Dissertations / Theses on the topic 'Pancreatic beta cell function'
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Pinnick, Katherine Elizabeth. "Pancreatic fat accumulation and effects on beta cell function." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492051.
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Type 2 Diabetes Mellitus (T2DM) is characterised by impaired pancreatic 13-cell function resulting in inadequate insulin secretion. The mechanisms involved in 13-cell dysfunction are largely unknown. Elevated fasting plasma non-esterified fatty acid (NEFA) concentrations have been identified as a risk factor for the development of T2DM. The work in this thesis investigates functional effects of NEFA on the 13-cell. Prolonged exposure to elevated NEFA has previously been associated with impaired insulin secretion, reduced insulin content and altered gene expression and lipid metabolism in the 13-cell. Determining the reversibility of these defects may lead to a greater understanding of the underlying mechanisms. Increased pancreatic fat content is positively associated with body mass index in humans and this may expose the 13-cell to high NEFA concentrations. However, the in vivo concentration and composition of NEFA in the pancreas is not known. An in vitro model of 13-cell 'recovery' from the deleterious effects of fatty acids is presented. The longterm culture (>48h) of mouse islets and INS-1 cells with NEFA (0.5mM) impaired glucose and tolbutamide-stimulated insulin secretion, but this was partially reversed by culture for 24h in the absence of exogenous fatty acids. Culture with oleic acid led to the accumulation of triacylglycerol (TAG) in cytosolic lipid droplets. The protein ADFP was found in close association with these droplets. In contrast, culture with palmitic acid produced large cytoplasmic 'splits'. The removal of exogenous fatty acids from the culture media led to a visible reduction in these morphological features. Extraction of the cellular lipids confirmed an increase in the TAG content following culture with NEFA and demonstrated the incorporation of the experimental fatty acid into the TAG and phospholipid (PL) fractions. Following removal of the fatty acids for 24h, TAG content was reduced and NEFA-induced changes in TAG and PL fatty acid composition were partially reversed. A reduction in TAG content in 'recovering' cells indicated the presence of active Iipases. Culture with NEFA increased lipolysis as shown by the measurement of glycerol in the culture media, but this was reduced in 'recovering' cells. Lipase inhibitors inhibited glycerol release but failed to inhibit a reduction in TAG content, and did not confirm a role for Iipases in the recovery of stimulated insulin secretion. Exposure of INS-1 cells to NEFA increased their oxidative capacity for fatty acids and this remained elevated in 'recovering' cells. Treatment with the CPT-1 inhibitor, etomoxir (10I-lM), impaired the fatty acid oxidative capacity of the 13-cell but did not affect the recovery of insulin secretion. A number of genes were upregulated following prolonged culture with NEFA, these included insulin I and II, CPT-1 and UCP2. These genes all displayed reduced expression in cells cultured further in the absence of exogenous fatty acids. The content and composition of fat in tissues from mice was investigated. The TAG composition reflected the major fatty acids found in the diet, with elevated proportions of palmitic and palmitoleic acid indicating the contribution of de novo lipogenesis and desaturase activity to this fatty acid pool. Pancreatic PL were highly unsaturated compared to liver PL, with arachidonic acid accounting for -25% of the PL fatty acids. In mice fed a high-fat (40%) diet (HFD) which was compositionally matched to a control (5%) diet, a 20-fold increase in pancreatic fat was found by 15 weeks. Adipocytes, which were positively labeled for perilipin were observed in the exocrine tissue of the pancreas in HFD mice and lipid droplets labeled for ADFP were identified in the cytoplasm of exocrine cells. By 15 weeks, the fatty acid composition of the TAG, PL and NEFA fractions showed significant differences between HFD and control mice. Perilipin-positive adipocytes were also identified in human pancreas samples and the percentage adipocyte area in histological sections positively correlated (r=0.64) to total pancreatic TAG content. In conclusion, the in vitro findings show the deleterious effects of fatty acids are not permanent. However, increased fat accumulation in the pancreas, as seen in obesity, could expose the 13-cell to elevated NEFA concentrations which, over many years, may lead to irreversible 13-cell failure.
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Duffy, Joan. "Effects of insulin sensitising agents on pancreatic beta cell function." Thesis, University of Ulster, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399052.
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Nishi, Kiyoto. "Nardilysin Is Required for Maintaining Pancreatic β-Cell Function." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225463.
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Tym, Amy. "Effect of protein glycation by methylglyoxal on pancreatic beta cell function." Thesis, University of Warwick, 2014. http://wrap.warwick.ac.uk/61717/.
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Methylglyoxal is a physiological dicarbonyl metabolite and potent argininedirected glycating agent. It often modifies proteins at functional sites producing loss of positive charge, structural distortion and inactivation. Plasma methylglyoxal is increased in hyperglycaemia associated with diabetes and is linked to the development of vascular complications of diabetes – particularly nephropathy, retinopathy and neuropathy. The effects of dicarbonyl glycation on beta cells and involvement in early stage dysfunction and development of type 2 diabetes mellitus are not known. The aim of this project was to investigate the effect of dicarbonyl protein glycation on beta cell function and related involvement in the development of diabetes. Studies were performed in an in vitro model of beta cell dysfunction - MIN6 insulinoma cells incubated under low and high glucose concentrations, and in a pre-clinical in vivo model of decline of glucose tolerance preceding development of type 2 diabetes - high fat diet-induced insulin resistant mice. Dicarbonyl metabolism and protein damage by glycation and oxidation were studied by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Localisation of methylglyoxal glycation adducts within the pancreas were visualised by immunostaining. Interactions between the extracellular matrix protein, collagen IV, and MIN6 cells in vitro were investigated and impairments in adhesion were assessed following glycation with methylglyoxal. Impairments in adhesion of MIN6 cells to methylglyoxal-glycated collagen IV were assessed using atomic force microscopy force spectroscopy. The results show that MIN6 cells were resistant to accumulation of methylglyoxal when incubated in high glucose concentration although the flux of methylglyoxal was increased 41%. Glycation of collagen IV by methylglyoxal impairs binding to MIN6 cells in vitro resulting in a 91% decrease in the energy necessary to detach cells from the extracellular matrix protein. In high fat diet fed mice the concentration of methylglyoxal in the pancreas was increased. Visualisation of MG-H1 adduct residues in the pancreas showed they were predominantly on the extracellular matrix. In conclusion, protein glycation by methylglyoxal occurs in MIN6 cells in vitro and in the mouse pancreas in vivo. Although the methylglyoxal concentration in the pancreas of high fat diet fed, insulin resistant mice was increased, the lack of a concurrent increase in methylglyoxal protein glycation adducts suggests there may be increased turnover of methylglyoxal-modified proteins. Impairment of beta cell attachment to the extracellular matrix protein, collagen IV, by methylglyoxal and increased protein turnover stimulated by an increased rate of methylglyoxal glycation may impair beta cell function in pre-diabetes in vivo. Glycation by methylglyoxal may contribute to beta cell glucotoxicity and dysfunction with progression to type 2 diabetes mellitus.
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Ullsten, Sara. "The Impact of Pancreatic Islet Vascular Heterogeneity on Beta Cell Function and Disease." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-330805.
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Diabetes Mellitus is a group of complex and heterogeneous metabolic disorders characterized by hyperglycemia. Even though the condition has been extensively studied, its causes and complex pathologies are still not fully understood. The occurring damage to the pancreatic islets is strikingly heterogeneous. In type 1 diabetes, the insulin producing beta cells are all destroyed within some islets, and similarly in type 2 diabetes, some islets may be severely affected by amyloid. At the same time other islets, in the near vicinity of the ones that are affected by disease, may appear fully normal in both diseases. Little is known about this heterogeneity in susceptibility to disease between pancreatic islets. This thesis examines the physiological and pathophysiological characteristics of islet subpopulations. Two subpopulations of islets were studied; one constituting highly vascularized islets with superior beta cell functionality, and one of low-oxygenated islets with low metabolic activity. The highly functional islets were found to be more susceptible to cellular stress both in vitro and in vivo, and developed more islet amyloid when metabolically challenged. Highly functional islets preferentially had a direct venous drainage, facilitating the distribution of islet hormones to the peripheral tissues. Further, these islets had an increased capacity for insulin secretion at low glucose levels, a response that was observed abolished in patients with recent onset type 1 diabetes. The second investigated islet subpopulation, low-oxygenated islets, was found to be an over time stable subpopulation of islets with low vascular density and beta cell proliferation. In summary, two subpopulations of islets can be identified in the pancreas based on dissimilarities in vascular support and blood flow. These subpopulations appear to have different physiological functions of importance for the maintenance of glucose homeostasis. However, they also seem to differ in vulnerability, and a preferential death of the highly functional islets may accelerate the progression of both type 1 and type 2 diabetes.
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Brown, James. "Regulation of uncoupling protein-2 expression, cell function and viability in pancreatic islets and beta-cells." Thesis, University of Wolverhampton, 2005. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419783.
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Mitchell, Ryan. "The effects of type 2 diabetes associated risk loci on pancreatic beta cell function." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/39040.
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The pancreatic islets of Langerhans play a fundamental role in the stabilisation of blood glucose levels. Pancreatic islets are spherical structures composed of multiple cell types, with each individual cell type secreting a peptide hormone, such as insulin and glucagon, which regulates whole body glucose homoeostasis. Defective hormone secretion from islet cells is a hallmark of certain metabolic diseases, including type 2 diabetes mellitus (T2D). The most abundant islet cell type is the pancreatic β-cell, a specialised cell type that secretes the hypoglycaemic hormone insulin in response to raised glucose levels. Alterations in both β-cell mass and function are the causative factor for the development of T2D. Both genetic and environmental factors are known to underlie the decline in β-cell function typical of T2D. Specifically, genome wide association studies (GWAS) have identified over 100 genomic loci that are associated with T2D risk. Among these loci, variants that lie within/near ADCY5, SLC30A8 and PAX6 show associations with both T2D and abnormal glycaemic parameters typical of a diabetic phenotype. Therefore, the aims of this thesis were to understand how variants associated with T2D manifest at the level of the pancreatic islet. The expression of these genes was therefore manipulated through the generation of tissue-specific transgenic and knockout mice and by RNA interference in human tissue. Reducing the expression of ADCY5, encoding adenylate cyclase five, in human islet tissue reduced glucose-stimulated insulin secretion. This was accompanied by impairments in the metabolic and non-metabolic parameters that govern the secretory response of islets to glucose and other secretagogue. Deleting ZnT8, a β-cell zinc transporter and the gene product of the Slc30a8 gene, in the mouse β-cell significantly impaired the ability of these animals to mount effective responses to glucose. Interestingly, the reverse phenotype, i.e. improved glucose tolerance, was seen in animal models that overexpress ZnT8 in the β-cell. Finally, deletion of Pax6 in the adult mouse resulted in a drastic diabetic phenotype accompanied with changes in the cellular architecture of the islet and alterations in β-cell glucose signalling. Therefore, ADCY5, SLC30A8/ZnT8 and PAX6 gene variants likely negatively impact upon β-cell mass and function leading to a diabetic phenotype. Furthermore, these genes highlight distinct pathways, intrinsic to the pancreatic β-cell, which could be therapeutically targeted in the treatment of T2D.
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Tsang, Siu-wai. "Involvement of Pdzd2 in the regulation of pancreatic beta-cell functions." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B39716430.
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Tsang, Siu-wai, and 曾少慧. "Involvement of Pdzd2 in the regulation of pancreatic beta-cell functions." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39793746.
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Karlsson, Ella. "Studies of neuropeptides in pancreatic beta cell function with special emphasis on islet amyloid polypeptide (IAPP)." Doctoral thesis, Uppsala University, Department of Medical Cell Biology, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-560.
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The presence of protein amyloid in pancreas and its association to diabetes was first described 100 years ago in 1901, but was not identified as Islet Amyloid Polypeptide (IAPP) until 1986. The aim of the present work was to determine the role of the beta cell hormone, IAPP, in normal pancreatic islet physiology and during early disturbances of islet function.
Intra-islet peptides, i.e. chromogranin peptides and an extra-islet peptide, i.e. leptin, were studied to identify possible endogenous regulators of IAPP and insulin secretion. Chromogranin-B, but not chromogranin-A or pancreastatin, had the ability to inhibit islet IAPP and insulin release, suggesting that chromogranin-B may serve as an autocrine regulator of IAPP and insulin secretion.
Leptin had a more potent effect on IAPP secretion than on insulin secretion, which was dissociated from effects on islet glucose metabolism. Glucose oxidation rates were increased at physiological leptin concentrations, whereas higher leptin concentrations showed an inhibitory effect and chronically high leptin concentrations had no effect.
Female NOD mice were studied to investigate the release of IAPP in the progression to type 1 diabetes. The release of IAPP was lower than that of insulin from immune cell infiltrated islets, indicating preferential insulin release during the early course of the disease.
IAPP is expressed at an early embryonic stage. The effect of IAPP on cell proliferation in neonatal rat islets was studied in the search for a physiological role of IAPP. IAPP concentrations of (1-1000) nM stimulated neonatal islet cell proliferation mostly in beta cells and to a lesser extent in alpha cells. IAPP did not have any marked effect on the islet cell death frequency. These data indicate a role for IAPP as a potential regulator of beta cell proliferation in neonatal pancreatic islet.
It is concluded that IAPP may be involved in regulation of pancreatic beta cell function both in fetal and adult life.
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Åkerblom, Björn. "Frk/Shb Signalling in Pancreatic Beta-cells : Roles in Islet Function, Beta-cell Development and Survival as Implicated in Mouse Knockout Models." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-89348.
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The adaptor protein Shb and the non-receptor tyrosine kinase Frk have been implicated in intracellular signalling in insulin-producing beta cells. In this thesis, knockout mice are used to further elucidate the role of Shb and Frk for beta cell number, cytokine-induced cell death, and glucose homeostasis. In addition, the effect of Shb deficiency upon tumour growth is studied in a mouse model of endogenous tumourigenesis. Previously, overexpression of Frk has been associated with increased beta cell replication, and increased susceptibility to cytokine induced beta cell destruction. To test whether Frk has a non-redundant role in regulating beta cell mass, beta cell number in Frk-/- mice was assessed at different stages of life. The results showed that Frk is involved in regulating beta cell number during embryonal and early postnatal life, but is probably redundant in the adult. An earlier study had suggested that Shb participates in cytokine-induced beta cell death, a model of autoimmune diabetes. To test this further, Shb-/- islets were exposed to cytokines, or to an ER-stress inducing agent. Shb knockout islets exhibited decreased cell death, and this effect appeared to be independent of NO, JNK, p38 MAP kinase, FAK and c-Abl, but may involve an augmented induction of Hsp70. Furthermore, glucose homeostasis in Shb-/- mice was impaired, with elevated basal blood sugar concentration and reduced glucose-induced insulin secretion. Previously Shb deficient mice had showed an impaired ability to sustain growth of implanted tumour cells, due to reduced angiogenesis. Tumour growth and angiogenesis were here assessed in an inheritable tumour model. Shb deficient mice exhibited fewer tumours, and reduced vessel density in small tumours, indicating impaired angiogenesis. However, a few large tumours developed in Shb-/- mice, suggesting that tumours can escape the angiogenic restriction caused by the absence of Shb.
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Naghiloo, Sheyda. "Proteomic Pathways to Type 2 Diabetes in the Pancreatic Islet." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/29172.
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Unveiling proteomic changes that occur through stages of pathogenesis can provide unparalleled insights into the mechanisms underpinning disease. Using fluorescence-activated cell sorting (FACS) and liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS), I aimed to characterise the deep proteome of both whole islets and individual islet cell types (alpha, beta, gamma, delta and epsilon) from mice and humans in variable states of health and disease. Acquisition of individual islet cell type proteomes will serve as a window of enquiry into islet cell regulation and intra-cellular communication providing insight into how these factors affect systemic glucose regulation. A panel of diverse mice were phenotypically characterised to observe their responses to diet or genetically induced metabolic stress. Characterisation of the islet proteomes of these mice revealed background strain as the major determinant of islet capacity to maintain function under increased metabolic stress. Isolation of the individual islet cell types using FACS requires the targeting of specific markers for each cell type. Currently, specific surface markers for several islet cell types are not known and/or antibodies are not available, and the alternative of using internal markers requires fixation. Standardised methods of protein fixation have a variable extent of modifications, for example paraformaldehyde, and hence are incompatible with peptide identification after MS analysis. I have overcome these obstacles by using a reversible crosslinker, dithiobis(succinimidyl propionate), which specifically targets primary amines in proteins. Upon reversal of the crosslinker, it leaves modifications of a standard size, which can be incorporated into the peptide identification analysis as a protein modification. In doing so, internal markers specific to each islet cell type can be utilized for isolation and subsequent proteomic analysis, whilst retaining greater than 96% protein identification compared to non-fixed cells. Preliminary MS analysis of isolated human β-cells revealed 4,561 proteins representing the largest human β-cell proteome to date.
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Turbitt, 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.
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Åkerblom, Björn. "Frk/Shb signalling in pancreatic beta-cells : roles in islet function, beta-cell development and survival as implicated in mouse knockout models /." Uppsala : Acta Universitatis Upsaliensis, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-89348.
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Du, Xiaoyu. "PLAGL1/ZAC, a transient neonatal diabetes mellitus locus gene, in pancreatic beta-cell development and function." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96741.
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Studies on congenital disorders of the pancreas have contributed to the identification of genes that are critical in beta-cell development and function. Transient neonatal diabetes mellitus (TNDM) is a rare congenital disorder of the pancreas. It involves severe insulin deficiency at birth that reverses over weeks or months but may relapse with diabetes in later life. PLAGL1 (pleiomorphic adenoma gene-like 1, also known as ZAC, zinc finger protein that regulates apoptosis and cell cycle arrest, and LOT1, Lost On Transformation 1) is one of the two possible genes at the TNDM locus and the multiple functions of PLAGL1/ZAC strongly suggest it as the causative gene of TNDM. We hypothesized that double dose expression of PLAGL1/ZAC impairs both beta-cell development and function. To test this hypothesis, we began with the study of ZAC ontogeny. In developing human pancreas, ZAC is expressed with considerable specificity in differentiated beta-cells, and its expression decreases dramatically from the second trimester to adult. These results imply a role of ZAC in a critical time window in beta-cell development, supporting its role in TNDM and explaining the transient nature of the TNDM. In vitro, effects of ZAC overexpression on beta-cell function was observed in INS-1 cells by using tetracycline regulatable system. Overexpression of ZAC inhibits glucose-stimulated insulin exocytosis and proinsulin biosynthesis. Glucose was found to be able to downregulate Lot1/Zac1 expression in INS-1 cells and mouse islets. These data suggest ZAC as a negative regulator in some glucose-regulated pathways whose abnormally high level impairs beta-cell function that explains the relapse of diabetes in TNDM. Finally, a gene expression profile study of INS-1 cells with or without induced ZAC expression identified STC1, IGF1R, SNAP25, GRP78, and P58IPK as possible targets of ZAC that mediate beta-cell dysfunctions. CRABP2, strongly upregulated by ZAC, together with G0S2, GADD45alpha, and FHL2, may mediate ZAC function in both normal beta-cell development and TNDM pathophysiology. In general, these studies suggest that tightly controlled expression level of ZAC is critical for beta-cell development and function. It provides strong evidence that ZAC overexpression causes TNDM. In addition, two previously unstudied genes, STC1 and CRABP2, are suggested to play potential important roles in beta-cell function and development.Les études portant sur les désordres congénitaux du pancréas ont contribué à l'identification de gènes critiques pour le développement et la fonction des cellules bêta. Le diabète néonatal transitoire (DNNT) est une maladie héréditaire du pancréas. Elle est caractérisée par une déficience sévère en insuline à la naissance qui disparaît après quelques semaines/mois mais pouvant réapparaître plus tard au cours de la vie. PLAGL1 (pleiomorphic adenoma gene-like 1, aussi connu comme ZAC, zinc finger protein that regulates apoptosis and cell cycle arrest, et LOT1, Lost On Transformation 1) est un des deux gènes dans la région critique du DNNT et ses multiples fonctions en font le candidat causatif le plus probable. Notre hypothèse est que sa surexpression compromet la fonction et le développement des cellules bêta. Notre étude ontgénique de ZAC dans le pancréas en développement, démontre que ZAC était exprimé avec une spécificité considérable dans les cellules bêta, expression qui diminuait à partir du second trimestre. Ces résultats supportent l'existence d'une fenêtre temporelle critique pour la fonction de ZAC dans le développement des cellules bêta, compatible avec la nature transitoire du DNNT. In vitro, les effets de la surexpression de ZAC ont été observés dans les cellules bêta INS-1 en utilisant un système d'expréssion inductible par la tétracycline. L'exocytose glucose-dépendante de l'insuline et la biosynthèse de la proinsuline sont diminués par la surexpression de ZAC. Le glucose pouvait diminuer l'expression de Lot1/Zac1 dans les INS-1 et dans les îlots murins, une observation qui propose ZAC comme un régulateur négatif de voies métaboliques régulées par le glucose dont les niveaux anormalement élevés affectent la fonction des cellules bêta. Le profile d'expression génique sur les INS-1 après induction de ZAC a identifié STC1, IGF1R, SNAP25, GRP78 et P58IPK comme cibles potentielles de ZAC intervenant dans les dysfonctionnements des cellules bêta. CRABP2, qui est fortement augmenté, tout comme G0S2, GADD45alpha et FHL2, pourrait servir de médiateur de ZAC dans le développement des cellules bêta et dans le DNNT. Ces études indiquent qu'une expression minutieusement contrôlés de ZAC est critiques pour le développement et la fonction des cellules bêta et que sa surexpression peut causer le DNNT. Finalement, un rôle de STC1 et CRABP2 dans la fonction et le développement des cellules bêta est suggéré.
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Patterson, 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.
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GALLI, ALESSANDRA. "MOLECULAR AND FUNCTIONAL CHARACTERIZATION OF THE MECHANOTRANSDUCTION SIGNALING PATHWAY IN PANCREATIC ENDOCRINE CELLS: IMPLICATIONS FOR BETA CELLS SURVIVAL, DIFFERENTIATION AND FUNCTION." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/827453.
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Le cellule β-pancreatiche svolgono un ruolo fondamentale nell’omeostasi glucidica, essendo le uniche cellule del corpo in grado di produrre e secernere insulina. Alterazioni della loro funzionalità o del loro numero determinano lo sviluppo del diabete mellito, un gruppo di patologie ad eziologia eterogenea caratterizzate da iperglicemia. L’approccio più efficace per trattare i pazienti diabetici dovrebbe consistere nel ripristinare la funzionalità o la massa β-cellulare tramite terapie rigenerative o sostitutive. Tra le terapie sostitutive particolarmente promettenti vi sono quelle che utilizzano cellule staminali embrionali o pluripotenti. Tuttavia, i protocolli ad oggi disponibili per promuovere il loro differenziamento in vitro non sono del tutto efficaci nel generare cellule β completamente mature. Le cellule β, infatti, per essere funzionali ed efficienti necessitano di uno specifico microambiente che fornisca molteplici stimoli chimici e fisici. Particolarmente studiati sono gli stimoli chimici, mentre poco conosciuti sono gli effetti delle proprietà fisiche della matrice extracellulare. Lo scopo del nostro studio è stato, quindi, quello di valutare l’impatto della nanotopografia sul differenziamento e la funzionalità β-cellulare e caratterizzarne i meccanismi molecolari coinvolti. Per riprodurre le proprietà nanotopografiche della matrice extracellulare sono stati utilizzati substrati di zirconio ingegnerizzati su scala nanometrica. Nel nostro lavoro abbiamo dimostrato che le cellule β percepiscono la nanotopografia della matrice e rispondono attraverso una riorganizzazione del citoscheletro di actina e dell’architettura nucleare. Tale processo, noto come meccanotrasduzione, permette il mantenimento delle isole di Langerhans per lungo tempo in cultura, preservando il differenziamento e la funzionalità delle cellule β. I nostri dati, inoltre, dimostrano che la nanostruttura induce una modifica della dinamicità, morfologia e funzionalità mitocondriale favorendo un cambiamento del metabolismo β-cellulare. Anche il processo mitomorfico sembra essere direttamente promosso dalla riorganizzazione del citoscheletro e dalla modifica delle interazioni dei mitocondri con altri organelli citoplasmatici. Nell’insieme, i nostri dati dimostrano che le cellule β percepiscono e rispondono alla nanotopografia attivando un processo meccanotransduttivo che promuove la sopravvivenza e la funzionalità β-cellulare. L’utilizzo di substrati ingegnerizzati che riproducono le proprietà biofisiche del microambiente rappresenta un ottimo strumento per approfondire le conoscenze sui meccanismi molecolari alla base della meccanotransduzione. Queste conoscenze saranno utili per potenziare le terapie rigenerative e per promuovere il differenziamento di cellule staminali in vitro, migliorando così anche l’efficacia delle terapie sostitutive.Pancreatic β-cells, the only cells within the body able to secrete large amount of insulin, play a crucial role in the control of glucose homeostasis and alteration of their function and mass leads to diabetes pathogenesis, a group of pathologies characterized by severe hyperglycemia. Therefore, preserving the remaining β-cell function and replacing the β-cell mass represent the most promising strategies to treat diabetes. Embryonic and pluripotent stem cells hold great promise in generating β-cells for novel therapeutic discoveries in diabetes mellitus. However, their differentiation in vitro is still inefficient, and functional studies reveal that most of these β-like cells still fail to fully mirror the adult β-cell physiology. For their proper growth and functioning, β-cells require a very specific environment, the islet niche, which provides a myriad of chemical and physical signals. While the nature and effects of chemical stimuli have been widely characterized, less is known about the mechanical signals. Therefore, aim of the proposed research was to investigate the contribution of nanotopographical cues on β-cell differentiation and function and to characterize the molecular mechanisms involved. To mimic the nanotopography of the extracellular matrix, cluster-assembled zirconia substrates with tailored roughness were employed. We demonstrated that β-cells perceive nanoscale features and convert these stimuli into mechanotransductive processes which modulate the cellular behavior, via remodeling of the actin cytoskeleton and nuclear architecture. These changes are also paralleled by modulation of mitochondrial dynamics, morphology, and function, favoring a metabolic switch of the cells. The mitomorphosis is driven by substrate-induced reorganization of the cytoskeleton and modification of the mitochondria interplay with other organelles. In conclusion, our data suggest that β-cells sense and respond to nanoscale features by activating a mechanotransductive pathway that promotes β-cell survival and function. By engineering microenvironments mirroring the biophysical niche properties it is possible to elucidate the β-cell mechanotransductive-regulatory mechanisms and to harness them for the promotion of β-cell differentiation capacity. This hopefully will allow us to improve the efficacy of β-cell transplantation therapies and to identify a core set of signaling pathways useful for accelerating regenerative strategies for diabetes treatment.
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Skog, Oskar. "Effects of Enterovirus Infection on Innate Immunity and Beta Cell Function in Human Islets of Langerhans." Doctoral thesis, Uppsala universitet, Klinisk immunologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-172586.
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This thesis focuses on enteroviral effects on human pancreatic islets. Most knowledge of viral effects on host cells relies on studies of immortalized cell lines or animal models. The islets represent a fundamentally different and less well studied cellular host. Also, enterovirus has been implicated in the etiology of type 1 diabetes (T1D). We show that when enterovirus replicates in human islets it activates innate immunity genes and induces secretion of the chemokines MCP-1 and IP-10. An important difference in activation of innate immunity by replicating EV and synthetic dsRNA is suggested, since the chemokine secretion induced by EV infection but not by dsRNA is reduced by female sex hormone. We also demonstrate a direct antiviral effect of nicotinamide, and even though this substance failed to prevent T1D in a large-scale study, this finding could have implications for the treatment/prevention of virus- and/or immune-mediated disease. We also had access to human pancreata from two organ donors with recent onset T1D and several donors with T1D-related autoantibodies, which gave us the opportunity to study ongoing pathogenic processes at and before the onset of T1D. Despite this, we could neither confirm nor reject the hypothesis that EV is involved in T1D development. Several observations, such as ultrastructural remodeling of the beta cell, activation of innate immunity, and immunopositivity to EV capsid protein 1, supported an ongoing virus infection, but direct evidence is still lacking. An interesting finding in the donors with recent onset T1D was that the islets were positively stained for insulin, but did not secrete insulin in response to glucose-stimulation. A similar effect was observed in EV-infected islets in vitro; EV destroyed islet function and insulin gene expression, but the islets still stained positive for insulin. This may be indicative of that a functional block in addition to beta cell destruction is involved in T1D pathogenesis. In conclusion, these studies of EV in isolated human islets in vitro support that this virus can cause T1D in vivo, but future studies will have to show if and how frequently this happens.
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Stokesberry, 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.
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Zmuda, Erik Jason. "The Roles Of ATF3, An Adaptive-response Gene, In Pancreatic Islet beta-cell Stress Response And Function." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1253113188.
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Ward, Kenya L. "The effects of free fatty acids and adipokines on pancreatic beta-cell gene expression, viability and function." Thesis, University of Wolverhampton, 2007. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441876.
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Scullion, Siobhan Mary Josephine. "Impact of acute or prolonged amino acid exposure on pancreatic beta-cell function, demise and destruction in BRIN-BD11 cells." Thesis, University of Ulster, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.529514.
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Wikström, Jakob D. "Mitochondrial form and function in pancreatic β-cells and brown adipocytes." Doctoral thesis, Stockholms universitet, Wenner-Grens institut, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-39336.
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This thesis is focused on the role of mitochondria in pancreatic β-cells and brown adipose tissue (BAT). Two main aspects of mitochondria were explored; mitochondrial functional efficiency and the interrelationship between mitochondrial shape and function. Mitochondria in β-cells were found to exhibit heterogeneity in mitochondrial membrane potential. This functional diversity decreased when cells were challenged with glucose stimuli, suggesting that at higher fuel levels low-activity mitochondria are recruited into a pool of high-activity mitochondria. Glucolipotoxic conditions increased the functional diversity suggesting that this may be of importance for diabetes pathophysiology. To examine mitochondrial efficiency in intact islets a high throughput islet respirometry method was developed. Due to increased uncoupling, islets from a diabetic animal model exhibit lower respiratory efficiency. Glucose, free fatty acids and amino acids all decreased respiratory efficiency. A large portion of the respiratory efficiency was mediated by reactive oxygen species and the adenine nucleotide translocase. In β-cells mitochondria were found to undergo cycles of fusion and fission. During glucolipotoxicity mitochondria fragmented and lost their fusion ability. Knock down of the fission protein Fis1 rescued the β-cells from glucolipotoxic induced cell death. BAT mitochondria also showed fusion and fission. The mitochondrial dynamics proteins Mfn2 and Drp1 were shown to strongly affect BAT mitochondrial morphology. In response to a combination of adrenergic and free fatty acid stimuli mitochondria drastically changed from long filamentous structures to fragmented spheres. Inhibiting fission by the negative form of Drp1 decreased BAT response to adrenergic stimuli by half. In conclusion, mitochondrial efficiency may be of importance for normal as well as compromised β-cell and islet function. Mitochondrial morphology appears critical for mitochondrial function in β-cells and BAT.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.
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Wang, 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.
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A thorough understanding of beta-cell proliferation, function, death and regeneration under normal condition as well as in the progression of diabetes is crucial to the conquest of this disease. The work presented in this thesis aimed to investigate the expression and role of a novel transcription factor, Zinc finger BED domain-containing protein 6 (ZBED6), in beta-cells. ZBED6 was present in mouse βTC-6 cells and human islets as a double nuclear band at 115/120 kDa and as a single cytoplasmic band at 95-100 kDa, which lacked N-terminal nuclear localization signals. Lentiviral shRNA-mediated stable silencing of ZBED6 in βTC-6 cells resulted in altered morphology, decreased proliferation, a partial S/G2 cell cycle arrest, increased expression of beta-cell specific genes, and higher rates of apoptosis. ChIP sequencing of human islets showed that ZBED6 binding was preferentially to genes that control transcription, macromolecule biosynthesis and apoptosis. We proposed that ZBED6 supported proliferation and survival of beta-cells, possibly at the expense of specialized beta-cell function, i.e. insulin production. To further investigate the role of ZBED6 in beta-cells, ChIP sequencing and whole transcriptome analysis were performed using MIN6 cells. More than 4000 putative target genes of ZBED6 were identified, including Pdx1, MafA and Nkx6.1. ZBED6-silencing resulted in differential expression of more than 700 genes, which was paralleled by an increase in the content and release of insulin in response to a high glucose concentration. Altered morphology/growth patterns as indicated by increased cell clustering were observed in ZBED6 silenced cells. We found also that ZBED6 decreased the ratio between N- and E-cadherin. A lower N- to E-cadherin ratio may hamper the formation of three-dimensional beta-cell clusters and cell-to-cell junctions with neural crest stem cells, and instead promote efficient attachment to a laminin support and monolayer growth. Thus, by controlling beta-cell adhesion and cell-to-cell junctions, ZBED6 might play an important role in beta-cell differentiation, proliferation and survival.
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Dubiel, Evan Alozie. "Towards the development and validation of biomaterial surfaces and scaffolds suitable for pancreatic beta-cell development and function." Thèse, Université de Sherbrooke, 2012. http://hdl.handle.net/11143/6123.
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Le diabète mellitus de type I est une maladie de plus en plus abondante. Cette dernière est caractérisée par la destruction auto-immunitaire des îlots de Langerhans incluant les cellules de type [bêta] qui produisent de l'insuline dans le pancréas endocrinien. Une option de traitement pour les patients atteints de cette maladie est notamment une greffe des îlots de Langerhans. Ce traitement est limité dû au nombre restreint de donneurs d'organes et aussi à la perte de fonctionnalité des îlots suite à la greffe. Les études effectuées tout au long de cette thèse ont pour optique d'adresser ces contraintes par le biais de la science des biomatériaux. La thèse débute avec un survol détaillé des concepts de base et des complexités associés aux interactions de type cellules et surfaces trouvées dans la littérature. II s'agit spécifiquement des interactions physiques et chimiques, des systèmes expérimentaux ainsi que des caractérisations et modifications associés aux interactions entre cellules et surfaces. La première étude de nature expérimentale examine la morphogenèse des cellules progénitrices ductales (PANC-1 cell line) vers des îlots qui produisent des agrégats semblables à des îlots (ILA). Le tout est fait sur des surfaces de carboxyméthyl dextrane (CMD) sur lesquelles le RGD est greffé via un lien covalent. L'expression des marqueurs d'lLAs (cytokeratin-19, Ki67, et E-cadherin) qui peuvent être associés à un changement de phénotype de ces cellules a été évaluée ainsi que la sécrétion et l'expression de l'insuline. La seconde étude de nature expérimentale a pour optique l'immobilisation de la fibronectine (FN) sur les mêmes surfaces de CMD mentionnées auparavant sur lesquelles des cellules ayant un phénotype [bêta] (INS-1 cell line) ont proliféré. Lors du processus d'immobilisation, plusieurs solutions ont été étudiées. L'immobilisation de la fibronectine sur des surfaces de CMD a été validée par la spectrométrie de photoélectrons induits par rayons X. Le mécanisme d'immobilisation a été déterminé par imagerie et mesures de force par microscopie à force atomique, la spectroscopie de dichroïsme circulaire ainsi que par la diffusion dynamique de la lumière. De plus, la croissance des cellules de type INS-1 et la sécrétion d'insuline ont été évaluées. La dernière étude de nature expérimentale visait l'étude de la coculture des cellules endothéliales et des îlots de porc dans un gel de fibrine. L'effet de la présence des cellules endothéliales sur la production d'insuline des îlots a été évalué. De plus, l'apoptose cellulaire en coculture a été évaluée et comparée aux cultures simples.
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Monkman, James. "Identification and functional characterisation of TGFB-regulated and cell surface candidates in pancreatic cancer." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/213218/1/James_Monkman_Thesis.pdf.
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This thesis is an investigation into the role of novel proteins that may influence pancreatic cancer cell migration and thereby tumour progression. Multiple approaches were used to select 41 candidate proteins for in-vitro loss-of-function experiments and several lead candidates were generated including GPRC5A and CRLF1. Further investigation is warranted to better define their cellular roles in pancreatic cancer.
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Picton, Sally. "Acute and long-term effects of nutrients, nutrient esters, drugs and cytotoxins on pancreatic beta cell function and integrity." Thesis, University of Ulster, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398965.
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De, Oliveira Alvelos Maria. "Alternative splicing in type 1 diabetes: The role of the splicing factor SRSF6 in pancreatic β-cell function and survival." Doctoral thesis, Universite Libre de Bruxelles, 2020. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/313254.
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Type 1 diabetes (T1D) is an autoimmune disease characterized by the selective destruction of pancreatic β-cells, mediated by autoreactive T cells.The resulting inflammatory response takes place in the context of a dialogue between invading immune cells and the targeted β-cells, and it is modulated by genetic susceptibility, acting on both immune and β-cells, and by inflammatory cytokines and chemokines. Stress pathways triggered within β-cells may potentiate autoimmunity, and T1D susceptibility genes shape β-cell responses to “danger signals”, innate immunity, and activation of apoptosis. However, the molecular mechanisms linking genetic variation, environmental triggers, and the signaling events promoting β-cell dysfunction and loss remain poorly clarified. Pre-mRNA splicing is a crucial mechanism for gene expression regulation, and more than 95% of the human multi-exonic primary transcripts undergo alternative splicing. Splicing dysregulation have been increasingly recognized to play a pivotal role in multiple pathologies, including autoimmune diseases. More than 15% of the mutations described in the Human Gene Mutation Database are predicted to affect splicing. Our group has shown that exposure to pro-inflammatory cytokines induces major changes on the β-cell transcriptome, affecting the splicing of genes that are key for β-cell function and survival. Importantly, our group identified that GLIS3, a susceptibility gene for both T1D and type 2 diabetes (T2D), modulates β-cell apoptosis via regulation of the splicing factor SRSF6, linking T1D genetic susceptibility and alternative splicing. The downregulation of GLIS3, either by germline mutations associated with monogenic forms of diabetes or risk single nucleotide polymorphisms, contribute to SRSF6 splicing factor downregulation. Splicing factors are the primary regulators of splicing and orchestrate functionally related transcripts into regulatory networks, therefore, oscillations of splicing factors’ expression levels have a major impact on splicing decisions. In the present study we aimed: 1. To evaluate the functional impact of SRSF6 downregulation in human pancreatic β-cells; 2. To identify the SRSF6-regulated splicing networks and to decode the SRSF6 cis-regulatory RNA binding elements.To fulfil these aims, human insulin-producing EndoC-βH1 cells were subjected to RNA sequencing (under control conditions or following SRSF6 knock down for 48h) to identify transcriptome-wide alternative splicing events regulated by SRSF6, and to individual-nucleotide resolution UV crosslinking and immunoprecipitation followed by high-throughput sequencing (iCLIP) to determine the SRSF6 mechanistic model of splicing regulation, its associated cis-regulatory elements and directly bound transcripts in human β-cells. We observed that SRSF6 depletion has a major impact on human pancreatic β-cell function and survival, leading to β-cell apoptosis and impaired insulin secretion. SRSF6 downregulation affects the splicing of transcripts involved in central pathways for β-cell function and survival, such as insulin secretion (e.g. INSR, SNAP25), apoptotic regulators (e.g. BCL2L11 (or BIM), BAX), and the mitogen-activated protein kinases (MAPKs) signaling pathway (e.g. MAPK8, MAPK9, MAP3K7). SRSF6 silencing potentiates the generation of constitutively active isoforms of pro-apoptotic inducers – BAX-β, and BIM-Small - leading to apoptosis activation, and also of different members of the MAPK signaling pathway contributing to the hyper-phosphorylation of the pathway, leading to activation of down-stream transcription factors and consequent β-cell apoptosis. These data indicate that specific splicing networks, regulated through diabetes susceptibility genes, control key pathways and processes involved in the function and survival of β-cells. The iCLIP analysis has shown that SRSF6 recognizes more than 100,000 of RNA binding sites in protein coding sequences, and it regulates splicing by preferentially binding into exons through a purine-rich consensus motif consisting of GAA triplets. The number of triplets in direct sequence correlates with increasing binding site strength. The SRSF6 binding position affects the splicing outcome, possibly resulting from the competition between alternative exons and their flanking constitutive exons for SRSF6 tethering. We identified SRSF6 binding sites on SRSF6-regulated cassette exons of several susceptibility genes for both T1D and T2D, and as a proof-of-concept, modulated the splicing of the LMO7 susceptibility gene using antisense oligonucleotides.In conclusion, our data suggest that SRSF6 is a master splicing regulator in pancreatic β-cells, downstream of the diabetes susceptibility gene GLIS3. SRSF6 silencing potentiates the splicing of constitutively active pro-apoptotic variants (BAX-β and BIM-Small), and exacerbates the MAPK signalling pathway. SRSF6 recognizes specific purine-rich RNA binding motifs, with important implications for the interpretation of sequence variants. This work unveiled a novel regulatory layer for β-cell demise and diabetes genetic susceptibility, namely through splicing mis-regulation. These observations raise the possibility that splicing networks regulated by candidate genes for diabetes contribute to β-cell dysfunction and death in diabetes.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
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Piccand, Julie. "Regulation of pancreatic and intestinal endocrine cell differentiation and function : roles of Pak3 and Rfx6." Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAJ057/document.
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Les hormones sécrétées par les cellules endocrines pancréatiques et intestinales participent à la régulation de l’homéostasie énergétique. Leur différenciation repose sur des programmes génétiques similaires contrôlés par le facteur de transcription Ngn3. Peu de choses sont connues sur les gènes activés par Ngn3 et leurs implications dans les mécanismes contrôlant la spécification et la maturation des cellules endocrines. Par conséquent, le transcriptome des progéniteurs endocrines a été déterminé dans l’équipe. Parmi les gènes fortement enrichis dans le lignage endocrine, j’ai caractérisé l’expression et la fonction de la kinase Pak3 et j’ai continué l’étude de la fonction pancréatique et intestinale du facteur de transcription Rfx6. J’ai montré que Pak3 est exprimé dans le lignage endocrine pendant le développement et chez l’adulte. Avec des expériences de perte de fonction, j’ai montré que ce gène inhibe la prolifération des progéniteurs endocrines et des cellules bêta durant l’embryogénèse. De plus, une étude métabolique a montré que les souris mutantes pour Pak3 sont intolérantes au glucose. En parallèle, en utilisant une souris conditionnelle pour Rfx6, j’ai montré que Rfx6 est nécessaire en aval de Ngn3 pour la différenciation des cellules endocrines pancréatiques et intestinales. Finalement, des expériences dans les souris adultes suggèrent que Rfx6 est nécessaire pour maintenir les cellules bêta, renouveler les cellules entéroendocrines et absorber les lipides dans l’intestin. En conclusion, ces études révèlent deux nouveaux gènes clés dans la régulation de la différenciation des cellules endocrines et de l’homéostasie énergétique dans le pancréas et l’intestinPancreatic and intestinal endocrine cells, and their secreted hormones, contribute to the regulation of energy homeostasis. Their differentiation relies on similar genetic programs controlled by the proendocrine transcription factor Ngn3. However, our knowledge of the endocrinogenic programs implemented by Ngn3 is still fragmentary. Therefore, the transcriptome of endocrine progenitors has been determined in the lab. Among the genes which showed a strong enrichment in the endocrine lineage, I studied the expression and function of Pak3, a serine/threonine kinase and further pursued the dissection of the function of the transcription factor Rfx6 in the pancreas and the intestine. I showed that Pak3 is expressed throughout pancreas development and maintained in adult islets. Using ex vivo loss of function experiments and in vivo characterisation of the Pak3-deficient mice, I identified Pak3 as an inhibitor of islet progenitors and beta-cell proliferation in the embryonic mouse pancreas. Furthermore, we performed metabolic studies which revealed that Pak3-deficient micehave an impaired glucose homeostasis, especially under challenging high fat diet. In parallel, using a conditional knockout mouse for Rfx6, we showed that Rfx6 is necessary downstream of Ngn3 for endocrine cell differentiation in the pancreas as well as in the intestine. Finally, additional experiments in adult mice suggest that Rfx6 is necessary to maintain pancreatic beta-cells, enteroendocrine cell turnover and intestinal lipid absorption. In conclusion, these studies revealed two novel key players in the regulation of endocrine cell differentiation and energy homeostasis in the pancreas and the intestine
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Kanase, Nilesh. "The impact of oxidative stress and potential antioxidant therapy on function and survival of cultured pancreatic β-islet cells." Thesis, University of the Highlands and Islands, 2011. https://pure.uhi.ac.uk/portal/en/studentthesis/the-impact-of-oxidative-stress-and-potential-antioxidant-therapy-on-function-and-survival-of-cultured-pancreatic-islet-cells(ec0cd703-3902-4410-8c58-e7c7e49f33e7).html.
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Dietary antioxidant curcumin derived from turmeric has been suggested to decrease the risk of many chronic diseases. Much of the existing data for curcumin stem from experiments performed at supra-physiological concentrations (μM-mM) that are impossible to attain through oral ingestion. It was therefore hypothesized that curcumin at low plasma achievable concentration, though itself not acting as a direct antioxidant might up-regulate the intracellular antioxidants and thus helping combat oxidative stress and protect β-islet cells. The results indicated that Curcumin, DMC and BDMC were able to scavenge hydroxyl radicals, but showed little scavenging ability against superoxide and nitric oxide radicals. Nanomolar concentrations of curcuminoids easily prevented the deleterious effects of H2O2 in pancreatic β-islet RINm5F cells. Non of the curcuminoids showed a detrimental effect on insulin secretion, but the model did not allow assessment of any potential positive effect on insulin secretion. The findings confirmed that nanomolar concentrations of curcumin offered protection in pancreatic β-islet cells against H2O2-indicated damage by modulating the proportion of oxidised GSH (GSSG): reduced GSH in the favour of GSH and the increasing the activity of SOD. This increase in GSH and SOD levels was, at least in part, on account of an increase in GR, SOD-1 and SOD-2 gene expression. The intracellular mechanism driving this modulation of antioxidant gene was, by virtue of blocking the H2O2 induced NF-κB activation.
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Dwomoh, L. "The role of beta-cell glutamate receptors in pancreatic endocrine function and in the pathogenesis of type 1 diabetes mellitus." Thesis, University of the West of England, Bristol, 2017. http://eprints.uwe.ac.uk/29385/.
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Background: Kainate receptors (KARs) are one of the three classes of ionotropic glutamate receptors (iGluRs) expressed primarily in the central nervous system (CNS) where they mediate information transfer and neurotransmitter release. Very little is known about native KARs and their interacting partners outside the CNS. Aim: The aim of this study was to investigate systematically the molecular composition and functional properties of KARs in pancreatic endocrine cells and also to investigate the role of KARs in the pathogenesis of T1DM. Methods: The presence of KAR subunits was investigated in pancreatic clonal β-cells (MIN6 and INS-1), α-cells (α-TC) and primary rat islets of Langerhans using RT-PCR and immunoblotting. The effect of KAR activation on intracellular calcium concentration and insulin secretion in MIN6 was investigated using FURA-2AM epifluorescence imaging and Mercodia insulin assay respectively. The effect of glutamate, kainate and glutamate transporter inhibitor (dihydrokainic acid) on survival and viability of INS1, α-TC and neuroblastoma cells (SH-SY5Y) were investigated using MTT cell viability assay. The presence of autoantibodies against GluR subunits in serum of T1DM patients and controls was investigated using ELISA and immunoblotting. Results: RT-PCR identified mRNAs for GluK2-5 KAR subunits in clonal β-and α-cells and all five subunits (GluK1-5) in primary rat islets of Langerhans. The presence of these subunits was confirmed using immunoblotting with GluK2/3 and GluK5 antibodies. In addition, auxiliary KAR subunits Neto 1 and Neto 2 were also identified in all cell types. FURA-2AM epifluorescence imaging of cultured MIN6 β-cells showed that activation of KARs with kainate induced significant increase in intracellular calcium concentration and insulin secretion. These effects of kainate were blocked by KAR antagonist (NBQX; 30μM) but not by an antagonist (GYKI-53655 hydrochloride; 100μM) of other iGluRs. Chronic exposure to kainate (0.1-0.5mM), glutamate (0.25-12mM) and dihydrokainic acid (0.1mM) cause significantly reduced viability of pancreatic endocrine and neuronal cells. ELISA and immunoblotting showed that serum of T1DM patients and non-diabetic controls react against components of synaptosomal plasma membrane and also against overexpressed GluR subunits. Conclusion: Together, these results indicate that a range of functional KAR subunits and their interacting proteins are expressed in the endocrine pancreas. These KAR subunits identified could assemble as homomeric or heteromeric channels in both β-and α-cells of the pancreas. The activation of these receptors is likely to have an impact on pancreatic hormone secretion and viability of endocrine cells in the islets of Langerhans. Much work ought to be carried out to optimise the methods for identification of autoantibodies against GluR subunits in serum of T1DM patients. This will help to understand the potential role of GluRs in the pathogenesis of T1DM.
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Chellan, Nireshni. "The effect of Cyclopia maculata extract on β-cell function, protection against oxidative stress and cell survival." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/95861.
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Thesis (PhD)--Stellenbosch University, 2014.ENGLISH ABSTRACT: Insights into the role of oxidative stress and pancreatic β-cell dysfunction in the pathogenesis of type 2 diabetes (T2D) reveals an opportunity for the development of novel therapeutics that directly protect and preserve β-cells. The protective role of dietary antioxidants, such as plant polyphenols, against oxidative stress induced diseases, including T2D, is increasingly under scrutiny. Polyphenol-rich extracts of Cyclopia spp, containing mangiferin, may provide novel therapeutics. An aqueous extract of unfermented Cyclopia maculata, containing more than 6 % mangiferin, was assessed for its protective effect in pancreatic β-cells in vitro, ex vivo and in vivo under conditions characteristic of T2D. The effect of mangiferin was also evaluated in vitro and ex vivo, with N-acetyl cysteine (NAC) as an antioxidant control. In this study, we established in vitro toxicity models in RIN-5F insulinoma cells based on conditions β-cells are exposed to in T2D; i.e. lipotoxicity, inflammation and oxidative stress conditions. To achieve this, cells were exposed to the following stressors: palmitic acid (PA), a pro-inflammatory cytokine combination and streptozotocin (STZ), respectively. Thereafter, the ability of the C. maculata extract, mangiferin and NAC to protect RIN-5F cells from the effects of these stressors was assessed by measuring β-cell viability, function and oxidative stress. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, adenosine triphosphate and annexin-V and propidium iodide assays. Cell function was evaluated by measuring glucose stimulated insulin secretion, cell proliferation and cellular calcium. To assess oxidative stress in the RIN-5F cells, diaminofluorescein-FM and dihydroethidium fluorescence, and superoxide dismutase enzyme activity were measured. The in vitro findings were then verified in isolated pancreatic rat islets using methods and models established in the RIN-5F experiments. The protective effect of the extract, NAC and metformin was assessed in STZ induced diabetic Wistar rats, using two treatment regimes, i.e. by treating rats with established diabetes and by pretreating rats prior to induction of diabetes by STZ. Glucose metabolism, oxidative stress and pancreatic morphology were assessed by performing an oral glucose tolerance test, measuring serum insulin, triglycerides, nitrites, catalase and glutathione. Hepatic thiobarbituric acid reactive substances and nitrotyrosine were also assessed. Immunohistochemical labelling of pancreata with insulin, glucagon and MIB-5 was used for morphological assessment. The extract improved β-cell viability, function and attenuated oxidative stress, most apparently in STZ and PA induced toxicity models comparable with NAC both in vitro and in isolated islets. Mangiferin was not as effective, showing only marginal improvement in RIN-5F cell and islet function, and oxidative stress. Pretreatment of STZ induced diabetic Wistar rats with extract was as effective as, if not better than, metformin in improving glucose tolerance, hypertriglyceridaemia and pancreatic islet morphology related to improved β-cell function. This study demonstrated that the aqueous extract of unfermented C. maculata was able to protect pancreatic β-cells from STZ and PA induced toxicity in vitro and ex vivo. In vivo, pretreatment with the extract improved glucose metabolism and pancreatic islet morphology in STZ induced diabetic Wistar rats.
AFRIKAANSE OPSOMMING: Insigte oor die rol wat oksidatiewe stres en pankreas β-sel disfunksie in die patogenese van tipe 2-diabetes (T2D) speel, bied 'n geleentheid vir die ontwikkeling van nuwe terapeutiese middels wat β-selle direk daarteen beskerm. Die beskermende rol van antioksidante in die dieët soos plantaardige polifenole teen oksidatiewe stres geinduseerde siektes soos T2D, is toenemend onder die soeklig. Polifenolryk ekstrakte van Cyclopia spp wat mangiferin bevat mag nuwe terapeutiese middels lewer. ‘n Waterekstrak van ongefermenteerde Cyclopia maculata wat meer as 6% mangiferin bevat, is ondersoek vir sy beskermende effek op pankreas ß-selle in vitro, ex vivo en in vivo teen kondisies kenmerkend aan T2D. Die effek van mangiferin is ook in vitro en ex vivo geëvalueer, met N-asetielsistien (NAC) as 'n antioksidant kontrole. In hierdie studie is in vitro toksisiteitsmodelle in RIN-5F insulinoomselle gevestig. Die modelle is gebaseer op toestande waaraan β-selle blootgestel word tydens T2D; d.w.s. lipotoksisiteit, inflammasie en oksidatiewe stres. Hiervoor is die selle aan die volgende stressors blootgestel: palmitiensuur (PA), ‘n pro-inflammatoriese sitokien mengsel en streptozotosien (STZ). Vervolgens is die vermoë van die C. maculata ekstrak, mangiferin en NAC om die RIN-5Fselle teen hierdie stressors te beskerm, beoordeel deur die meting van β-sellewensvatbaarheid, funksie en oksidatiewe stres. Sellewensvatbaarheid is bepaal met 3-(4,5-dimetielthiazol-2-yl)-2,5-difenieltetrazolium bromied, adenosientrifosfaat en anneksien-V and propidium jodied toetse. Selfunksie is geëvalueer d.m.v. glukose gestimuleerde insuliensekresie, selproliferasie en sellulêre kalsium bepaling. Oksidatiewe stres in die RIN-5Fselle is geëvalueer d.m.v. diaminofluorescein-FM en dihidroethidium fluoressensie bepalings, asook meting van superoksied dismutase ensiemaktiwiteit. Die in vitro bevindings is daarna in geїsoleerde rot pankreaseilande bevestig deur die metodes en modelle wat in die RIN-5F eksperimente gebruik is. Die antidiabetiese effekte van die ekstrak, NAC en metformien in STZ-geїnduseerde diabetiese Wistar rotte is bepaal d.m.v. twee behandlingsregimes, d.w.s. die behandeling van rotte met gevestigde diabetes of deur die behandeling voor die induksie van diabetes te begin. Glukose metabolisme, oksidatiewe stres en veranderinge in die pankreasmorfologie is ondersoek d.m.v. orale glukose toleransie toetse en die bepaling van serum insulien, trigliseriedes, nitriete, katalase en glutationien. Hepatiese tiobarbituursuur reaktiewe stowwe en nitrotirosien is ook geëvalueer. Immunohistochemiese kleuring van pankreas snitte is gebruik vir morfologiese assessering van insulien, glukagon en MIB-5. Die ekstrak het mees opvallend β-sel lewensvatbaarheid en funksie verbeter, terwyl oksidatiewe stres verminder is in die STZ- en PA-geїnduseerde toksisiteitmodelle. Bogenoemde effekte van die ekstrak in vitro en in die geїsoleerde eilande was vergelykbaar met die van NAC. Mangiferin was minder effektief, met slegs ‘n marginale verbetering in die funksie van RIN-5Fselle en eilande, asook t.o.v. oksidatiewe stres. Behandeling van die Wistar rotte met die ekstrak voor induksie van diabetes met STZ was net so effektief, of selfs beter as metformien in terme van verbeterde glukosetoleransie, trigliseriedvlakke en die morfologie van pankreas eilande wat verband gehou het met β-sel funksie. Hierdie studie het getoon dat die waterekstrak van ongefermenteerde C. maculata pankreas β-selle teen veral STZ- en PA-geїnduseerde toksisiteit in vitro en ex vivo beskerm het. In vivo het behandeling met die ekstrak voor en na induksie van diabetes, glukosemetabolisme en die morfologie van pankreas eilande in STZ-geїnduseerde diabetiese Wistar rotte verbeter.
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Otter, 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.
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Tziampazis, Evangelos. "Engineering functional, insulin-secreting cell systems : effect of entrapment on cellular environment and secretory response." Thesis, Georgia Institute of Technology, 1993. http://hdl.handle.net/1853/10026.
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Swann, Louise Crystelle. "Evaluation of the presence, function and possible mechanism of action of the extracellular calcium receptor in pancreatic beta cells." Thesis, University of Ulster, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415064.
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Odori, Shinji. "GPR119 expression in normal human tissues and islet cell tumors: evidence for its islet-gastrointestinal distribution, expression in pancreatic beta and alpha cells, and involvement in islet function." Kyoto University, 2013. http://hdl.handle.net/2433/174786.
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Barlow, Jonathan. "Mitochondrial involvement in pancreatic beta cell glucolipotoxicity." Thesis, University of Plymouth, 2015. http://hdl.handle.net/10026.1/3314.
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High circulating glucose and non-esterified free fatty acid (NEFA) levels can cause pancreatic β-cell failure. The molecular mechanisms of this β-cell glucolipotoxicity are yet to be established conclusively. In this thesis by exploring mitochondrial energy metabolism in INS-1E insulinoma cells and isolated pancreatic islets, a role of mitochondria in pancreatic β-cell glucolipotoxicity is uncovered. It is reported that prolonged palmitate exposure at high glucose attenuates glucose-stimulated mitochondrial respiration which is coupled to ADP phosphorylation. These mitochondrial defects coincide with an increased level of mitochondrial reactive oxygen species (ROS), impaired glucose-stimulated insulin secretion (GSIS) and decreased cell viability. Palmitoleate, on the other hand, does not affect mitochondrial ROS levels or cell viability and protects against the adverse effects of palmitate on these phenotypes. Interestingly, palmitoleate does not significantly protect against mitochondrial respiratory or insulin secretion defects and in pancreatic islets tends to limit these functions on its own. Furthermore, strong evidence suggests that glucolipotoxic-induced ROS are of a mitochondrial origin and these ROS are somehow linked with NEFA-induced loss in cell viability. To explore the mechanism of glucolipotxic-induced mitochondrial ROS and associated cell loss, uncoupling protein-2 (UCP2) protein levels and activity were probed in NEFA exposed INS-1E cells. It is concluded that UCP2 neither mediates palmitate-induced mitochondrial ROS production and the related cell loss, nor protects against these deleterious effects. Instead, UCP2 dampens palmitoleate protection against palmitate toxicity. Collectively, these data shed important new light on the area of glucolipotoxicity in pancreatic β-cells and provide novel insights into the pathogenesis of Type 2 diabetes.
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Cui, Ju, and 崔菊. "Kinesin-1 in pancreatic beta cell and renal epithelial cell." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hdl.handle.net/10722/197835.
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Hanna, Katie. "Novel mechanisms of glucolipotoxic pancreatic beta cell death." Thesis, Nottingham Trent University, 2018. http://irep.ntu.ac.uk/id/eprint/35356/.
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Glucolipotoxicity (GLT) is the term given to the combined and damaging effect of increased glucose and fatty acid levels on pancreatic beta cells (β-cells) (Poitout et al, 2010). There is mounting evidence that glucolipotoxicity is the cause of the decline in β-cell function found in type 2 diabetes (T2D). T2D is a chronic metabolic disorder characterised by sustained elevated blood glucose and free fatty acids, with a continuously increasing prevalence (Olokoba et al, 2012). It is estimated 415 million people currently are living with diabetes and 193 million are undiagnosed, of those 90% are T2D cases. (chatterjee et al, 2017). There are multiple aims in this thesis including the identification of GLT-induced inflammatory pathways of the pancreatic β-cell resulting from NF-κB activation. To identify novel transcription factors associated with GLT-induced reduction in insulin secretion and insulin gene expression and whether their expression is associated with the presence CD40. To observe whether the addition of carnosine to cultured cells can prevent/reverse the up-regulation in GLT-induced factors which potentially result in β-cell damage. Finally, to observed whether GLT can induce histone modifications resulting from disruption in the TCA cycle. To mimic GLT conditions INS-1 rat pancreatic β-cells were cultured in media supplemented with 28mM glucose, 200µM palmitic acid and 200µM oleic acid. The results showed following 5-day incubation ±GLT, there was an increase in TNF receptor CD40 and a CD40-dependent increase in NF-κB. Further to this exposure of INS-1 cells to GLT conditions resulted in a 3.7-fold increase in iNOS mRNA and increased 4-HNE and 3-NT adduct formation (43.4% and 33% respectively) indicating potential GLT-induced β-cell damage. The addition of 10mM carnosine was able to prevent/reverse the up-regulation of GLT-induced NF-κB activity, iNOS protein expression and 4-HNE and 3-NT adduction, identifying it as a potential therapeutic strategy for T2D. GLT-induced up-regulation of CD40 is also shown to be involved in the modulation of various genes, including insulin. siRNA down-regulation of CD40 resulted in increased insulin gene expression via modulation of ID4. Independent of CD40, a protein usually associated with MODY is observed. GLT results in 33.3% down-regulation of HNF4α, which has a knock-on effect on Rab protein expression resulting in down-regulation of insulin secretion. There by indicating that HNF4α is important in normal insulin secretion. This research found that GLT can result in acetylation of histones H3 and H4, subsequent to TCA cycle dysregulation and disruption to fatty acid synthesis and cholesterol biosynthesis pathways, indicating that GLT can affect gene transcription.
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Hill, Jennifer. "Bacterial Regulation of Host Pancreatic Beta Cell Development." Thesis, University of Oregon, 2018. http://hdl.handle.net/1794/23140.
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Diabetes is a metabolic disease characterized by the loss of functional pancreatic beta cells. The incidence of diabetes has risen rapidly in recent decades, which has been attributed at least partially to alterations in host-associated microbial communities, or microbiota. It is hypothesized that the loss of important microbial functions from the microbiota of affected host populations plays a role in the mechanism of disease onset. Because the immune system also plays a causative role in diabetes progression, and it is well documented that immune cell development and function are regulated by the microbiota, most diabetes microbiota research has focused on the immune system. However, microbial regulation is also required for the development of many other important tissues, including stimulating differentiation and proliferation. We therefore explored the possibility that the microbiota plays a role in host beta cell development. Using the larval zebrafish as a model, we discovered that sterile or germ free (GF) larvae have a depleted beta cell mass compared to their siblings raised in the presence of bacteria and other microbes. This dissertation describes the discovery and characterization of a rare and novel bacterial gene, whose protein product is sufficient to rescue this beta cell developmental defect in the GF larvae. Importantly, these findings suggest a possible role for the microbiota in preventing or prolonging the eventual onset of diabetes through induction of robust beta cell development. Furthermore, the loss of rare bacterial products such as the one described herein could help to explain why low diversity microbial communities are correlated with diabetes.
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Hrvatin, Sinisa. "Exploring the Use of Human Pluripotent Stem Cells to Create Functional Pancreatic \(\beta\) Cells." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10728.
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Directed differentiation of human pluripotent stem cells (hPSCs) has the potential to produce human cell types that can be used for disease modeling and cell transplantation. Two key challenges in the differentiation from hPSCs to \(\beta\) cells are the specification from pancreatic progenitors to insulin-expressing \((INS^+
)\) cells and the maturation of \(INS^+\) cells into glucose responsive β cells. To address the first, two high-content chemical screens identified PKC inhibitors as inducers of \(INS^+\) cells from pancreatic progenitors. PKC inhibition generated up to tenfold more \(INS^+\) cells while PKC agonists blocked differentiation into \(INS^+\) cells. Transplantation of \(PKC\beta\) inhibitor-treated pancreatic progenitors, containing higher
proportions of endocrine progenitors and endocrine cells, resulted in mature \(\beta\) cells showing higher levels of glucose-stimulated human c-peptide production in vivo. This indicates that in vitro derived \(INS^+\)
cells might be competent to mature into functional \(\beta\) cells. To address the second challenge, we first studied mouse and human \(\beta\) cell maturation in vivo. Postnatal mouse \(\beta\) cell maturation was marked by an increase in the glucose threshold for insulin secretion and by expression of the gene urocortin 3. To study human \(\beta\) cell maturation, a Method for Analyzing RNA following Intracellular Sorting (MARIS) was developed and used for transcriptional profiling of sorted human fetal and adult \(\beta\) cells. Surprisingly, transcriptional differences between human fetal and adult \(\beta\) cells did not resemble differences between mouse fetal and adult \(\beta\) cells, calling into question inter-species homology at the late stages of development. A direct comparison between hPSC-derived \(INS^+\) cells, and \(\beta\) cells produced during human development is essential to validate directed differentiation and provide a roadmap for maturation of hPSC-derived \(INS^+\) cells. Genome-wide transcriptional analysis of sorted \(INS^+\) cells derived from three hPSC-lines suggest that different lines produce highly similar \(INS^+\) cells, confirming robustness of directed differentiation protocols. Furthermore, nonfunctional hPSC-derived \(INS^+\) cells resemble human fetal \(\beta\) cells, which are distinct from adult \(\beta\) cells. We therefore suggest that in vitro directed differentiation mimics normal human development and reveal differences in gene expression that may account for the functional differences between hPSC-derived \(INS^+\) cells and true \(\beta\) cells.
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Gray, Elizabeth. "Functional significance of the extracellular calcium sensing receptor on pancreatic beta cells." Thesis, King's College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416004.
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Chung, Won-suk. "Induction of pancreatic beta cells in zebrafish." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3352460.
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Dronfield, David Martin. "Viruses, islet cell antibodies and pancreatic B-cell function." Thesis, Queen Mary, University of London, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281595.
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Robertson, Heather. "Endothelin-1 and pancreatic islet cell function." Thesis, University of Nottingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416286.
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Westermark, Pål. "Models of the metabolism of the pancreatic beta-cell." Doctoral thesis, KTH, Numerical Analysis and Computer Science, NADA, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-408.
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The pancreatic β-cell secretes insulin in response to a raised blood glucose level. Deficiencies in this control system are an important part of the etiology of diabetes. The biochemical basis of glucose-stimulated insulin secretion is incompletely understood, and a more complete understanding is an important component in the quest for better therapies against diabetes.
In this thesis, mathematical modeling has been employed in order to increase our understanding of the biochemical principles that underlie glucosestimulated insulin secretion of the pancreatic β-cell. The modeling efforts include the glycolysis in theβ-cell with particular emphasis on glycolytic oscillations. The latter have earlier been hypothesized to be the cause of normal pulsatile insulin secretion. This model puts this hypothesis into quantitative form and predicts that the enzymes glucokinase and aldolase play important roles in setting the glucose concentration threshold governing oscillations. Also presented is a model of the mitochondrial metabolism in the β-cell, and of the mitochondrial shuttles that connect the mitochondrial metabolism to the glycolysis. This model gives sound explanations to what was earlier thought to be paradoxical behavior of the mitochondrial shuttles during certain conditions. Moreover, it predicts a strong signal from glucose towards cytosolic NADPH formation, a putative stimulant of insulin secretion. The model also identifies problems with earlier interpretations of experimental results regarding the β- cell mitochondrial metabolism. As an aside, an earlier proposed conceptual model of the generation of oscillations in the TCA cycle is critically analyzed.
Further, metabolic control analysis has been employed in order to obtain mathematical expressions that describe the control by pyruvate dehydrogenase and fatty acid oxidation over different aspects of the mitochondrial metabolism and the mitochondrial shuttles. The theories developed explain recently observed behavior of these systems and provide readily testable predictions.
The methodological aspects of the work presented in the thesis include the development of a new generic enzyme rate equation, the generalized reversible Hill equation, as well as a reversible version of the classical general modifier mechanism of enzyme action.
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Yang, Yu Hsuan Carol. "Identification and characterization of pancreatic beta-cell survival factors." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/46424.
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Hughes, Jonathan Martyn. "Streptozotocin and sugar transport in pancreatic beta cell lines." Thesis, University of Bath, 1993. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386772.
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Farr, Ryan. "Molecular Markers of Pancreatic β-cell Death." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17308.
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Abstract Loss of insulin-producing β-cells is central to the development of Type 1 diabetes (T1D). Currently, we lack diagnostic tools to quantitate this β-cell loss. Non-protein coding RNAs called microRNAs (miRNAs/miRs) play an important role in islet development and function. Recent detection of miRNAs in peripheral circulation, has renewed interest in microRNA biomarkers of diabetes. Comparably, circulating insulin cell-free (cf)DNA has been proposed as a direct biomarker of β-cell death. DNA methylation studies have identified specific sites within DNA that are unmethylated in β-cells but methylated in other cell types, thus providing a handle to discriminate between cfDNA from β-/non-β-cells. Previous research carried out in the Hardikar lab identified a signature of 20 miRNAs (the ‘RAPID’ signature) with potential as a biomarker of β-cell death. The RAPID signature was revised to accommodate other microRNAs finally constituting a panel of 50 microRNAs (PREDICT T1D panel). An analysis of these 50 miRNAs, as well as insulin cfDNA in serum/plasma from individuals before, during and after clinical diagnosis of T1D is presented. Human islet cell death assays using sodium nitroprusside exposure identified a subset of 27 miRNAs and insulin cfDNA associated with islet cell stress/death. Non-obese diabetic mice (N=32) were found to have elevated candidate miRNAs prior to immune infiltration and glycaemic dysfunction. This trend was also noted in the human progression to T1D; 26 miRNAs were elevated in (N=19) high-risk individuals and those at diagnosis (N=199) but decreased within 6-weeks after diagnosis. Furthermore, candidate miRNAs exhibited differential abundance with disease duration, residual C-peptide, and microvascular complications in 180 subjects with prolonged T1D. At diagnosis, miRNAs and cfDNA associated with GAD III autoantibody titres (N=167 P-values range from 0.044 to <0.0001) and HbA1c levels (N=187, P-values range from 0.047 to 0.00095). Such biomarkers may inform medical researchers as to how to predict the development of T1D, monitor response to interventions such as islet transplantation, vaccines & drugs aiming to retard β-cell loss. In basic research, such an assay may help to select treatments to block β-cell death and guide the development of new treatments to lessen the burden of diabetes.
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Halvorsen, Tanya L. "Growth regulation and differentiation in the human pancreatic beta cell /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2001. http://wwwlib.umi.com/cr/ucsd/fullcit?p3000408.
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