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Effekte von Adipozytokinen auf INS-1E Beta-ZellenSpinnler, Robert 27 August 2014 (has links)
ABSTRACT
Aims/hypothesis: Obesity is associated with a dysregulation of beta-cell and adipocyte function. The molecular interactions between adipose tissue and beta-cells are not yet fully elucidated. We investigated, whether or not the adipocytokine nicotinamide phosphoribosyltransferase (Nampt), which has been associated with obesity and type 2 diabetes mellitus (T2DM) directly influences beta-cell survival and function.
Methods: The effect of Nampt on viability of INS-1E cells was assessed by WST-1 assay. Apoptosis was measured by Annexin V/PI and TUNEL assay. Activation of apoptosis signaling pathways was evaluated. Adenylate kinase release was determined to assess cytotoxicity. Chronic and acute effects of the adipocytokine Nampt and its enzymatic product nicotinamide mononucleotide (NMN) on insulin secretion were assessed by glucose stimulated insulin secretion in human islets.
Results: While stimulation of beta-cells with the cytokines IL-1β, TNFα and IFN-γ or palmitate significantly decreased viability, Nampt showed no direct effect on viability in INS-1E cells or in human islets, neither alone nor in the presence of pro-diabetic conditions (elevated glucose concentrations and palmitate or cytokines). At chronic conditions over 3 days of culture, Nampt and its product NMN had no effects on insulin secretion. In contrast, both Nampt and NMN potentiated glucose stimulated insulin secretion acutely during 1h incubation of human islets.
Conclusion/interpretation: Nampt did influence neither beta-cell viability nor apoptosis but acutely potentiated glucose stimulated insulin secretion.
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Role of DHS in translation control of islet β-cell replication during high fat induced obesity and glucose intoleranceLevasseur, Esther Marie 12 July 2017 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Insulin resistance in liver, muscle, and adipose tissue almost invariably occurs
during obesity. To compensate, the insulin-producing β-cell increases insulin production
by expanding cellular mass. The inability of the β-cell to fully compensate leads to
hyperglycemia and ultimately type 2 diabetes. The enzyme deoxyhypusine synthase
(DHS) catalyzes the spermidine-dependent posttranslational modification of Lys50 of
eukaryotic translation initiation factor 5A (eIF5A) to form hypusine (Hyp). Studies have
demonstrated this modification of eIF5A to contribute to cellular proliferation in
cancerous cells, but its role in the physiologic proliferation of islet β-cells is unknown. I
hypothesized eIF5A-Hyp to be required for the proliferation of islet β cells during the
early phase of insulin resistance, allowing the β-cell to respond to the increased demand
for insulin to maintain glucose homeostasis. To test this hypothesis, deletion of DHS was
induced post-developmentally in β-cells by crossing Dhs-fl/fl mice with MIP1-CreERT
mice, and animals were fed for 1 or 4 weeks with a 60% kcal from fat diet (HFD) or
normal chow diet (NCD, 16% kcal from fat diet). NCD-fed and HFD-fed animals had
normal glucose homeostasis after one week feeding, regardless of genotype. However,
after 4 weeks of HFD, KO mice had significantly worse glucose intolerance compared to
control mice. eIF5A-Hyp levels increased in β-cells of control animals and as expected
remained low in the KO mice. β-cell proliferation was significantly increased after 1 week
of HFD as measured by PCNA staining, however KO mice showed no increase. Cyclin
D2 protein, but not mRNA, was increased in control animals fed a HFD; this protein
increase was not observed in KO animals. Furthermore, polyribosomal profile of
isolated islets of 1 week HFD-fed mice showed the Ccnd2 mRNA bound to the monoribosome fractions in the KO animals compared to the controls, resulting in
changes of global translation. Interestingly, Ccnd1 polyribosome to monoribosome ratio
showed no changes in translation compared to Ccnd2. Taken together, these results
suggest that DHS (and, consequently, eIF5A-Hyp) is necessary for the adaptive
proliferative and functional response of β-cells during high fat diet induced obesity and
glucose intolerance.
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The Roles of Danio Rerio Nrf2 Paralogs in Response to Oxidative Stress in the Pancreatic Beta CellDoszpoly, Agnes 06 1900 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Oxidative stress can disrupt cellular homeostasis, leading to cellular dysfunction and apoptosis. The Nrf2 transcription factor regulates the antioxidant response in cells by binding to antioxidant response elements (ARE) in DNA and activating genes of enzymes that combat oxidative stress. During the pathogenesis of diabetes mellitus (DM), β-cells are exposed to increased amounts of reactive oxygen species (ROS) that cause oxidative stress. Zebrafish (ZF) are excellent models for studying the dynamic mechanisms associated with DM pathogenesis, and we recently developed a ZF model of β-cell apoptosis caused by ROS. Two paralogs of Nrf2 have been identified in ZF, Nrf2a and Nrf2b, but their roles in pancreas development and/or β-cell survival are unknown. To investigate their roles, Nrf2a and Nrf2b antisense morpholinos (MO) were injected into Day 0 ZF embryos and analyzed over time. While Nrf2a MO showed no obvious phenotypes compared to WT, Nrf2b MO exhibited reduced pancreas size and islets with disrupted morphology. Ins:NTR Nrf2a MO showed reduced β-cell loss upon exposure to Metronidazole (MTZ) under generation of ROS compared to WT. Sequence analysis of ZF nrf2b in 3-day post-fertilization (dpf) embryos revealed a novel splice variant containing an additional exon that has not been described. Further investigation of Nrf2a and Nrf2b is likely to yield additional insights regarding the function and regulation of the NRF2-signaling pathway and their roles in β-cell protection under oxidative stress.
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Engineered human pluripotent stem cell lines for following differentiation into pancreatic islets and addressing their maturationZanfrini, Elisa 17 January 2024 (has links)
No description available.
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Pharmacology of the GLP-1 analog exenatide extended-release in healthy catsRudinsky, Adam Joseph 27 May 2015 (has links)
No description available.
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FLUOXETINE: EXAMINING THE SELECTIVE SEROTONIN RE-UPTAKE INHIBITOR’S EFFECTS ON SEROTONIN AND HEDGEHOG SIGNALING IN THE PANCREATIC BETA CELLAyyash, Ahmed January 2018 (has links)
Major depressive disorder (MDD) is one of the most common psychiatric illnesses worldwide, with pharmacotherapy as a first-line option for the management of this illness. The National Center for Health Statistics found that the use of antidepressants has increased by more than 4 fold in the last 20 years. While SSRI’s act centrally to treat MDD, their peripheral effects are often overlooked. Interestingly, components of the serotonergic system including the serotonin transporter (SERT), serotonin receptors, and enzymes important for serotonin synthesis (tryptophan hydroxylase 1 and 2; Tph1 and Tph2) are affected by SSRI treatment both centrally and peripherally. This disruption of serotonin signaling in the pancreas is of particular interest as there is a considerable link between the serotonin and hedgehog signaling pathways, both of which are important for pancreatic beta cell function. I hypothesize that pancreatic beta cell exposure to the SSRI fluoxetine in vitro will lead to altered hedgehog signaling ultimately resulting in a disruption in insulin secretion. / Thesis / Master of Science in Medical Sciences (MSMS)
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Effect of Exposure to Sulphur-containing Heterocyclic Aromatic Compounds on Beta Cell FunctionPerera, Ineli January 2020 (has links)
Type 2 diabetes (T2D) is characterized by impaired beta cell function. The generation of various types of cellular stresses, including oxidative stress and ER stress, and the induction of cellular senescence can contribute to beta cell dysfunction. Recent studies have demonstrated associations between petrochemical exposure and beta cell dysfunction, particularly through induction of cellular stress. One class of compounds, commonly found in crude oil, are sulphur-containing heterocyclic aromatic compounds (S-HACs). S-HACs have been previously demonstrated to induce cellular stress in mammalian cells. This thesis aims to determine if S-HACs can induce cellular stress in beta cells and, consequently, impair beta cell function, particularly insulin production.
Rat pancreatic beta cells, INS-1Es, were treated with two commonly occurring S-HACs, BNT(2,3D) and DBT, at doses which reflect non-occupational exposure levels. Upon treatment, various functional assays and qPCR experiments were performed for examining glucose uptake, ROS production, cellular senescence, ER stress and intracellular insulin production. It was observed that both BNT(2,3D) and DBT significantly increased glucose uptake and ROS production in the beta cells and upregulated the mRNA expression of various ER stress markers. In addition, BNT(2,3D) also induced cellular senescence, likely through a p53-independent pathway. This suggests that S-HACs may induce oxidative stress and ER stress in exposed beta cells, and some S-HACs may cause irreversible cell cycle arrest in response to these cellular stresses. However, intracellular insulin content in the INS-1Es was not altered by exposure to either S-HAC, suggesting that S-HACs may not impair insulin production. Nevertheless, the significant accumulation of ROS in S-HAC-exposed beta cells and the subsequent induction of cellular senescence by some S-HACs may alter other important beta cell functions, including mitochondrial function and insulin secretion, which could lead to the development of T2D; suggesting the potential for S-HACs to be novel beta cell toxicants. / Thesis / Master of Science (MSc)
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Engraftment of Pancreatic Islets in Alternative Transplantation Sites and the Feasibility of in vivo Monitoring of Native and Transplanted Beta-Cell MassEspes, Daniel January 2016 (has links)
Islet transplantation is a possible curative treatment for type 1 diabetes (T1D). Currently the liver dominates as implantation site, despite the many challenges encountered at this site. Acute hypoxia in islets transplanted to muscle and omentum, two possible alternative sites, was prevailing. However, it was rapidly reversed at both implantation sites, in contrast to when islets were transplanted intraportally. At the intramuscular site hypoxia was further relieved by co-transplantation of an oxygen carrier, polymerized hemoglobin, which also improved the functional outcome. The complement system was activated after islet transplantation to muscle, but did not hamper graft function. Both mouse and human islets transplanted to omentum become well re-vascularized and have a functional blood flow and oxygenation comparable with that of endogenous islets. Animals transplanted with islets to the omentum had a superior graft function compared with animals receiving intraportal islet grafts. Alloxan-diabetic animals were cured with a low number of islets both when the islets were implanted in the omentum and muscle. The islet grafts responded adequately to both glucose and insulin and displayed a favorable mRNA gene expression profile. A challenge in diabetes research and in islet transplantation is that there are no established techniques for quantifying beta-cell mass in vivo. By using radiolabeled Exendin-4, a GLP-1 receptor agonist, beta-cell mass after transplantation to muscle of mice was quantified. The results may well be translated to the clinical setting. By comparing the pancreatic accumulation of [11C]5-hydroxy tryptophan ([11C]5-HTP) as detected by positron emission tomography (PET) in T1D patients with that of healthy controls, a 66% decrease was observed. This may in fact represent the loss of beta-cells, taking into account that other cells within the islets of Langerhans are largely unaffected in T1D. In conclusion, the data presented support the use of alternative implantation sites for islet transplantation. In addition to improving the functional outcome this may enable more transplantations since the number of transplanted islets may be reduced. The techniques investigated for quantifying transplanted and endogenous beta-cell mass may greatly improve our knowledge of the pathophysiology of T1D and become a valuable tool for evaluation of beta-cell mass.
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Examining the Role of Endoplasmic Reticulum Stress in Pancreatic Beta-cell BiologyTeodoro, Tracy 31 August 2012 (has links)
Pancreatic beta-cells are responsible for secreting insulin into the circulation to maintain whole body glucose homeostasis. While pancreatic beta-cells have a large capacity to secrete insulin, their function progressively deteriorates during the pathogenesis of type 2 diabetes as a result of both genetic predisposition and environmental factors. Obesity is the largest risk factor for developing type 2 diabetes and is associated with various conditions that can impair normal beta-cell function, including excess free fatty acids, inflammation and insulin resistance. Accumulating evidence in the literature suggests that endoplasmic reticulum (ER) stress contributes to the molecular mechanism of pancreatic beta-cell failure during the progression of type 2 diabetes. In this thesis, I have examined the role of the ER stress sensor ATF6-alpha and also the ER-resident chaperone GRP78 in pancreatic beta-cell homeostasis and function. Work presented in Chapter 2 examined the function of naturally occurring ATF6-alpha protein variants associated with type 2 diabetes. I also examined the role of endogenous ATF6-alpha in pancreatic beta-cells, which is described in Chapter 3. Results from these analyses suggest that the ATF6-alpha gene is not a type 2 diabetes susceptibility gene; however, ATF6-alpha protein expression is important to beta-cell function and survival. Finally, ER stress markers have been detected in pancreatic beta-cells and insulin sensitive tissues (such as adipose and liver), which promote beta-cell dysfunction and insulin resistance, respectively. In Chapter 4, I examined the contribution of ER stress in beta-cell dysfunction specifically by generating transgenic mice over-expressing GRP78. The mice were subsequently challenged by high fat diet to determine their susceptibility to developing symptoms of type 2 diabetes. Indeed increased chaperone capacity in pancreatic beta-cells protected against obesity-induced glucose intolerance and insulin resistance. Overall, these data support the hypothesis that ER stress contributes to beta-cell dysfunction in type 2 diabetes progression.
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Diferenciace dospělých kmenových buněk na inzulín produkující beta buňky / Differentiation of adult stem cells into insulin-producing beta cellsKoblas, Tomáš January 2011 (has links)
Ph.D. Thesis abstract: Diabetes mellitus is a chronic disease characterized by a metabolic disorder in which there is a low level or complete lack of the insulin. Diabetes mellitus type 1 (DM1) is caused by an autoimmune reaction leading to the destruction of the insulin producing beta cells in the pancreas. In consequence, low or non-existent insulin production leads to a complete dependence on exogenous insulin supplementation. DM1 causes serious long-term complications. Although strict control of blood sugar could prevent the onset and development of diabetic complications only 5% of diabetic patients are able to achieve such control. Hence it is evident that the current methods of treatment are neither sufficient to treat this disease, nor prevent late complications in most patients. The most promising therapeutic approach in the treatment of diabetes is the restoring of insulin production. One such method is the transplantation of insulin-producing tissue. However, a lack of available insulin- producing tissue limits such therapeutic approach. Therefore an alternative source of insulin producing cells have to be found to obtain a sufficient amount of safe and efficient insulin producing tissue. Pancreatic stem/progenitor cells could represent such an available alternative source. Despite the evidence...
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