Mädler, Kathrin
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Mädler, Kathrin
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Mädler, Kathrin
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Maedler, Kathrin
Kathrin, Maedler
Maedler, K.
Mädler, K.
Maedler, Kathrin Prof. Dr.
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Item-typ:Veröffentlichung, Novel players in the rescue of ß-cells from inflammation-mediated destruction in type 2 diabetes mellitus(2013-10-15); ; ; Chronic inflammation is consequential to the etiology of both T1D and T2D. Cytokine and chemokine production by infiltrating macrophages and by ß-cells themselves in a diabetic milieu contributes to their destruction in inflamed islets and thus to progression of diabetes. In order to find potential targets for inhibition of this deleterious response of islets, the investigation of underlying mechanisms for triggering inflammation is essential. The expression of a novel family of adhesion molecules called Sialic acid-binding immunoglobulin-like lectins (Siglecs) in pancreatic islets was observed in cell type specific manner. Siglec-7, expressed on the ß-cells, was down-regulated in diabetes. Over-expression of Siglec-7 in cultured isolated islets prevented ß-cell dysfunction and apoptosis under chronic diabetic stimuli and also in diabetic islets. The protective effect of Siglec-7 was mediated by the inhibition of the NF-κB pathway and the subsequent decrease in cytokine secretion. Also, activated immune cells showed loss of Siglec-7 expression. Ultimately, restoration of Siglec-7 in stressed islets caused a reduction in the number of recruited migrating monocytes. Siglec-7 expression on ß-cells contributes to the inhibition of pro-inflammatory activation of these cells in diabetes. Restoration of Siglec-7 expression or signaling may be a potential therapeutic strategy to preserve ß-cell function and mass in the manifestation of diabetes. This strategy would not only rescue the ß-cells, but also inhibit systemic inflammation observed in T2D.Dissertation278 120 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Targeting beta-cell apoptosis in diabetes: The role of mammalian Sterile Kinase 1 (MST1)(2013-03-04); ; ; Pancreatic beta-cell death is the fundamental cause of type 1 and type 2 diabetes (T1/T2D). Loss of function and survival signals and the activation of pro-apoptotic mediators are characteristic for diabetic β-cells. Strategies to prevent beta-cell apoptosis and restore beta-cell survival are currently unavailable; thus in urgent need and critical for an effective treatment of both T1/T2D. The mechanisms of beta-cell death in a diabetic milieu are complex and not well defined; multiple triggering factors have been identified, which initiate a variety of signaling cascades in beta-cells that affect the expression of apoptotic genes and the subsequent beta-cell failure. The knowledge of the common key regulator of beta-cell apoptosis offers novel therapeutic targets for the treatment of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a serine threonine kinase, which mediates apoptosis in response to cytotoxic stress. MST1 is both, cleaved and activated by caspases, and also serves as an activator of caspases to amplify the apoptotic signaling pathways. In search for a common pro-apoptotic pathway, I investigated whether MST1 triggers beta-cell death in diabetes. In the present thesis, I explored the possible patho-physiological activation of MST1 in beta-cells under diabetic conditions and its downstream signaling, which may be a major common pathway of beta-cell death in diabetes. My data establish MST1 as a master regulator of apoptotic beta-cell death. I show that MST1 was strongly activated in beta-cells under diabetogenic conditions in vitro and in vivo. MST1 cleavage&phosphorylation was increased in human and mouse primary islets and in the beta-cell line INS-1E cells when exposed to a complex diabetic milieu. This correlated with the activation of known MST1 targets (H2B, JNK), increased beta- cell apoptosis and impaired insulin secretion. Notably, MST1 activation and beta-cell apoptosis were profoundly increased in diabetic islets from T2D patients, obese diabetic Leprdb/db mice as well as hyperglycemic high fat/ high sucrose fed mice. My data suggest a potential crosstalk between MST1 and pro-survival PI3K/AKT signaling pathways. MST1 and AKT negatively regulated each other and constitute a stress-sensitive survival pathway. Under acute stress conditions, AKT promoted cell survival by inhibiting MST1, but prolonged stress decreased AKT, which allowed pro-apoptotic MST1 signaling. Overexpression of MST1 itself increased beta-cell apoptosis and impaired function indicating 5 that MST1 alone is sufficient to promote beta-cell failure. MST1 overexpression decreased antiapoptotic PDX1, Bcl-2 and Bcl-xL and increased proapoptotic Bax, Bim and cytochrome c release and activation of caspase-9 and -3 indicating activation of the mitochondrial (intrinsic) pathway of cell death. The beta-cell transcription factor pancreatic duodenal homeobox-1 (PDX1) was identified as a novel MST1 substrate. MST1 overexpression in beta-cells strongly decreased PDX1 without changes in PDX1 mRNA levels; this demonstrates that the decrease in PDX1 expression was regulated at the post-transcriptional level and related to its reduced stability. MST1 directly phosphorylated PDX1 at Thr11, resulting in its ubiquitination and degradation and subsequent reduction in PDX1 target genes and loss of glucose-stimulated insulin secretion. Amazingly, PDX1-phosho-deficient mutant (T11-PDX1) restored PDX1 function and insulin secretion. This suggests (1) that MST1-induced PDX1 phosphorylation at T11 leads directly to PDX1 de-stabilization and impaired beta-cell function and (2) that PDX1 is a crucial target of MST1 in the regulation of beta-cell function. MST1 deficiency restored beta-cell function and survival in human and rodent cells. MST1-knock down in β-cells protected them from cell death induced by multiple diabetic stimuli. Importantly, detailed in vivo studies show that MST1 deficient mice did not develop diabetes. Together, my work shows that MST1 acts as an essential apoptotic molecule in the presence of diabetic stimuli and is a common component in the diverse signaling pathways leading to β-cell apoptosis. My results suggest that MST1 is a critical mediator of impaired beta-cell function and apoptosis. Inhibiting the MST1-pathway could be an important strategy to prevent beta-cell apoptosis.Dissertation320 157 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, A TLR4-triggered complex inflammation in pancreatic islets causes beta-cell failure in diabetes(2017-09-25); ; ; Type 2 Diabetes (T2D) is strongly associated with obesity and characterized by chronic insulin resistance, progressive failure of pancreatic beta-cells, and ultimately hyperglycaemia. The association of T2D with chronic sterile inflammation has been extensively demonstrated, and the elevation of inflammatory mediators can predict type 2 diabetes progression. Pro-inflammatory cytokines and chemokines can cause insulin resistance in peripheral insulin-sensing tissues like fat, liver and muscle, and also lead to progressive beta-cell failure. This eventually shifts metabolism from relative insulin insufficiency - due to the greater insulin demand in obesity - to definite insulin deficiency, while on the beta-cell level - from compensation to decompensation. Toll-like receptor (TLR)-4 signaling is one of the major pro-inflammatory pathways activated by exogenous pathogen-related or endogenous danger-related molecules. Its ligands, including the classical ligand LPS as well as saturated fatty acids and CXCL10, among others, are increased systemically in patients with T2D as well as in at-risk individuals. TLR4-deficiency or its pharmacological inhibition have been shown to ameliorate obesity- or lipid-induced tissue inflammation and insulin resistance in humans and in mouse models. Increasing evidence also connects TLR4 to islet inflammation and beta-cell dysfunction in the context of the pathogenesis of T2D, but many underlying mechanisms remain unknown. In the first part of this thesis, I aimed to uncover the role of TLR4 activation by lipopolysaccharide (LPS), the classical TLR4 ligand, in islet inflammation and beta-cell function in human islets. My special focus was to identify the inflammatory mechanism in the intercellular level the possible interplay among different cells in human islets. I found that LPS-triggered TLR4 activation in cultured human islets induced beta-cell dysfunction, apoptosis and a pro-inflammatory profile with markedly increased IL-1beta, IL-6, TNFalpha and IL-8 production. Macrophage-depletion demonstrates that islet resident macrophages are responsible for the production of IL-1beta, while all the other cyto-/chemokines are predominantly produced from islet endocrine cells. IL-6 is partially responsible for the LPS-induced beta-cell dysfunction, while IL-8 produced from alpha-cells is responsible for monocyte migration to islets during TLR4-activation-induced islet inflammation. This complex inflammatory response in islets is further potentiated in obese individuals, with more IL-1beta, IL-6 and IL-8 expression and a tendency to more islet macrophage accumulation, suggesting a possibly self-augmented inflammatory cycle involving alpha-cells, beta-cells and islet macrophages, which may explain the higher susceptibility of obese individuals to the development of beta-cell damage und eventually T2D. Ageing is known to be associated to elevated T2D risk, though the underlying mechanism remains largely undiscovered. In the second part of this thesis, I aimed to find out if ageing could aggravate obesity-induced T2D, and further focus on the effects on beta-cell function and the role of inflammation in such processes. In a mouse model of high fat diet induced obesity, I found an adverse potentiation of impaired glucose homeostasis, beta-cell dysfunction and chronic tissue inflammation by the combination of obesity and aging. In contrast, TLR4-deficiency exhibited a protection against those deleterious effects through inhibiting pro-inflammatory cytokine expression and switching tissue macrophage activation to a more anti-inflammatory phenotype. In both parts of this thesis, I provide further evidence that TLR4 and inflammation play a causative role in the development of T2D, and thereby support the concept of TLR4- or inflammation-targeted therapeutic strategies.Dissertation349 135 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, beta-MSCs: Successful fusion of bone marrow mesenchymal stromal cells with beta-cells results in a beta-cell like phenotype(2015-06-29); ; ; Bone marrow mesenchymal stromal cells (MSC) have anti-inflammatory, anti-apoptotic and immunosuppressive properties and are a potent source for cell therapy. Cell fusion has been proposed for rapid generation of functional new reprogrammed cells. In this study, we aimed to establish a fusion protocol of bone marrow derived human MSCs with the rat beta-cell line (INS-1E) as well as isolated human pancreatic islets in order to generate functional insulin producing beta-MSCs as a cell-based treatment for diabetes. Human eGFP-puromycin MSCs were co-cultured with either stably mCherry-expressing rat INS-1E cells or human dispersed islet cells and treated with phytohemagglutinin (PHA-P) and polyethylene glycol (PEG) to induce fusion. MSCs and fused cells were selected by puromycin treatment. With an improved fusion protocol, 29.79 ± 2.92% of all MSCs generated beta-MSC heterokaryons based on double positivity for mCherry and eGFP. After fusion and puromycin selection, human NKX6.1 and insulin as well as rat Neurod1, Nkx2.2, MafA, Pdx1 and Ins1 mRNA were highly elevated in fused human MSC/INS-1E cells, compared to the mixed control population. Such induction of beta-cell markers was confirmed in fused human MSC/human dispersed islet cells, which showed elevated NEUROD1, NKX2.2, MAFA, PDX1 and insulin mRNA compared to mixed control. Fused cells had higher insulin content and insulin positive beta-MSCs also expressed nuclear PDX1. Our results show an efficient protocol for fusion of human MSCs and beta-cells, which resulted in a beta-cell like phenotype. This could be a novel tool for cell-based therapies of diabetes.Dissertation238 153 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Investigating the Hippo signaling pathway in pancreatic beta-cells(2016-12-07); ; ; Apoptosis and loss of function are hallmarks of pancreatic beta-cell failure in both type 1 and type 2 diabetes. Targeting beta-cell apoptosis and dysfunction therefore represents an attractive therapeutic approach to the treatment of both T1D and T2D. The initial triggers and the mechanisms of beta-cell death are complex and not fully understood. The Hippo pathway plays a key role in organ size and development through the regulation of proliferation, apoptosis and differentiation. In the present thesis, I investigated the role of Hippo signaling pathway components including NF2, YAP and LATS2 in pancreatic beta-cells in normal physiological as well as in diabetic state. NF2 is an upstream regulator of the Hippo signaling pathway. I showed that NF2 was expressed in both INS-1E cells and primary human islets. Loss of NF2 in pancreatic beta-cells could rescue beta-cell apoptosis through inhibition of LATS2 activity without compromising beta-cell function as well as beta-cell functional identity genes. Transcriptional co-activator YAP is a terminal effector of the Hippo signaling pathway. YAP is not expressed in primary adult beta-cells. This could be the reason for the almost non-existing proliferation capacity of human beta-cells. Re-expression of the constitutively active form of YAP promoted human beta-cell proliferation by regulating transcription factor forkhead box M1 (FOXM1) without altering beta-cell function and functional identity genes. Also, YAP re-expression protected beta-cells and isolated human islets from apoptosis under diabetogenic conditions. My data showed that YAP overexpression induced small redox proteins thioredoxin-1 and thioredoxin-2 (Trx1/2) at both mRNA and protein levels in both INS-1E cells and human islets and Trx1/2 was required for the anti-apoptotic function of YAP. Together, exogenously introduced YAP functions as pro-proliferative and anti-apoptotic molecule in pancreatic beta-cells. Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of nutritional status at the cellular and organismic level. While mTORC1 mediates beta cell growth and expansion, its hyper-activation has been observed in pancreatic islets from animal models of type 2 diabetes and leads to beta cell loss. My data showed that mTORC1 activity was highly increased in type 2 diabetic islets and in human islets exposed to increased glucose concentration, while mTORC2 signaling was diminished. Inhibition of mTORC1 by S6K1 selective inhibitor improved glucose-induced insulin secretion and restored mTORC2 activity in type 2 diabetic islets as well as in isolated diabetic islets from high-fat diet treated mice. This suggests elevated mTORC1 activation as striking pathogenic hallmark of type 2 diabetic islets contributing to impaired beta-cell function and survival in the presence of metabolic stress. Large-tumor suppressor 2 (LATS2) is a core component of the Hippo signaling pathway and an endogenous upstream regulator of YAP. My data showed that overexpression of LATS2 itself was sufficient to induce pancreatic beta-cell apoptosis and impair beta-cell function. Notably, LATS2 induced beta-cell apoptosis through activated mechanistic target of rapamycin complex 1 (mTORC1) by suppression of AMP-activated protein kinase (AMPK) signaling. In addition, while LATS2 overexpression was able to further potentiate chemically-induced defective autophagy and subsequent beta-cell apoptosis, its silencing rescued beta-cell apoptosis. Loss of LATS2 in isolated human islets and beta-cells resulted in resistance to apoptosis induced by diabetogenic conditions in vitro and improved glycemia and insulin secretion in the multiple-low dose streptozotocin (MLD-STZ) mouse model in vivo. My data suggest that LATS2 acts as a pro-apoptotic molecule in pancreatic beta-cells and its inhibition could be an important strategy to improve beta-cell survival in diabetes. Taken together, my data highlight the importance of expression and activation of Hippo signaling elements in proliferation, survival and insulin secretion of pancreatic beta-cells. My results suggest that understanding the Hippo signaling pathway in pancreatic beta-cell physiology and pathology would offer a new sight to prevent beta-cell failure in diabetes.Dissertation340 200 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, The Ubiquitin-Proteasome System (UPS) affects beta-cell survival and function(2018-05-07); ; ; Loss of insulin-producing pancreatic beta-cells is the hallmark of both type 1 diabetes and type 2 diabetes. The mechanism and the components involved in beta-cell death and failure are not yet fully clarified. Identification of key signaling components that promote beta-cell death, understanding their mechanisms of action in detail is crucial in disease pathogenesis as well as for novel therapeutic interventions to halt beta-cell failure during development and progression of diabetes. The ubiquitin-proteasome system (UPS) regulates the stability of many proteins involved in important cellular processes: cell cycle progression, cell differentiation, cell signaling pathways and apoptosis. In this work, I identified two genes within the proteasomal protein control system that are dysregulated in beta-cells under diabetic conditions; F-box protein 28, a substrate recruiting a component of the Skp1-Cul1-F-box (SCF) ligase complex (SCFFBXO28) and the deubiquitinase USP1. Both UPS components have an important function in beta-cell survival in diabetes. F-box only protein 28 (FBXO28) is part of the ubiquitination machinery, namely of the E-3 Ubiquitin Ligase complex that recruits proteins for degradation or for altering their localization or functional activities. My results show that FBXO28 protein levels were reduced under diabetic conditions. Loss of FBXO28 induced beta-cell death, whereas its overexpression improved beta-cell survival, and regulated expression of beta-cell transcription factor NEUROD1 without altering insulin secretion as well as of several beta-cell identity and functional genes. This suggests FBXO28 acts as a pro-survival protein in beta-cells. On the contrary, Ubiquitin-specific protease 1 (USP1), a member of the USP family and a well-known deubiquitinating enzyme (DUB) impairs beta-cell survival in diabetes. USP1 is responsible for removing ubiquitin from substrate proteins and thus influences cellular processes such as survival, differentiation, immunity, and DNA damage response (DDR). Genetic depletion or pharmacological inhibition of USP1 blocked beta-cell death in several experimental models of diabetes in vitro and ex vivo. While DDR signals were elevated in diabetes, USP1 inhibition attenuated the DDR in islets suggesting that the anti-apoptotic action of USP1 inhibition is mediated through suppression of DDR. I have identified a novel function of USP1 in the control of beta-cell survival as potential therapeutic target for the suppression of beta-cell death in diabetes. Taken together, my data highlight the importance of an appropriate expression and activation of ubiquitin-proteasome components for pancreatic beta-cell survival. My results prove that the ubiquitin-proteasome plays a key role in beta-cell survival/failure in diabetes. Further in-depth understanding of the UPS system in beta-cells and establishing its pathways would open up novel approaches towards diabetes therapy.Dissertation385 188 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Islet vascularization in Type 2 Diabetes Mellitus(2015-11-06); ; ; Diabetes is a complex metabolic disorder characterized by the failure to maintain normoglycemia stemming from dysfunctional islet of Langerhans. It is caused by an autoimmune destruction of insulin secreting beta-cells in case of type 1 diabetes (T1D), or non-insulin dependent diabetes, caused by lack on insulin action and production in type 2 diabetes (T2D) and by insulin insufficiency during pregnancy as in gestational diabetes mellitus (GDM). T2D accounts for at least 90% of the cases of diabetes, although it may remain undetected or at a pre-diabetic stage for several years. Thus, therapeutic intervention to prevent the progression to T2D is a major goal to subside the incidence of the disease and thus prevent further metabolic complications. T2D is most commonly associated with obesity and thus peripheral insulin resistance. In the face of insulin resistance there occurs an array of molecular mechanisms, one of the major activator being inflammation. In serum, adipose tissue, liver and pancreatic islets from T2D patients, pro-inflammatory cytokines like IL-1beta, CXCL10, TNFalpha, IL-6 have been detected and clinical trials are initiated to prevent inflammatory action. In our study, we showed anti-mouse CXCL10 antibody prevented diabetes progression; it improved glucose tolerance, insulin sensitivity and restored glucose stimulated insulin secretion in the HFD fed mice. CXCL10 antagonism also prevented upregulation of pro-inflammatory cytokines, IL-1beta, IL-6 and CXCL10 mRNA in isolated islets, CXCL10 in adipose tissue and liver of high fat/high sucrose diet (HFD) fed mice. Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral antidiabetics widely in use for T2D treatment. The first agent of its class sitagliptin was approved by the FDA in 2006 and since has been investigated for its direct effects on islet function. The gluco-incretin hormones GIP and GLP-1 secreted by the intestinal endocrine cells potentiate glucose stimulated insulin secretion but are rapidly inactivated by DPP-4. We treated cultured human islets with a diabetic milieu of high glucose, palmitate, cytokines and H2O2 in presence of the DPP-4 inhibitor linagliptin. Linagliptin restored beta-cell function and turnover, via mechanism involving stabilization of secreted GLP-1 in islet supernatants. Obesity induced insulin resistance requires expansion of beta-cell mass to maintain normoglycemia. There occurs a compensatory islet hyperplasia, progressing with altered islet vascularization and possibly angiogenesis, inflammation and eventually leading to reduced beta-cell mass, beta-cell failure and hyperglycemia. The molecular mechanisms involved in the concomitant pathophysiology of islet endothelial cells in T2D has focused on effects mediated by VEGF-A. In this study, we aimed to identify the regulation of and the changes driven by the Angiopoietin/Tie angiogenic factors in islet vascularization and function during the progression of T2D. Ang-1 expressed by perivascular cells and beta-cells and Ang-2 expressed by endothelial cells exert their autocrine and paracrine effects via the cognate receptor Tie-2, on the endothelial cells. Tie-2 signaling maintains quiescent vasculature via constitutive Ang-1 expression whereas Ang-2 is known to be in play in demand for angiogenesis or pathological stimuli involving inflammation. Ang/Tie regulation and thus its role in diabetes and islet vascularization is so far poorly understood. Islet vessel area was increased in autopsy pancreases from T2D subjects, compared to controls. Vessel markers Tie-1, Tie-2 and CD31 were upregulated in mouse islets upon HFD feeding from 8 to 24 weeks. Ang-2 was transiently upregulated in mouse islets at 8 weeks of HFD as well under gluco-lipotoxicity in vitro in human and mouse islets, in contrast to its downregulation with cytokine treatment. Ang-1 on the other hand was oppositely regulated, with reduction under glucolipotoxic conditions and upregulation by cytokine milieu. Modulation of such changes in Ang-2 expression by its overexpression or the inhibition of its receptor Tie-2 impaired beta-cell function at basal conditions but protected islets from cytokine induced apoptosis in vitro. In vivo, beta-cell-specific Ang-2 overexpression in mice induced vascularization under normal diet but contrastingly hypovascularized islets under HFD together with increased apoptosis and reduction of beta-cell mass. Our data show that increased islet hypervascularization is paralleled with T2D. Maintaining physiological Ang-2 levels is important for islet vascularization and beta-cell survival.Dissertation319 107 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, The transcription coactivator Yes-associated protein (YAP) influences beta cell proliferation and diabetes(2020-02-10); ; ; Beta cell failure is a hallmark of both type 1 and type 2 diabetes. The mechanisms of the initiation of beta cell dysfunction and beta cell death are not completely understood. Investigating the mechanism of action of various signal molecules involved in beta cell apoptosis and proliferation can result in novel targets for diabetes treatment. The Hippo pathway is a vital cascade that plays a fundamental role during cell and organ development. It also regulates beta cell proliferation, apoptosis, and differentiation through its main components including NF2, MST1/2, LATS1/2 and YAP. Yes associated protein (YAP) is a main downstream target of Large Tumor Suppressor (LATS) 1/2 and transcriptional co-activator that enhances expression of several genes by interaction with TEAD transcription factor. YAP is highly expressed during pancreas development. As soon as endocrine islet cells origin, YAP is limited to exocrine and duct cells and excluded from the endocrine part. Also later in mature beta cells, I found that YAP is not expressed. In my doctoral thesis I asked the question whether YAP re-expression can restore the almost absent proliferative capacity in mature beta cells. We also clarified the effect of YAP on pancreatic beta cells in both physiological and diabetic states. Therefore, I re-expressed the active form of YAP specifically in beta cells and in human islets. Indeed, I found that YAP re-expression enhances beta cell proliferation without changing beta cell function and identity. The Forkhead Box M1 (FOXM1)-YAP crosstalk plays a crucial role in switching on beta cell proliferation, regeneration and cell cycle progression. In parallel, YAP re-expression has an anti-apoptotic effect on beta cells under diabetic conditions. In a second part of this study, I analyzed the differential expression of mechanistic target of rapamycin complexes (mTORC), master regulators of nutritional status at both cellular and organismic levels, in human and mouse diabetic islets under diabetogenic conditions. Our results revealed a hyperactivity of mTORC1 in human islets from patients with type 2 diabetes. Moreover, specific mTORC1 inhibition can restore beta cell function in diabetes. Altogether, my data suggest that high metabolic overload leads to mTORC1 hyperactivity; such beta cell stress impairs beta cell function and survival during the progression of diabetes. As beta cells have lost important pro-proliferative factors during maturation and identity, such as YAP, they are unable to compensate for a chronic high metabolic demand. The results of my work propose that a transient overexpression of YAP restores beta cell proliferation during stress and could stand as future beta cell regeneration therapy for functional beta cell mass expansion. It could further be used as tool for cell replacement therapy to restore beta cell survival during islet transplantation.Dissertation236 420 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Novel strategies and targets for the detection and cure of Diabetes Mellitus(2015-11-12); ; ; In diabetes, adipocyte inflammation leads to altered secretion of adipocytokines. The adipocytokine Nampt was investigated, together with its enzymatic product NMN. Neither Nampt nor NMN showed any influence on cell survival and apoptosis in isolated human islets and did not alter insulin secretion during chronic exposure, but both potentiated insulin secretion if added acutely to high glucose concentrations. Secondly we developed a strategy to monitor the functional à ²-cell mass by measuring Mn2 uptake into à ²-cells by MRI. We were able to show Mn2 signals correlating with functional in vivo tests in STZ and HFD induced diabetes mouse models, pointing to Mn2 MRI as a useful tool to monitor functional à ²-cell mass in vivo. The protein family of the Siglecs was found to be expressed on human islet cells and Siglec-7 showed protective effects on failure and apoptosis of isolated human islets. FACS analyses revealed that mice, in contrast to humans, are not expressing Siglecs in endocrine cells. Due to the lacking expression, Siglec-F knockout did not influence blood glucose levels and in vivo and in vitro insulin secretion of diabetic mice.Dissertation257 150 - Some of the metrics are blocked by yourconsent settings
Item-typ:Veröffentlichung, Involvement of Pattern Recognition Receptors in Coxsackievirus B Infection of Human Islets(2013-03-01); ; ; T1DM is an autoimmune disease in which beta-cells are selectively destroyed by the immune system. As consequence of beta-cell destruction insulin levels decline resulting in elevated blood glucose levels. The disease is highly associated with genetic susceptibility. Over the last decades the overall incidence is rising especially in children under the age of 5. This increase is too big to be explained by genetic factors only, suggesting that environmental factors contribute to the manifestation of the disease. Such environmental factors may be viral infections, which have been associated with T1DM for many years. Epidemiological studies and analysis of pancreatic tissue samples show the clear involvement of EVs and among those, coxsackievirus B (CVB) in T1DM. In the present study isolated human islets were infected with two serotypes CVB3 and CVB4 and molecular mechanisms of infections were investigated. Infections with both viruses showed that mainly beta-cells were infected which resulted in specific beta-cell apoptosis and impaired beta-cell function. Gene expression analysis revealed that upon CVB3 and CVB4 infections genes encoding pro-inflammatory proteins were highly expressed, especially those of CXCL10 and IFNb. Such induction of inflammatory related genes is mediated by pattern recognition receptors (PRR´s). The present study showed the binding or CVB3 and CVB4 RNA to PKR and in addition to the PRR´s TLR3 and TLR7. TLR3 depleted human islets infected with CVB3 and CVB4, showed lower expression levels of cytokine and chemokine genes, especially of CXCL10 and IFNb genes, indicating that induction of gene expression was TLR3 mediated. In addition, TLR3 depleted and CVB3 and CVB4 infected human islets showed less apoptosis, suggesting that the TLR3 pathway was involved in virus-induced beta-cell death.Dissertation250 93