are indispensible in the regulation of body glucose homeostasis and metabolism. Bitter gourd (BG, Momordica charantia) is known for its hypoglycemic activity, but the active compounds and molecular target have not been clearly understood. This study aimed at examining effects of wild BG (Hualien No.4) water extract and fraction on the glucose uptake of hepatocytes (FL83B hepatic cell line) and on the insulin secretion of islet beta cells (RIN-m5F and HIT-T15 cell line). Glucose uptake by FL83B cells was measured by the reduction of glucose concentration in the culture media after cells were treated with insulin (positive control) or MC extract/fractions for 16 or 20 hrs. Insulin secretion was measured after RIN-m5F and HIT-T15 cells were treated with 10mM glucose (positive control) or MC extract/fractions for 1 hour. Insulin secretion was also measured in HIT-T15 cells pretreated with 100uM palmitic acid for 48 hours to blunt the response of insulin secretion to glucose. The results shows that the P-fraction (containing insulin-like peptide), the WE (water extract) and its low MW (<3kD) fractions (WES) of MC significantly enhanced the glucose uptake of FL83B and the insulin secretion in both of the two beta cell lines (p<0.05). WE and WES were further hydrolyzed by incubation with β-glucosidase. The hydrolyzed products were sequentially extracted by ethyl acetate (EA) and butanol(B). The two extracts of WE also significantly enhanced glucose uptake of FL83B and insulin secretion of HIT-T15 (P<0.05). In addition, the EA extract of theβ-glucosidase hydrolyzed WES also increased the glucose uptake of FL83B and the insulin secretion in both of the beta cells (P <0.05). It was found that one fraction obtained from the prepared HPLC separation of the EA extract of the β-glucosidase hydrolyzed WES significantly improved the impaired insulin secretion of HIT-T15 pretreated with palmitic acid. In conclusion, these results suggest that the hypoglycemic effect of Hualien No. 4 wild BG is attributed, at least in part, to its active component(s) that enhanced the glucose uptake of liver and the insulin secretion of islet beta cells.
Zhao, Shangang. "Monoacylglycerol, alpha/beta-hydrolase domain-6, and the regulation of insulin secretion and energy metabolism." Thèse, 2015. http://hdl.handle.net/1866/13533.
Full textThe glycerolipid/ free fatty acid (GL/FFA) cycle is a key metabolic pathway that links glucose and fatty acid metabolism and it consists of lipogenesis and lipolysis. GL/FFA cycling, especially in its lipolysis arm, generates various lipid signaling molecules to regulate insulin secretion in pancreatic ß-cells and non-shivering thermogenesis in adipocytes. Currently, the lipolysis-derived lipid signals involved in this process are uncertain. Triglyceride hydrolysis in mammalian cells is accomplished by the sequential actions of adipose triglyceride lipase to produce diacylglycerol, by hormone sensitive lipase to produce monoacylglycerol (MAG) and by MAG lipase (MAGL) that releases free fatty acid and glycerol. Our work shows that in pancreatic ß-cell, the classical MAGL is poorly expressed and that MAG hydrolysis is mainly conducted by the newly identified α/β-Hydrolase Domain-6 (ABHD6). Inhibition of ABHD6 by its specific inhibitor WWL70, leads to long-chain saturated 1-MAG accumulation inside the cells, accompanied by enhanced glucose-stimulated insulin secretion (GSIS). Decreasing the MAG levels by overexpression of ABHD6 in the ß-cell line INS832/13 reduces GSIS, while increasing MAG levels by ABHD6 knockdown enhances GSIS. Acute exposure of INS832/13 cells to various MAG species dose-dependently stimulates insulin secretion and restores GSIS suppressed by the pan-lipase inhibitor orlistat. Also, various biochemical and pharmacological experiments show that saturated 1-MAG levels species rather than unsaturated or 2-MAG species best correlate with insulin secretion. Furthermore, whole-body and β-cell-specific ABHD6-KO mice exhibit enhanced GSIS in vivo, and their isolated islets show elevated MAG production and GSIS. Inhibition of ABHD6 in low dose streptozotocin diabetic mice restores GSIS and improves glucose tolerance. Results further show that ABHD6-accessible MAGs not only enhance GSIS, but also potentiate fatty acid and non-fuel-induced insulin secretion without alteration in glucose oxidation and utilization as well as fatty acid oxidation. We have identified that MAG binds and activates the vesicle priming protein Munc13-1, thereby inducing insulin exocytosis. Based on all these observations, we propose that lipolysis-derived saturated 1-MAG acts as a metabolic coupling factor to regulate insulin secretion and ABHD6 is a negative modulator of insulin secretion. Besides its role in ß-cells, ABHD6 is also highly expressed in adipocytes and its level is increased with obesity. Mice globally lacking ABHD6 on high fat diet (HFD) show modestly reduced food intake, decreased body weight gain, insulinemia and fasting glycemia and improved glucose tolerance and insulin sensitivity and enhanced locomotor activity. In addition, ABHD6-KO mice display increased energy expenditure and cold-induced thermogenesis. In accordance with this, these mice show elevated UCP1 level in white and brown adipocytes, indicating browning of white adipocytes. The browning phenotype is reproduced in the mice either chronically treated with the ABHD6 inhibitor WWL70 or an antisense oligonucleotides targeting ABHD6. White and brown adipose tissues isolated from whole body ABHD6 KO mice show greatly elevated levels of 1-MAG, but not 2-MAG. Increasing MAG levels by either exogenous administration of 1-MAG or ABHD6 inhibition or genetic deletion induces browning of white adipocytes in a cell-autonomous manner. Further evidence indicates that 1-MAGs can transactivate PPARα and PPARγ and the browning effect induced by WWL70 or exogenous MAG is abolished by PPARα and PPARγ antagonists. In vivo administration of the PPARα antagonist GW6471 to ABHD6 KO mice partially reversed the ABHD6-KO effects on body weight gain, and abolishes the enhanced thermogenesis, white adipose browning and fatty acid oxidation in brown adipose tissue. All these observations indicate that ABHD6 regulates not only insulin and glucose homeostasis but also energy homeostasis and adipose tissue function. Thus, ABHD6-accessible 1-MAG not only acts as a metabolic coupling factor to regulate fuel and non-fuel induced insulin secretion by activating Munc13-1 in beta cells, but also regulates glucose, insulin and energy homeostasis. The latter effects are mediated at least in part via browning of white adipocytes and enhanced brown fat function through the activation of PPARα and PPARγ. Collectively these findings suggest that ABHD6 is a promising target for developing therapeutics against obesity, type 2 diabetes and metabolic syndrome.
Rose, Tobias. "Stimulus-secretion coupling in pancreatic β-cells of healthy and diabetic rats in tissue slice preparation." Doctoral thesis, 2006. http://hdl.handle.net/11858/00-1735-0000-0006-B6DF-F.
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