The role of viruses in Type I diabetes: two distinct cellular and molecular pathogenic mechanisms of virus-induced diabetes in animals

Jun, Hee-Sook; Yoon, Ji Won

doi:10.1007/s001250051614

Cited by 130 publications

(99 citation statements)

References 41 publications

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“…Another recent study has observed the presence of CXCL10 and infiltration of lymphocytes expressing the corresponding chemokine receptor CXCR3 in islets from pancreatic tissues of deceased recent-onset type 1 diabetic patients, regardless of enterovirus infection; this suggests a significant role for this chemokine in inducing insulitis [17]. Viral infection can also cause direct injury to beta cells [39]. Coxsackievirus-induced beta cell death in cultured human islets has been reported [40].…”

Section: Discussionmentioning

confidence: 97%

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

et al. 2010

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Aims/hypothesis Exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, is reported to have modest antiinflammatory effects in addition to that of improving beta cell survival. We therefore sought to determine whether exendin-4 decreases expression of the gene encoding chemokine (C-X-C motif) ligand (CXCL)10, which plays a role in initiating insulitis in type 1 diabetes. Methods The expression of CXCL10 in human islets was determined at the mRNA level by real-time RT-PCR analysis and at the protein level by western blotting. The level of CXCL10 in culture medium was measured by ELISA. Pathway-specific gene expression profiling was carried out to determine the expression of a panel of genes encoding chemokines and cytokines in human islets exposed to cytokines. Results IFN-γ induced expression of CXCL10 through activation of signal transducer and activator of transcription-1 (STAT-1). A combination of cytokines (IL-1β, TNF-α and IFN-γ) showed strong synergy in the induction of numerous chemokines and cytokines through nuclear factor kappa B and STAT-1. Exendin-4 suppressed basal expression of several inflammatory mediators. In combination with phosphodiesterase inhibitors, exendin-4 also decreased IFN-γ-induced CXCL10 expression in human islets and in MIN6 cells (a mouse beta cell line), and its secretion into the culture medium. Exendin-4 action was mimicked by forskolin, an activator of adenylyl cyclase, and by dibutyryl cyclic AMP. Protein kinase A was not involved in mediating exendin-4 action on CXCL10. The mechanism of exendin-4's anti-inflammatory action involved decreases in STAT-1 levels. Conclusions/interpretation These findings suggest that the GLP-1-cyclic AMP pathway decreases islet inflammation in addition to its known effects on beta cell survival.

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Section: Discussionmentioning

confidence: 97%

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

et al. 2010

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“…In a rodent model, it has been suggested that viruses are involved in the pathogenesis of Type 1 diabetes in at least two distinct ways: (i) by inducing beta-cellspecific autoimmunity; and (ii) by inducing cytolytic infection leading to the destruction of the beta cells [24]. The infection of genetically susceptible strains of mice with a high titre of EMC-D (D variant of the encephalomyocarditis) results in the rapid onset of diabetes within 3 days, largely due to the replication of the virus within beta cells.…”

Section: Discussionmentioning

confidence: 99%

T lymphocyte response against pancreatic beta cell antigens in fulminant Type 1 diabetes

et al. 2004

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Aims/hypothesis. Fulminant Type 1 diabetes is a novel subtype of Type 1 diabetes that involves the abrupt onset of insulin-deficient hyperglycaemia. This subtype appears to be non-autoimmune because of the absence of diabetes-related autoantibodies in the serum, and of insulitis in pancreatic biopsy specimens. The pathogenesis of the disease is still unknown. In this study, we investigated whether T cell autoimmune responses are involved in fulminant Type 1 diabetes. Methods. Cellular immune responses to beta cell autoantigens were studied by enzyme-linked immunospot (ELISPOT) assay in 13 fulminant Type 1 diabetic patients and 49 autoantibody-positive autoimmune Type 1 diabetic patients. Results were compared with those of 18 Type 2 diabetic patients, six secondary diabetic patients (diabetes due to chronic pancreatitis) and 35 healthy controls. Results. Nine of 13 (69.2%) GAD-reactive Th1 cells, and three of 12 (25%) insulin-B9-23-reactive Th1 cells were identified in fulminant Type 1 diabetic patients by ELISPOT, as in autoantibody-positive Type 1 diabetic patients. Four fulminant Type 1 diabetic patients possessed the highly diabetes-resistant allele DR2, three of whom had GAD-reactive Th1 cells in the periphery. Conclusions/interpretation. Peripheral immune reaction was observed in 69.2% of fulminant Type 1 diabetic patients, indicating that autoreactive T cells might contribute, at least in part, to the development of fulminant Type 1 diabetes.

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“…Up to now, 13 different viruses, most of them belonging to the enterovirus family, have been found to be associated with the onset of Type 1 Diabetes in humans and in various animal models [7]. Different mechanisms have been proposed for the role of viruses in the pathogenesis of Type 1 Diabetes.…”

mentioning

confidence: 99%

“…GADD65) and a viral antigen, leading to autoimmune destruction of the beta cell [11]; (iv) viral infection, coupled with one or more of the factors described above, acting in conjunction to induce beta cell death [12]. For example, mouse infection with a high titre of the D variant of the encephalomyocarditis (EMC-D) virus leads to beta-cell destruction and diabetes mainly as a result of viral replication within beta cells, while mouse infection with a low titre of EMC-D virus leads to diabetes as a chronic process, caused by the destruction of beta cells by soluble mediators such as IL-1β, TNF-α/β and NO produced by macrophages or the beta cells themselves [7].…”

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confidence: 99%

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

et al. 2003

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Aims/hypothesis. Viral infections and local production of IFN-γ might contribute to beta-cell dysfunction/ death in Type 1 Diabetes. Double stranded RNA (dsRNA) accumulates in the cytosol of viral-infected cells, and exposure of purified rat beta cells to dsRNA (tested in the form of polyinosinic-polycytidylic acid, PIC) in combination with IFN-γ results in beta-cell dysfunction and apoptosis. To elucidate the molecular mechanisms involved in PIC + IFN-γ-effects, we determined the global profile of genes modified by these agents in primary rat beta cells. Methods. FACS-purified rat beta cells were cultured for 6 or 24 h in control condition or with IFN-γ, PIC or a combination of both agents. The gene expression profile was analysed in duplicate by high-density oligonucleotide arrays representing 5000 full-length genes and 3000 EST's. Changes of greater than or equal to 2.5-fold were considered as relevant.Results. Following a 6-or 24-h treatment with IFN-γ, PIC or IFN-γ and PIC, we observed changes in the expression of 51 to 189 genes. IFN-γ modified the expression of MHC-related genes, and also of genes involved in beta-cell metabolism, protein processing, cytokines and signal transduction. PIC affected preferentially the expression of genes related to cell adhesion, cytokines and dsRNA signal transduction, transcription factors and MHC. PIC and/or IFN-γ up-regulated the expression of several chemokines and cytokines that could contribute to mononuclear cell homing and activation during viral infection, while IFN-γ induced a positive feedback on its own signal transduction. PIC + IFN-γ inhibited insulin and GLUT-2 expression without modifying pdx-1 mRNA expression. Conclusion/interpretation. This study provides the first comprehensive characterization of the molecular responses of primary beta cells to dsRNA + IFN-γ, two agents that are probably present in the beta cell milieu during the course of virally-induced insulitis and Type 1 Diabetes. Based on these findings, we propose an integrated model for the molecular mechanisms involved in dsRNA + IFN-γ induced beta-cell dysfunction and death. [Diabetologia (2003[Diabetologia ( ) 46:1641[Diabetologia ( -1657

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The role of viruses in Type I diabetes: two distinct cellular and molecular pathogenic mechanisms of virus-induced diabetes in animals

Cited by 130 publications

References 41 publications

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

T lymphocyte response against pancreatic beta cell antigens in fulminant Type 1 diabetes

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

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