Дисертації з теми "Pancreatic β-islet cell"
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Mokhtari, Dariush. "MEKK-1 and NF-κB Signaling in Pancreatic Islet Cell Death". Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8896.
Повний текст джерелаTian, Geng. "On the Generation of cAMP Oscillations and Regulation of the Ca2+ Store-operated Pathway in Pancreatic Islet α- and β-cells". Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-191852.
Повний текст джерелаCadavez, Trigo Lisa. "Islet amylold in type 2 diabetes: The role of chaperones in endoplasmic reticulum stress and amyloid formation in pancreatic β-cell". Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/290734.
Повний текст джерелаNgamjariyawat, Anongnad. "The beneficial Effects of Neural Crest Stem Cells on Pancreatic β–cells". Doctoral thesis, Uppsala universitet, Institutionen för neurovetenskap, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-233157.
Повний текст джерелаKanase, 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.
Повний текст джерелаElshebani, Asma Basheir. "Studies of the Effect of Enterovirus Infection on Pancreatic Islet Cells." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7208.
Повний текст джерелаZallocco, Lorenzo. "Protein post translational modifications and diabetes. Pro-inflammatory cytokines reshape lysin acetylome of rat clonal β cells and human pancreatic islets". Doctoral thesis, Università di Siena, 2022. http://hdl.handle.net/11365/1203952.
Повний текст джерелаBerg, Anna-Karin. "Enterovirus Infections of β-Cells : A Mechanism of Induction of Type 1 Diabetes?" Doctoral thesis, Uppsala University, Department of Women's and Children's Health, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6019.
Повний текст джерелаThe process of β-cell destruction that leads to type 1 diabetes (T1D) is incompletely understood and it is believed to be a result of both genetic and environmental factors. Enterovirus (EV) infections of the β-cells have been proposed to be involved, however, the effects of EV infections on human β-cells have been little investigated. This thesis summarises studies of three different Coxsackie B4 virus strains that have previously been shown to infect human islets. The effects of infections with these EV were studied in vitro in human islets and in a rat insulin-producing cell line. In addition, a pilot study was performed on isolated human islets to investigate the ability to treat such infections with an antiviral compound.
It was found that one of the virus strains replicated in human β-cells without affecting their main function for at least seven days, which in vivo may increase a virus’s ability to persist in islets.
Nitric oxide was induced by synthetic dsRNA, poly(IC), but not by viral dsRNA in rat insulinoma cells in the presence of IFN-γ, suggesting that this mediator is not induced by EV infection in β-cells and that poly(IC) does not mimic an EV infection in this respect.
All three virus strains were able to induce production of the T-cell chemoattractant interferon-γ-inducible protein 10 (IP-10) during infection of human islets, suggesting that an EV infection of the islets might trigger insulitis in vivo.
Antiviral treatment was feasible in human islets, but one strain was resistant to the antiviral compound used in this study.
To conclude, a potential mechanism is suggested for the involvement of EV infections in T1D. If EV infections induce IP-10 production in human islet cells in vivo, they might recruit immune cells to the islets. Together with viral persistence and/or virus-induced β-cell damage, this might trigger further immune-mediated β-cell destruction in vivo.
Brusco, Noemi. "Phenotyping of single pancreatic islets reveals a crosstalk between proinsulin intracellular alteration, ER stress and loss of β cell identity in impaired glucose tolerant and type 2 diabetic patients". Doctoral thesis, Università di Siena, 2021. http://hdl.handle.net/11365/1127686.
Повний текст джерелаAhmed, Meftun. "Oscillatory Ca2+ signaling in glucose-stimulated murine pancreatic β-cells : Modulation by amino acids, glucagon, caffeine and ryanodine". Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1408.
Повний текст джерелаJaffredo, Manon. "Communications intercellulaires dynamiques au sein des îlots pancréatiques analysées par multi-electrode arrays : rôles physiologiques et applications biotechnologiques en diabétologie." Thesis, Bordeaux, 2021. http://www.theses.fr/2021BORD0120.
Повний текст джерелаPancreatic islets are the main sensor of glycaemia and they integrate all the metabolic and hormonal inputs to adapt in real time the secretion of hormones such as insulin by β cells and glucagon by α cells. In type 1 diabetes (T1D) β cells are destroyed by immune attack, and in T2D, β cell mass, function and the intra-islet network are altered. The islet micro-organs are highly reactive due to their electrical properties encoding rapid information and due to intercellular communications between β cells and β/non-β cells. Nevertheless, non-invasive, high resolution and long-term approaches for analysis are still lacking. Extracellular electrophysiology with multi-electrode arrays (MEAs) allows this analysis of islets by measuring both cellular as well as multicellular signals (SPs) due to β cell coupling. During my PhD, I used MEAs (i) to explore islet physiology/pathophysiology and (ii) for biotechnological applications in diabetology. I have shown that biphasic kinetics of insulin secretion are encoded by SPs through dynamic changes in β cell coupling. An important intestinal hormone (GLP-1) increases the 2nd phase of β-cell activity while diabetic conditions (glucotoxicity) reduce the 1st phase. Islet responses to nutrients also require α/β cell cooperation since α cell ablation in the inducible GluDTR mice model reduced both the basal and 2nd phase of β cell activity generated by glucose and a physiological mix of amino acids. I have also performed the electrophysiological characterization of human β cells derived from induced pluripotent stem cells (iPSC), determined their coupling, established their quality control and shown the functional impact of a mutation of interest (ZnT8) edited by CRISPR/Cas9. A functional quality control of human islets prior to transplantation in T1D patients was also performed for correlations with clinical data. Finally, my SP recordings analyzed in real time by microelectronics has contributed to validate an in silico model of biosensor in a FDA-approved simulator of T1D patients. In conclusion, my work demonstrates (i) the role of intra-islet communications in the dynamic physiological adaptation of these micro-organs, (ii) and that detailed characterization of SPs opens new applications from artificial pancreas to personalized cell therapy
Andersson, Annika K. "Role of Inducible Nitric Oxide Synthase and Melatonin in Regulation of β-cell Sensitivity to Cytokines". Doctoral thesis, Uppsala University, Department of Medical Cell Biology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3537.
Повний текст джерелаThe mechanisms of β-cell destruction leading to type 1 diabetes are complex and not yet fully understood, but infiltration of the islets of Langerhans by autoreactive immune cells is believed to be important. Activated macrophages and T-cells may then secrete cytokines and free radicals, which could selectively damage the β-cells. Among the cytokines, IL-1β, IFN-γ and TNF-α can induce expression of inducible nitric synthase (iNOS) and cyclooxygenase-2. Subsequent nitric oxide (NO) and prostaglandin E2 (PGE2) formation may impair islet function.
In the present study, the ability of melatonin (an antioxidative and immunoregulatory hormone) to protect against β-cell damage induced by streptozotocin (STZ; a diabetogenic and free radical generating substance) or IL-1β exposure was examined. In vitro, melatonin counteracted STZ- but not IL-1β-induced islet suppression, indicating that the protective effect of melatonin is related to interference with free radical generation and DNA damage, rather than NO synthesis. In vivo, non-immune mediated diabetes induced by a single dose of STZ was prevented by melatonin.
Furthermore, the effects of proinflammatory cytokines were examined in islets obtained from mice with a targeted deletion of the iNOS gene (iNOS -/- mice) and wild-type controls. The in vitro data obtained show that exposure to IL-1β or (IL-1β + IFN-γ) induce disturbances in the insulin secretory pathway, which were independent of NO or PGE2 production and cell death. Initially after addition, in particular IL-1β seems to be stimulatory for the insulin secretory machinery of iNOS –/- islets, whereas IL-1β acts inhibitory after a prolonged period. Separate experiments suggest that the stimulatory effect of IL-1β involves an increased gene expression of phospholipase D1a/b. In addition, the formation of new insulin molecules appears to be affected, since IL-1β and (IL-1β + IFN-γ) suppressed mRNA expression of both insulin convertase enzymes and insulin itself.
Ahmed, Meftun. "Oscillatory Ca2+ signaling in glucose-stimulated murine pancreatic β-cells : Modulation by amino acids, glucagon, caffeine and ryanodine". Doctoral thesis, Uppsala University, Department of Medical Cell Biology, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1408.
Повний текст джерелаOscillations in cytoplasmic Ca2+ concentration ([Ca2+]i) is the key signal in glucose-stimulated β-cells governing pulsatile insulin release. The glucose response of mouse β-cells is often manifested as slow oscillations and rapid transients of [Ca2+] i. In the present study, microfluorometric technique was used to evaluate the role of amino acids, glucagon, ryanodine and caffeine on the generation and maintenance of [Ca2+] i oscillations and transients in individual murine β-cells and isolated mouse pancreatic islets. The amino acids glycine, alanine and arginine, at around their physiological concentrations, transformed the glucose-induced slow oscillations of [Ca2+] i in isolated mouse β-cells into sustained elevation. Increased Ca2+ entry promoted the reappearance of the slow [Ca2+] i oscillations. The [Ca2+] i oscillations were more resistant to amino acid transformation in intact islets, supporting the idea that cellular interactions are important for maintaining the oscillatory activity. Individual rat β-cells responded to glucose stimulation with slow [Ca2+] i oscillations due to periodic entry of Ca2+ as well as with transients evoked by mobilization of intracellular stores. The [Ca2+] i oscillations in rat β-cells had a slightly lower frequency than those in mouse β-cells and were more easily transformed into sustained elevation in the presence of glucagon or caffeine. The transients of [Ca2+] i were more common in rat than in mouse β-cells and often appeared in synchrony also in cells lacking physical contact. Depolarization enhanced the generation of [Ca2+] i transients. In accordance with the idea that β-cells have functionally active ryanodine receptors, it was found that ryanodine sometimes restored oscillatory activity abolished by caffeine. However, the IP3 receptors are the major Ca2+ release channels both in β-cells from rats and mice. Single β-cells from ob/ob mice did not differ from those of lean controls with regard to frequency, amplitudes and half-widths of the slow [Ca2+] i oscillations. Nevertheless, there was an excessive firing of [Ca2+] i transients in the β-cells from the ob/ob mice, which was suppressed by leptin at close to physiological concentrations. The enhanced firing of [Ca2+] i transients in ob/ob mouse β-cells may be due to the absence of leptin and mediated by activation of the phospholipase C signaling pathway.
Khand, Bishnu. "Studies on differentiation of mouse GS-2 ES-cells to pancreatic β-islet-like cells and their functional maturation status". Thesis, 2018. https://etd.iisc.ac.in/handle/2005/5392.
Повний текст джерелаJohnson, Justin Sean. "Pdx-1 modulates endoplasmic reticulum calcium homeostasis in the islet β cell via transcriptional enhancement of SERCA2b". Thesis, 2014. http://hdl.handle.net/1805/6455.
Повний текст джерелаDiabetes mellitus affects an estimated 285 million people worldwide, and a central component of diabetes pathophysiology is diminished pancreatic islet beta cell function resulting in the inability to manage blood glucose effectively. The beta cell is a highly specialized metabolic factory that possesses a number of specialized characteristics, chief among these a highly developed endoplasmic reticulum (ER). The sarco endoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) pump maintains a steep Ca2+ gradient between the cytosol and ER lumen, and while the Pancreatic and duodenal homeobox 1 (Pdx-1) transcription factor is known to play an indispensable role in beta cell development and function, recent data also implicate Pdx-1 in the maintenance of ER health. Our data demonstrates that a decrease of beta cell Pdx-1 occurs in parallel with decreased SERCA2b expression in models of diabetes, while in silico analysis of the SERCA2b promoter reveals multiple putative Pdx-1 binding sites. We hypothesized that Pdx-1 loss under inflammatory and diabetic conditions leads to decreased SERCA2b with concomitant alterations in ER health. To test this, siRNA-mediated knockdown of Pdx-1 was performed in INS-1 cells. Results revealed reduced SERCA2b expression and decreased ER Ca2+, which was measured using an ER-targeted D4ER adenovirus and fluorescence lifetime imaging microscopy. Co-transfection of human Pdx-1 with a reporter fused to the human SERCA2 promoter increased luciferase activity three-fold relative to the empty vector control, and direct binding of Pdx-1 to the proximal SERCA2 promoter was confirmed by chromatin immunoprecipitation. To determine whether restoration of SERCA2b could rescue ER stress induced by Pdx-1 loss, Pdx1+/- mice were fed high fat diet for 8 weeks. Isolated islets from these mice demonstrated increased expression of spliced Xbp1, signifying ER stress, while subsequent SERCA2b overexpression in isolated islets reduced spliced Xbp1 levels to that of wild-type controls. These results identify SERCA2b as a direct transcriptional target of Pdx-1 and define a novel role for altered ER Ca2+ regulation in Pdx-1 deficient states.
"The role of cystic fibrosis transmembrane conductance regulator in insulin secretion in pancreatic islet β-cells". 2013. http://library.cuhk.edu.hk/record=b5549850.
Повний текст джерела在β細胞上,葡萄糖刺激的胰島素分泌伴隨著複雜的電活動,這種電活動被描述為細胞膜電位去极化疊加的動作電位的爆發。葡萄糖引起的ATP敏感的鉀離子通道(K[subscript Asubscript Tsubscript P])的關閉被普遍認為是β細胞去極化的初始事件,初始的去極化啟動了電壓依賴的鈣離子通道,由此產生的鈣離子內流成為構成動作電位的去極化電流,引起了細胞內鈣離子的震盪,從而引起胰島素的釋放。雖然氯離子電流被認為參與了β細胞去極化電流,但是,人們仍然不能確定是哪一種氯離子通道介導了這個去極化電流。在我們研究的第一部分,CFTR被證明功能性的表達在β細胞上,並且可以被葡萄糖激活。CFTR可以被葡萄糖激活这一性质,在CFTR超表達的CHO 细胞上被進一步驗證。在原代培養的β細胞與β細胞株RIN-5F细胞中的葡萄糖引起的全細胞電流、膜電位的去極化、動作電位的幅度與頻率、鈣震盪和胰島素的分泌可以被CFTR的抑制劑或缺陷所降低。與野生型小鼠相比,CFTR基因敲除的小鼠,禁食之後,具有更高的血糖濃度,然而其胰島素的濃度低。
我們研究中的第二部分,利用了數學模型去闡明CFTR 在胰島素分泌的電活動中的角色。結果顯示, CFTR電導的減低可以使細胞的細胞膜去極化,從而導致需要更高的電刺激去引發動作電位,这些結果證明了CFTR對於维持細胞膜電位的貢獻。同時增加細胞內氯離子濃度和CFTR的電導可以引起更大頻率的膜電位的震盪,這一點證明了氯離子對於細胞膜電位震盪有著重要的作用。在数学模型中,CFTR電導的降低可以消除通過改變ATP/ADP值所引起的電火花, 這與我們在試驗中發現的CFTR參與了葡萄糖引起的動作電位是一致的。總而言之,我們的数学模型證明了CFTR對於胰島素的分泌是非常重要的,它通過介導氯離子外流對細胞膜電位的產生貢獻並且參與了電火花的產生,所有這些都進一步驗證了我們在實驗部分的發現。
综上所述,現有的研究揭示了CFTR,通過對β細胞膜電位作用與参与了動作電位的產生,在葡萄糖刺激胰島素分泌过程中的鮮為人知的重要角色。這個發現為揭示CFRD的病理機制提供了全新的視角,並且可能為開發治療CFRD的方法帶来了曙光。
Cystic fibrosis (CF) is a recessive autosomal genetic disease resulted from mutations of cystic fibrosis transmembrane conductance regulator (CFTR). CF affects critically the lung, liver, pancreas, intestine and reproductive tract. CF patients also exhibit a high percentage of diabetes, which almost reach 50% in adult. The pathological cause of diabetes in CF patients, also called CF related diabetes (CFRD), is still controversial. It has been reported that CFTR expressed in the islet β cells, which is responsible for insulin secretion. However, the exact role of CFTR in islet β-cell and its relation to diabetes have been ignored. The present study aims to elucidate the role of CFTR in the process of insulin secretion by pancreatic islet β cells.
Glucose-stimulated insulin secretion is associated with a complex electrical activity in the pancreatic islet β-cell, which is characterized by a slow membrane depolarization superimposed with bursts of action potentials. Closing ATP-sensitive K⁺ channels (K[subscript Asubscript Tsubscript P]) in response to glucose increase is generally considered the initial event that depolarizes the β-cell membrane and activates the voltage-dependent Ca²⁺ channels, which constitutes the major depolarizing component of the bursting action potentials giving rise to the cytosolic calcium oscillations that trigger insulin release. While Cl⁻ has been implicated in an unknown depolarization current of the β-cell, the responsible Cl⁻ channel remains unidentified. In the first part of our study, we show functional expression of CFTR and its activation by glucose in the β-cell. Activation of CFTR by glucose was also demonstrated in CHO cell over-expression system. The glucose-elicited whole-cell currents, membrane depolarization, electrical bursts (both magnitude and frequency), Ca²⁺ oscillations and insulin secretion could be abolished or reduced by inhibitors/knockdown of CFTR in primary mouse β-cells or RIN-5F β-cell line, or significantly attenuated in isolated mouse islet β-cells from CFTR mutant mice compared to that of wildtype. Significantly increased blood glucose level accompanied with reduced level of insulin is found in CFTR mutant mice compared to the wildtype. The results strongly indicate a role of CFTR in the process of insulin secretion.
In the second part of our study, mathematical model is built up to clarify the role of CFTR in the electrical activity during insulin secretion. It is shown that reduction of CFTR conductance hyperpolarizes the membrane of the β-cell, for which it requires a larger electrical stimulus to evoke an action potential, indicating the contribution of CFTR to the membrane potential as demonstrated by our experimental results. Increase in intracellular Cl⁻ concentration and the conductance of CFTR result in higher frequency of membrane potential oscillations, demonstrating that Cl⁻ is crucial for the membrane potential oscillations. The electrical spikes induced by increase of ATP/ADP in the model are abolished by decreasing CFTR conductance, which is consistent with our findings that CFTR is involved in the generation of action potentials induced by glucose. In other word, our model demonstrates that CFTR is crucial for insulin secretion by its contribution to membrane potential and participating in the generation of electrical spikes via conducting Cl⁻ efflux, which confirms our findings in the experimental study.
Taken together, the present study reveals a previously unrecognized important role of CFTR in glucose-stimulated insulin secretion via contributing to the membrane potential and the participating in the generation of action potential in islet β cells. This finding sheds new light into the understanding of the pathogenesis of CFRD and may provide grounds for the development of new therapeutic approaches for CFRD.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Guo, Jinghui.
"December 2012."
Thesis (Ph.D.)--Chinese University of Hong Kong, 2013.
Includes bibliographical references (leaves 156-164).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.
Abstract --- p.i
摘要: --- p.iii
Acknowledgement: --- p.v
LIST OF PUBLICATIONS --- p.vi
Declaration --- p.viii
ABBREVIATIONS --- p.xi
LIST OF FIGURES --- p.xiii
Chapter Chapter 1: --- General introduction --- p.1
Chapter 1.1 --- The function of islet β cells and diabetes --- p.1
Chapter 1.1.1 --- The introduction of the pancreas --- p.1
Chapter 1.1.2. --- Glucose metabolism and blood glucose regulation --- p.6
Chapter 1.1.2.2 --- Blood glucose regulation --- p.7
Chapter 1.1.3 --- Insulin secretion by the islet β cell --- p.10
Chapter 1.1.4 --- Diabetes --- p.14
Chapter 1.2 --- Cystic fibrosis-related diabetes --- p.17
Chapter 1.2.1 --- Cystic fibrosis --- p.17
Chapter 1.2.2 --- CFTR --- p.19
Chapter 1.3 --- Mathematical model for insulin secretion --- p.25
Chapter 1.4 --- Aim and hypothesis --- p.27
Chapter 1.4.1 --- CFTR may be activated by glucose --- p.27
Chapter 1.4.2 --- Activation of CFTR may depolarize the membrane potential --- p.28
Chapter 1.4.3 --- CFTR-mediating Cl-efflux may be involved in the generation of electrical spikes --- p.28
Chapter 1.4.4 --- Calcium oscillation depends on CFTR --- p.28
Chapter 1.4.5 --- Insulin secretion --- p.29
Chapter 1.5 --- Approaches to test the hypothesis --- p.29
Chapter Chapter 2: --- Materials and Methods --- p.31
Chapter 2.1 --- Cell culture --- p.31
Chapter 2.1.1 --- RIN-5F cell --- p.31
Chapter 2.1.2 --- CHO cell --- p.31
Chapter 2.2 --- Islet isolation and culture --- p.32
Chapter 2.3 --- CFTR knockdown --- p.33
Chapter 2.4 --- Western blot --- p.35
Chapter 2.5 --- Immunofluorescence --- p.37
Chapter 2.6 --- Membrane potential (Vm) measurement --- p.38
Chapter 2.7 --- Intracellular chloride imaging --- p.39
Chapter 2.8 --- Intracellular calcium imaging --- p.40
Chapter 2.9 --- Patch-clamp --- p.40
Chapter 2.10 --- Blood glucose measurement --- p.42
Chapter 2.11 --- Insulin ELISA --- p.42
Chapter 2.12 --- Statistics --- p.42
Chapter Chapter 3: --- Contribution of CFTR on the eletrophysiological properties in insulin secretion --- p.43
Chapter 3.1 --- Introduction --- p.43
Chapter 3.2 --- Results --- p.45
Chapter 3.2.1 --- Functional expression of CFTR in mouse islet β cells --- p.45
Chapter 3.2.2 --- CFTR activation by glucose --- p.46
Chapter 3.2.3 --- Involvement of CFTR in the maintenance of membrane potential of islet β cells --- p.47
Chapter 3.2.4 --- CFTR is involved in the generation of spikes induced by glucose --- p.50
Chapter 3.2.5 --- Generation of spikes burst in the β cell depends on intracellular chloride. --- p.52
Chapter 3.2.6 --- Inhibition/mutation of CFTR attenuates calcium oscillation induced by glucose --- p.53
Chapter 3.2.7 --- Inhibition/mutation of CFTR impairs insulin secretion --- p.53
Chapter 3.3 --- Discussion --- p.71
Chapter Chapter 4: --- Mathematical model for the role of CFTR in the process of insulin secretion in islet β cell --- p.74
Chapter 4.1 --- Introduction to the mathematical modeling in the process of insulin secretion --- p.74
Chapter 4.2 --- Methods --- p.77
Chapter 4.2.1 --- Components in the model --- p.77
Chapter 4.2.2 --- Assumptions and approaches in modeling --- p.78
Chapter 4.2.3 --- Modeling ion channels and transporters --- p.79
Chapter 4.2.3.1 --- KATP channel --- p.79
Chapter 4.2.3.2 --- Sodium channel --- p.82
Chapter 4.2.3.3 --- Voltage Dependent calcium channel --- p.83
Chapter 4.2.3.4 --- NCX --- p.84
Chapter 4.2.3.5 --- Na-K pump --- p.85
Chapter 4.2.3.6 --- Kv channel --- p.87
Chapter 4.2.3.7 --- Ca pump --- p.88
Chapter 4.2.3.9 --- CFTR --- p.90
Chapter 4.2.3.10 --- NKCC --- p.91
Chapter 4.3 --- Results --- p.93
Chapter 4.3.1 --- Role CFTR in regulation of the basal membrane potential in β cells --- p.93
Chapter 4.3.2 --- Role of intracellular chloride concentration in the burst spikes induced by glucose --- p.95
Chapter 4.3.3 --- Role of CFTR in the burst spikes induced by glucose --- p.96
Chapter 4.4 --- Discussion --- p.105
Chapter Chapter 5: --- General discussion and conclusion --- p.109
Chapter 5.1 --- General discussion --- p.109
Chapter 5.1.1 --- Role of CFTR in endocrine pancreas and diabetes --- p.109
Chapter 5.1.2 --- Role of CFTR as a cell metabolic sensor --- p.111
Chapter 5.1.3 --- Role of CFTR in excitable cells --- p.113
Chapter 5.2 --- Conclusion --- p.114
Appendix A --- p.115
Appendix B --- p.118
Reference: --- p.156
Bansal, Pritpal. "Insulin-induced Suppression of A-type GABA Receptor Signaling in the INS-1 Pancreatic β-cell Line". Thesis, 2010. http://hdl.handle.net/1807/25419.
Повний текст джерела"Protective mechanism(s) of anti-oxidants in pancreatic-islet β-cells against glucose toxicity and oxidative stress". 2011. http://library.cuhk.edu.hk/record=b5896936.
Повний текст джерела"August 2011."
Thesis (M.Phil.)--Chinese University of Hong Kong, 2011.
Includes bibliographical references (leaves 123-131).
Abstracts in English and Chinese.
ABSTRACT --- p.i
論文摘要 --- p.vi
ACKNOWLEDGEMENTS --- p.ix
PUBLICATIONS --- p.x
Abstracts --- p.x
ABBREVIATIONS --- p.xii
Chapter 1. --- GENERAL INTRODUCTION --- p.1
Chapter 1.1. --- Diabetes --- p.1
Chapter 1.1.1. --- Overview --- p.1
Chapter 1.1.2. --- Diagnostic Criteria of Type-2 Diabetes --- p.2
Chapter 1.1.3. --- Type-2 Diabetes (T2DM) --- p.3
Chapter 1.1.3.1. --- Impaired Insulin Synthesis and Insulin Secretory Defects in Type-2 Diabetes --- p.3
Chapter 1.1.3.2. --- β-Cell Dysfunction --- p.5
Chapter 1.1.3.3. --- Insulin Resistance --- p.5
Chapter 1.1.4. --- Glucose Toxicity --- p.6
Chapter 1.1.4.1. --- Fasting Hyperglycemia --- p.8
Chapter 1.1.4.2. --- Postprandial Hyperglycemia --- p.8
Chapter 1.2. --- Oxidative Stress --- p.8
Chapter 1.2.1. --- ROS and Mitochondria --- p.8
Chapter 1.2.2. --- ROS Production by Mitochondria --- p.9
Chapter 1.2.3. --- The Relationship of Glucose Recognition by β-cells and Oxidative Stress --- p.11
Chapter 1.2.4. --- Important Roles of Glutathione in Pancreatic β-cells and Glutathione Synthesis --- p.14
Chapter 1.2.5. --- N-acetyl-L-cysteine - A Potential Drug Treatment for Type-2 Diabetes? --- p.17
Chapter 1.3. --- Role of F-actin Cytoskeleton on Glucose-induced Insulin Secretion --- p.18
Chapter 1.4. --- Current Clinical Treatments for Type-2 Diabetes Mellitus --- p.21
Chapter 1.4.1. --- Metformin --- p.22
Chapter 1.4.2. --- Sulfonylureas --- p.22
Chapter 1.4.3. --- Thiazolidinediones --- p.23
Chapter 1.4.4. --- Glinides (Meglitinide Analogues) --- p.23
Chapter 1.4.5. --- α-Glucosidase (AG) Inhibitors --- p.24
Chapter 1.4.6. --- Dipeptidyl Peptidase-4 (DPP-4) Inhibitors --- p.24
Chapter 1.4.7. --- (Clinical) Antioxidant Treatment --- p.24
Chapter 1.5. --- Animal Models Used in Type-2 Diabetes Research --- p.25
Chapter 1.6. --- Aims of Study --- p.27
Chapter 2. --- RESEARCH DESIGN & METHODS --- p.28
Chapter 2.1. --- Materials --- p.28
Table 1. Sources and concentrations of drugs tested in this study: --- p.28
Culture Medium - --- p.29
General Reagents --- p.29
Chapter 2.2. --- Isolation of Islets of Langerhans and Single Pancreatic β-Cells --- p.31
Chapter 2.3. --- Measurement of Mitochondrial ROS Levels --- p.32
Chapter 2.4. --- Measurement of Islets Insulin Release and Insulin Content --- p.34
Chapter 2.4.1. --- Preparation of Samples --- p.34
Chapter 2.4.2. --- Enzyme-Link Immunosorbent Assay (ELISA) --- p.35
Chapter 2.5. --- Immunocytochemistry --- p.35
Chapter 2.6. --- Data and Statistical Analysis --- p.37
Chapter 3. --- RESULTS --- p.38
Chapter 3.1. --- "Effects of L-NAC, Various Oxidative Stress Inducers/Reducers and Actin Polymerisation/Depolymerisation Inducers on Releasable Insulin Levels and Insulin Contents in Response to Low Glucose (5 mM) and High Glucose (15 mM) of Isolated Pancreatic Islets of (db+/m+) and (db+/db+) Mice" --- p.38
Chapter 3.1.1. --- Effect of L-NAC on Insulin Secretion and Insulin Contents --- p.38
Chapter 3.1.2. --- Effect of Cytochalasin B on Insulin Secretion and Insulin Contents --- p.39
Chapter 3.1.3. --- Effect of 4-Phenyl Butyric Acid on Insulin Secretion and Insulin Contents --- p.43
Chapter 3.1.4. --- Effect of Ursodeoxycholic Acid on Insulin Secretion and Insulin Contents --- p.46
Chapter 3.1.5. --- Effect of Hydrogen Peroxide on Insulin Secretion and Insulin Contents --- p.49
Chapter 3.1.6. --- Effect of Jasplakinolide on Insulin Secretion and Insulin Contents --- p.53
Chapter 3.1.7. --- Effect of Thapsigargin on Insulin Secretion and Insulin Contents --- p.57
Chapter 3.1.8. --- Effect of BSO on Insulin Secretion and Insulin Contents --- p.61
Chapter 3.2. --- "Effects of L-NAC, Various Oxidative Stress Inducers/Reducers and Actin Polymerisation/Depolymerisation Inducers on Mitochondrial ROS Levels in Response to High Glucose (15 mM) Challenge in Isolated Single Pancreatic β-Cells of (db +/m+) and (db +/db +) Mice" --- p.65
Chapter 3.2.1. --- "Effects of L-NAC (20 mM), 4-Phenyl Butyric Acid (4-PBA) (1 mM), Ursodeoxycholic Acid (UA) (500 μg/ml), H202 (200 μM), Thapsigargin (0.5 μM) and DL-Buthionine-[S,R]-Sulfoximine (BSO) (0.1 μM) Pre-treatments on Mitochondrial ROS Level in Response to High Glucose (15 mM) Challenge" --- p.65
Chapter 3.2.2. --- "Effects of L-NAC (20 mM), Cytochalasin B (10 μM) and Jasplakinolide (5 μM) Pre-treatments on Mitochondrial ROS Level in Response to High Glucose (15 mM) Challenge_" --- p.76
Chapter 3.3. --- "Effects of L-NAC, Various Oxidative Stress Inducers/Reducers and Actin Polymerisation/Depolymerisation Inducers on F-actin Cytoskeleton Levels Incubated in Low Glucose (5 mM) and High Glucose (15 mM) Medium in Single Pancreatic β-Cells of Non-Diabetic (db +/m+) and Diabetic (db +/db +) Mice" --- p.81
Chapter 4. --- DISCUSSION --- p.100
Chapter 4.1. --- General Discussion --- p.100
Chapter 5. --- SUMMARY --- p.120
Chapter 6. --- FUTURE PERSPECTIVES --- p.121
Chapter 7. --- REFERENCES --- p.123
Templin, Andrew Thomas. "Mechanisms of translational regulation in the pancreatic β cell stress response". Thesis, 2014. http://hdl.handle.net/1805/6162.
Повний текст джерелаThe islet beta cell is unique in its ability to synthesize and secrete insulin for use in the body. A number of factors including proinflammatory cytokines, free fatty acids, and islet amyloid are known to cause beta cell stress. These factors lead to lipotoxic, inflammatory, and ER stress in the beta cell, contributing to beta cell dysfunction and death, and diabetes. While transcriptional responses to beta cell stress are well appreciated, relatively little is known regarding translational responses in the stressed beta cell. To study translation, I established conditions in vitro with MIN6 cells and mouse islets that mimicked UPR conditions seen in diabetes. Cell extracts were then subjected to polyribosome profiling to monitor changes to mRNA occupancy by ribosomes. Chronic exposure of beta cells to proinflammatory cytokines (IL-1 beta, TNF-alpha, IFN-gamma), or to the saturated free fatty acid palmitate, led to changes in global beta cell translation consistent with attenuation of translation initiation, which is a hallmark of ER stress. In addition to changes in global translation, I observed transcript specific regulation of ribosomal occupancy in beta cells. Similar to other privileged mRNAs (Atf4, Chop), Pdx1 mRNA remained partitioned in actively translating polyribosomes during the UPR, whereas the mRNA encoding a proinsulin processing enzyme (Cpe) partitioned into inactively translating monoribosomes. Bicistronic luciferase reporter analyses revealed that the distal portion of the 5’ untranslated region of mouse Pdx1 (between bp –105 to –280) contained elements that promoted translation under both normal and UPR conditions. In contrast to regulation of translation initiation, deoxyhypusine synthase (DHS) and eukaryotic translation initiation factor 5A (eIF5A) are required for efficient translation elongation of specific stress relevant messages in the beta cell including Nos2. Further, p38 signaling appears to promote translational elongation via DHS in the islet beta cell. Together, these data represent new insights into stress induced translational regulation in the beta cell. Mechanisms of differential mRNA translation in response to beta cell stress may play a key role in maintenance of islet beta cell function in the setting of diabetes.
Maganti, Vijaykumar Aarthi. "Mechanisms of transcriptional regulation in the maintenance of β cell function". Thesis, 2015. http://hdl.handle.net/1805/7944.
Повний текст джерелаThe islet β cell is central to the maintenance of glucose homeostasis as the β cell is solely responsible for the synthesis of Insulin. Therefore, better understanding of the molecular mechanisms governing β cell function is crucial to designing therapies for diabetes. Pdx1, the master transcription factor of the β cell, is required for the synthesis of proteins that maintain optimal β cell function such as Insulin and glucose transporter type 2. Previous studies showed that Pdx1 interacts with the lysine methyltransferase Set7/9, relaxing chromatin and increasing transcription. Because Set7/9 also methylates non-histone proteins, I hypothesized that Set7/9-mediated methylation of Pdx1 increases its transcriptional activity. I showed that recombinant and cellular Pdx1 protein is methylated at two lysine residues, Lys123 and Lys131. Lys131 is involved in Set7/9 mediated augmented transactivation of Pdx1 target genes. Furthermore, β cell-specific Set7/9 knockout mice displayed glucose intolerance and impaired insulin secretion, accompanied by a reduction in the expression of Pdx1 target genes. Our results indicate a previously unappreciated role for Set7/9 in the maintenance of Pdx1 activity and β cell function. β cell function is regulated on both the transcriptional and translational levels. β cell function is central to the development of type 1 diabetes, a disease wherein the β cell is destroyed by immune cells. Although the immune system is considered the primary instigator of the disease, recent studies suggest that defective β cells may initiate the autoimmune response. I tested the hypothesis that improving β cell function would reduce immune infiltration of the islet in the NOD mouse, a mouse model of spontaneous type 1 diabetes. Prediabetic NOD mice treated with pioglitazone, a drug that improves β cell function, displayed an improvement in β cell function, a reduction in β cell death, accompanied by reductions in β cell autoimmunity, indicating that β cell dysfunction assists in the development of type 1 diabetes. Therefore, understanding the molecular mechanisms involved in β cell function is essential for the development of therapies for diabetes.
Benterki, Isma. "Rôles des facteurs de croissance dans la prolifération de la cellule β-pancréatique en réponse à un excès de nutriments : étude du facteur de croissance HB-EGF et du récepteur à l’EGF". Thèse, 2015. http://hdl.handle.net/1866/13131.
Повний текст джерелаType 2 diabetes (T2D) results from insulin resistance in peripheral tissues and impaired insulin secretion from the pancreatic β-cell. Over the time, compensation of the β cell islets for insulin resistance fails, and therefore leads to a gradual decline in β-cell function. Several factors may contribute to β-cell compensation. However, the cellular and molecular mechanisms underlying β-cell compensation remain unknown. The purpose of this thesis was to identify what mechanism could lead to β cell compensation in response to nutrients excess and specifically the increase in proliferation and β-cell mass. Thus, with increasing insulin resistance and circulating factors in the 6 month rats infused with glucose + intralipid, the hypothesis was made and confirmed in our study that the growth factor HB-EGF would activate the EGF receptor, and subsequent signaling pathways such as mTOR and FoxM1, both involved in the proliferation of the pancreatic beta-cell. Collectively, these results allow us to understand better the molecular mechanisms involved in the β cell compensation in the insulin resistance state and may serve as a potential new therapeutic approach to prevent or delay T2D development.
Amyot, Julie. "Rôles du stress du réticulum endoplasmique et de l'immunité innée dans l'inhibition de la transcription du gène de l'insuline : étude du facteur de transcription ATF6 et du récepteur TLR4." Thèse, 2011. http://hdl.handle.net/1866/6961.
Повний текст джерелаType 2 diabetes is characterized by insulin resistance and impaired insulin secretion from the pancreatic β-cell. Endoplasmic reticulum (ER) stress and innate immunity have both been reported to alter pancreatic β-cell function. However, it is not clear whether these factors can affect the transcription of the insulin gene. The aim of this thesis was to assess the role of ER stress and innate immunity in the regulation of the insulin gene. Pancreatic β-cells have a well-developed endoplasmic reticulum (ER) due to their highly specialized secretory function to produce insulin in response to glucose and nutrients. In a first study, using several approaches we showed that ATF6 (activating transcription factor 6), a protein implicated in the ER stress response, directly binds to the A5/Core of the insulin gene promoter in isolated rat islets. We also showed that overexpression of the active (cleaved) fragment of ATF6α, but not ATF6β, inhibits the activity of an insulin promoter-reporter construct. However, the inhibitory effect of ATF6α was insensitive to mutational inactivation or deletion of the A5/Core. Therefore, although ATF6 binds directly to the A5/Core of the rat insulin II gene promoter, this direct binding does not appear to contribute to its repressive activity. In recent years, the gut microbiota was proposed has an environmental factor increasing the risk of type 2 diabetes. Subjects with diabetes have higher circulating levels of lipopolysaccharides (LPS) than non-diabetic patients. Recent observations suggest that the signalling cascade activated by LPS binding to Toll-Like Receptor 4 (TLR4) exerts deleterious effects on pancreatic β-cell function; however, the molecular mechanisms of these effects are incompletely understood. We showed that exposure of isolated human, rat and mouse islets of Langerhans to LPS dose-dependently reduced insulin gene expression. This was associated in mouse and rat islets with decreased mRNA expression of two key transcription factors of the insulin gene, PDX-1 (pancreatic duodenal homeobox 1) and MafA (mammalian homologue of avian MafA/L-Maf). LPS repression of insulin, PDX-1 and MafA expression was not observed in islets from TLR4-deficient mice and was completely prevented in rat islets by inhibition of the NF-kB signalling pathway. These results demonstrate that LPS inhibits β-cell gene expression in a TLR4-dependent manner and via NF-kB signaling in pancreatic islets, suggesting a novel mechanism by which the gut microbiota might affect pancreatic β-cell function. Our findings provide a better understanding of the molecular mechanisms underlying insulin gene repression in type 2 diabetes, and suggest potential therapeutic targets that might prevent or delay the decline of β-cell function in the course of type 2 diabetes, which affects more than two million Canadians.