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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 1 diabetes mellitus (T1D) is characterized by severe insulin deficiency resulting from chronic and progressive destruction of pancreatic beta-cells by the immune system. The triggering of autoimmunity against the beta-cells is probably caused by environmental agent(s) acting in the context of a predisposing genetic background. Once activated, the immune cells invade the islets and mediate their deleterious effects on beta-cells via mechanisms such as Fas/FasL, perforin/granzyme, reactive oxygen and nitrogen species and pro-inflammatory cytokines. Binding of cytokines to their receptors on the beta-cells activates MAP-kinases and the transcription factors STAT-1 and NFkappa-B, provoking functional impairment, endoplasmic reticulum stress and ultimately apoptosis. This review discusses the potential mediators and mechanisms leading to beta-cell destruction in T1D.
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PMID:Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes. 1843 26

Cytokines contribute to pancreatic beta-cell apoptosis in type 1 diabetes (T1D) by modulation of beta-cell gene expression networks. The transcription factor Activator Protein-1 (AP-1) is a key regulator of inflammation and apoptosis. We presently evaluated the function of the AP-1 subunit JunB in cytokine-mediated beta-cell dysfunction and death. The cytokines IL-1beta+IFN-gamma induced an early and transitory upregulation of JunB by NF-kappaB activation. Knockdown of JunB by RNA interference increased cytokine-mediated expression of inducible nitric oxide synthase (iNOS) and endoplasmic reticulum (ER) stress markers, leading to increased apoptosis in an insulin-producing cell line (INS-1E) and in purified rat primary beta-cells. JunB knockdown beta-cells and junB(-/-) fibroblasts were also more sensitive to the chemical ER stressor cyclopiazonic acid (CPA). Conversely, adenoviral-mediated overexpression of JunB diminished iNOS and ER markers expression and protected beta-cells from cytokine-induced cell death. These findings demonstrate a novel and unexpected role for JunB as a regulator of defense mechanisms against cytokine- and ER stress-mediated apoptosis.
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PMID:JunB Inhibits ER Stress and Apoptosis in Pancreatic Beta Cells. 1871 65

CD8+ T cells are important contributors to the initiation and progression of type 1 diabetes (T1D). A very significant fraction of islet-associated CD8 T cells in NOD mice recognize epitopes of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), a non-essential endoplasmic reticulum-resident protein of unclear function. IGRP is also a target of CD8 T cell responses in human T1D patients. In NOD mice, most IGRP-reactive CD8 T cells target the IGRP(206-214) epitope and are diabetogenic. We have shown that the pathogenic activity of this T cell subset is controlled by genetic elements associated with diabetes susceptibility and resistance. One of these elements (Il2) has been recently implicated in susceptibility to several human autoimmune disorders, including TID. In mice, Il2 polymorphisms control a negative feedback mechanism initiated by activated, IL2-producing autoreactive T cells in the pancreatic lymph nodes that increases the regulatory activity of CD4+CD25+ T cells. Not all IGRP-reactive CD8 T cell clones are pathogenic, however, and we have evidence that some of these clonotypes are actually anti-diabetogenic. We had previously shown that administration of altered peptide ligands (APL) targeting IGRP(206-214)-reactive CD8 T cells resulted in diabetes protection only at doses that did not delete low-avidity clones, suggesting a protective role for these clonotypes. I discuss evidence showing that transgenic expression of a low-avidity IGRP(206-214)-reactive T cell receptor (TCR) efficiently prevents the development of insulitis and diabetes in NOD (non-obese diabetic) mice and that these cells do so by killing autoantigen-loaded antigen presenting cells in the pancreas-draining lymph nodes. These results illustrate a novel mechanism for regulation of immune responses to self-antigens and expose a new target for therapeutic intervention. Here I briefly summarize work done by us and others indicating that a prevalent subset of autoreactive CD8 T-cells in the NOD mouse are major (albeit likely dispensable) players in the pathogenesis of spontaneous autoimmune diabetes in the NOD mouse; that these T cells are targets of genetic elements affording autoimmune disease susceptibility and resistance; that they can either be diabetogenic or anti-diabetogenic according to their avidity for peptide/MHC; and that they can serve as useful targets for therapeutic intervention.
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PMID:Genetic and therapeutic control of diabetogenic CD8+ T cells. 1920 63

Accumulating evidence suggests that endoplasmic reticulum (ER) stress by mechanisms that include ER Ca(2+) depletion via NO-dependent down-regulation of sarcoendoplasmic reticulum Ca(2+) ATPase 2b (SERCA2b) contributes to beta-cell death in type 1 diabetes. To clarify whether the molecular pathways elicited by NO and ER Ca(2+) depletion differ, we here compare the direct effects of NO, in the form of the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP), with the effects of SERCA2 inhibitor thapsigargin (TG) on MAPK, nuclear factor kappaB (NFkappaB), Bcl-2 proteins, ER stress, and apoptosis. Exposure of INS-1E cells to TG or SNAP caused caspase-3 cleavage and apoptosis. Both TG and SNAP induced activation of the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP). However, other classical ER stress-induced markers such as up-regulation of ER chaperone Bip and alternative splicing of the transcription factor Xbp-1 were exclusively activated by TG. TG exposure caused NFkappaB activation, as assessed by IkappaB degradation and NFkappaB DNA binding. Inhibition of NFkappaB or the Bcl-2 family member Bax pathways protected beta-cells against TG- but not SNAP-induced beta-cell death. These data suggest that NO generation and direct SERCA2 inhibition cause two quantitative and qualitative different forms of ER stress. In contrast to NO, direct ER stress induced by SERCA inhibition causes activation of ER stress signaling pathways and elicit proapoptotic signaling via NFkappaB and Bax.
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PMID:Inhibition of nuclear factor-kappaB or Bax prevents endoplasmic reticulum stress- but not nitric oxide-mediated apoptosis in INS-1E cells. 1955 21

Genes interact in networks to orchestrate cellular processes. Analysis of these networks provides insights into gene interactions and functions. Here, we took advantage of normal variation in human gene expression to infer gene networks, which we constructed using correlations in expression levels of more than 8.5 million gene pairs in immortalized B cells from three independent samples. The resulting networks allowed us to identify biological processes and gene functions. Among the biological pathways, we found processes such as translation and glycolysis that co-occur in the same subnetworks. We predicted the functions of poorly characterized genes, including CHCHD2 and TMEM111, and provided experimental evidence that TMEM111 is part of the endoplasmic reticulum-associated secretory pathway. We also found that IFIH1, a susceptibility gene of type 1 diabetes, interacts with YES1, which plays a role in glucose transport. Furthermore, genes that predispose to the same diseases are clustered nonrandomly in the coexpression network, suggesting that networks can provide candidate genes that influence disease susceptibility. Therefore, our analysis of gene coexpression networks offers information on the role of human genes in normal and disease processes.
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PMID:Coexpression network based on natural variation in human gene expression reveals gene interactions and functions. 1979 78

Both ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are common, highly heritable conditions, the pathogenesis of which are incompletely understood. Gene-mapping studies in both conditions have over the last couple of years made major breakthroughs in identifying the mechanisms by which these diseases occur. Considering RA, there is an over-representation of genes involved in TNF signalling and the NFKappaB pathway that have been shown to influence the disease risk. There is also considerable sharing of susceptibility genes between RA and other autoimmune diseases such as systemic lupus erythematosus, type 1 diabetes, autoimmune thyroid disease and celiac disease, with thus far little overlap with AS. In AS, genes involved in response to IL12/IL23, and in endoplasmic reticulum peptide presentation, have been identified, but a full genomewide association study has not yet been reported.
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PMID:Genetics of ankylosing spondylitis and rheumatoid arthritis: where are we at currently, and how do they compare? 1982 41

Proinflammatory cytokines play a crucial role in the pathogenesis of type 1 diabetes mellitus. One of the cytokine-regulated pathways mediating inflammation in this autoimmune disease is the arachidonic acid metabolism pathway, comprising both the induction of cyclooxygenases and the production of different prostaglandins. Cytokine toxicity is mediated in many cell types, including pancreatic beta cells through this pathway. Interestingly, some cell types have been shown to be insensitive to such toxicity, and this correlated with a high expression of prostacyclin synthase (PGIS). Using insulin-producing RINm5F cells as a model for pancreatic beta cells, PGIS was overexpressed and exhibited a large protective effect against cytokine toxicity. This protective effect of PGIS against cytokine toxicity correlated with a decreased activation of the transcription factor NFkappaB and the inducible NO synthase promoter as well as a reduced inducible NO synthase protein expression and nitrite production. A reduction in the cytokine-stimulated endoplasmic reticulum and mitochondrial stress was also found in the PGIS-overexpressing cells. Moreover, cytokine-induced caspase-3 activation and reduction of glucose oxidation and cell proliferation were suppressed. Thus, PGIS overexpression apparently protects insulin-producing cells against cytokine toxicity via suppression of endoplasmic reticulum and mitochondrial stress-mediated cell death pathways.
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PMID:Protection against cytokine toxicity through endoplasmic reticulum and mitochondrial stress prevention by prostacyclin synthase overexpression in insulin-producing cells. 2015 82

Interleukin 1 (IL-1) is a 17 kDa protein highly conserved through evolution and is a key mediator of inflammation, fever and the acute-phase response. IL-1 has important functions in the innate immune defense against microbes, trauma and stress, and is also an effector molecule involved in tissue destruction and fibrosis. The inhibition of IL-1 action has clinical efficacy in many inflammatory diseases, such as hereditary autoinflammatory disorders, familial hereditary fever, gout, rheumatoid arthritis and type 2 diabetes mellitus (T2DM). The latter is a common metabolic condition caused by insulin resistance and pancreatic beta-cell failure, the causes of both of which have inflammatory components. IL-1 signaling has roles in beta-cell dysfunction and destruction via the NFkappaB and mitogen-activated-protein-kinase pathways, leading to endoplasmic reticulum and mitochondrial stress and eventually activating the apoptotic machinery. In addition, IL-1 acts on T-lymphocyte regulation. The modulating effect of IL-1 on the interaction between the innate and adaptive immune systems and the effects of IL-1 on the beta-cell point to this molecule being a potential interventional target in autoimmune diabetes mellitus. Genetic or pharmacological abrogation of IL-1 action reduces disease incidence in animal models of type 1 diabetes mellitus (T1DM) and clinical trials have been started to study the feasibility, safety and efficacy of IL-1 therapy in patients with T1DM. Here, we review the rationale for blocking IL-1 in patients with T1DM.
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PMID:Blockade of interleukin 1 in type 1 diabetes mellitus. 2017 77

The 65-kDa isoform of glutamic acid decarboxylase (GAD65) is the major autoantigen implicated in the development of type 1 diabetes mellitus (T1DM). The bulk manufacture of GAD65 is a potential issue in the fight against T1DM but current production platforms are expensive. We show that a catalytically inactive form of GAD65 (GAD65mut) accumulates at up to 2.2% total soluble protein in transgenic tobacco leaves, which is more than 10-fold the levels achieved with active GAD65, yet the protein retains the immunogenic properties required to treat T1DM. This higher yield was found to be a result of a higher rate of protein synthesis and not transcript availability or protein stability. We found that targeting GAD65 to the endoplasmic reticulum, a strategy that increases the accumulation of many recombinant proteins expressed in plants, did not improve production of GAD65mut. The production of a catalytically inactive autoantigen that retains its immunogenic properties could be a useful strategy to provide high-quality therapeutic protein for treatment of autoimmune T1DM.
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PMID:Recombinant human GAD65 accumulates to high levels in transgenic tobacco plants when expressed as an enzymatically inactive mutant. 2037 24

Type 1 diabetes is an autoimmune disorder characterized by chronic inflammation and pancreatic beta-cell loss. Here, we demonstrate that the proinflammatory cytokine interleukin-1beta, combined with interferon-gamma, induces the expression of the Bcl-2 homology 3 (BH3)-only activator PUMA (p53 up-regulated modulator of apoptosis) in beta-cells. Transcriptional activation of PUMA is regulated by nuclear factor-kappaB and endoplasmic reticulum stress but is independent of p53. PUMA activation leads to mitochondrial Bax translocation, cytochrome c release, and caspase-3 cleavage resulting in beta-cell demise. The antiapoptotic Bcl-XL protein is localized mainly at the mitochondria of the beta-cells and antagonizes PUMA action, but Bcl-XL is inactivated by the BH3-only sensitizer DP5/Hrk in cytokine-exposed beta-cells. Moreover, a pharmacological mimic of the BH3-only sensitizer Bad, which inhibits Bcl-XL and Bcl-2, induces PUMA-dependent beta-cell death and potentiates cytokine-induced apoptosis. Our data support a hierarchical activation of BH3-only proteins controlling the intrinsic pathway of beta-cell apoptosis in the context of inflammation and type 1 diabetes.
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PMID:p53 up-regulated modulator of apoptosis (PUMA) activation contributes to pancreatic beta-cell apoptosis induced by proinflammatory cytokines and endoplasmic reticulum stress. 2042


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