Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of antibodies reacting with the p53 tumor suppressor protein has been described in patients with some autoimmune disorders. In this study we looked for serum anti-p53 antibodies in 64 patients with autoimmune type 1 diabetes mellitus within 4 mo of diagnosis. The presence of anti-p53 antibodies was observed in 6/64 (9.4%) subjects with type 1 diabetes, and in 1/44 (2.3%) subjects with other organ-specific autoimmune diseases (18 primary biliary cirrhosis, 10 autoimmune hepatitis, 16 thyroid diseases), but in none of 45 control subjects. No relationship was found between antibodies directed against islet- and non-islet-specific antigens and anti-p53 antibodies. These findings support a possible role for p53 in some autoimmune disorders.
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PMID:Serum anti-p53 autoantibodies in patients with type 1 diabetes. 1150 28

Glutamic acid decarboxylase (GAD) is one major autoantigen involved in the pathogenesis of autoimmune insulin dependent diabetes mellitus (IDDM). Molecular mechanisms regulating GAD expression in pancreatic beta cell are still ill-defined. Here we investigated the effect of streptozotocin (STZ), a beta cell-specific toxin, on the expression of GAD67 in MIN6N8a mouse beta cell. A 5-6-fold increase in the expression GAD67 mRNA was found in cells treated with 1.25mM STZ for 12h. Addition of NAD+ to the incubation medium slightly reduced the STZ-induced upregulation of GAD67. STZ increased p53 levels that in turn up-modulated GAD67 expression. This effect was abolished upon addition of the antioxidant N-acetyl cysteine (NAC). STZ also activated NF-kappaB and blockade of NF-kappaB activation inhibited the STZ-mediated upregulation of GAD67 expression. As a whole these data show that low dose of STZ up-regulates GAD67 expression in mouse bate cell and that NF-kappaB activation through oxidative stress plays a key role in this phenomenon. They also suggest that various stimuli promoting NF-kappaB activation may up-regulate expression of GAD autoantigen in mouse beta cells.
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PMID:Streptozotocin upregulates GAD67 expression in MIN6N8a mouse beta cells. 1236 54

The tumor suppressor p53 regulates apoptosis, cell cycle, and oncogenesis. To explore the roles of p53 in autoimmunity, we studied type 1 diabetes and innate immune responses using C57BL/6 mice deficient in p53. We found that p53-deficient mice were more susceptible to streptozotocin-induced diabetes than control mice, and they produced higher levels of interleukin-1, -6, and -12. The innate immune response of p53-/- macrophages to lipopolysaccharides and gamma-interferon was significantly enhanced compared with p53+/+ cells. p53-/- macrophages produced more proinflammatory cytokines and higher levels of total and phosphorylated signal transducer and activator of transcription (STAT)-1. These results indicate that p53 inhibits autoimmune diabetes and innate immune responses through downregulating STAT-1 and proinflammatory cytokines.
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PMID:Tumor suppressor p53 inhibits autoimmune inflammation and macrophage function. 1585 29

The effects of ginseng extracts (GE) and several ginsenosides on cytokine-induced apoptosis were evaluated. In pancreatic beta-cell line MIN6N8 cells, the inhibitory effect of GE was significantly observed at 25-100 microg/mL: an 86-100% decrease of cytoplasmic DNA fragments quantified by an ELISA. The inhibitory effect of red ginseng (RG) extract was greater than that of white ginseng (WG) extract (IC50, 3.633 vs 4.942 microg/mL). Screening of several known ginsenosides, which were present in ginseng extracts at 0.124-1.19% (w/w) by HPLC analysis, revealed that the ginsenosides were responsible for the inhibition of beta-cell apoptosis at 0.1-1.0 microg/mL. The molecular mechanism, by which GE inhibited beta-cell apoptosis, appeared to involve the reduction of nitric oxide (NO) and reactive oxygen species (ROS) production, inhibition on p53/p21 expression, and inhibition on cleavage of caspases and poly(ADP-ribose) polymerase (PARP). This study suggests that ginseng may inhibit cytokine-induced apoptosis in beta-cells and, thus, may contribute via this action to the antidiabetic influence in type 1 diabetes.
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PMID:Protective effect of ginseng on cytokine-induced apoptosis in pancreatic beta-cells. 1738 Nov 3

Pancreas transplantation in type 1 diabetes patients could result in (re)activation of allo- and autoreactive T lymphocytes. Anti-thymocyte globulin (ATG) induction treatment is a successful, but broadly reactive anti-lymphocyte therapy used in pancreas and islet transplantation. A more selective alternative is daclizumab, a monoclonal antibody directed against the interleukin-2 receptor (CD25) on activated lymphocytes. We tested the hypothesis that daclizumab is more selective and has less immunological side effects than ATG. Thirty-nine simultaneous pancreas-kidney transplantation patients with type 1 diabetes were randomized for induction therapy with ATG or daclizumab. Auto- and recall immunity was measured cross-sectionally by lymphocyte stimulation tests with a series of auto- and recall antigens in 35 successfully transplanted patients. T cell autoimmunity to islets was low in both groups, except for a marginal but significantly higher reactivity against glutamic acid decarboxylase (GAD)65 in daclizumab-treated patients. The memory responses to recall antigens were significantly higher in the daclizumab-treated group compared to ATG-treated patients, specifically against purified protein derivative (PPD) (anti-bacterial immunity), Haemophilus influenzae virus matrix protein-1 (anti-viral immunity) and p53 [anti-tumour (auto)immunity]. These data imply that daclizumab is more specifically affecting diabetes-related immune responses than ATG. The autoimmunity is affected effectively after daclizumab induction, while memory responses towards bacterial, viral and tumour antigens are preserved.
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PMID:Selective unresponsiveness to beta cell autoantigens after induction immunosuppression in pancreas transplantation with anti-interleukin-2 receptor antibody versus anti-thymocyte globulin. 1745 76

The aim of this study was the search of association of polymorphous markers Pro72Arg and C(-594)CC of TP53 gene with diabetic polyneuropathy (DPN) in patients with type 1 diabetes mellitus with or without clinical signs of DPN. We have found that polymorphous marker Pro72Arg of TP53 gene was associated with DPN in Russian patients with type 1 diabetes mellitus living in Moscow. The carriers of Arg allele and Arg/Arg genotype had higher risk of DPN development (OR = 1.96; CI = 1.32-2.90; and OR = 2.14; CI = 1.23-3.73; relatively). On the contrary, the carriage of Pro allele was associated with the lower risk of DPN development (OR = 0.51; CI = 0.34-0.76). We have not found any association of polymorphous marker C(-594)CC of TP53 gene with DPN in Russian patients with type 1 diabetes mellitus living in Moscow.
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PMID:[Association of polymorphous markers Pro72Arg and C(-594)CC OF TP53 gene with diabetic polyneuropathy in patients with type 1 diabetes mellitus living in Moscow]. 1831 16

Diabetes mellitus is one of the chronic systemic disorders with major influences of the oral cavity microenvironment. Oral manifestations of diabetes are diverse; they are represented by candidose, lichen plan, recurrent aphthous stomatitis, gingivitis, salivary disorders, oral mucosa atrophy and rarely hypertrophy; a possible link between oral cancer and diabetes is suspected, both in animal models and humans. We report a case of a young woman with type 1 diabetes with class I Kennedy edentation with mobile denture prosthesis; latter in the clinical follow-up, a hyperplasic lesion of the oral mucosa with p53 expression within the epithelial nuclei was identified, p53 being the more likely pathogenic pathway involved in diabetes-related oral cancer. The approach of this patient required multidisciplinary investigations and careful follow-up.
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PMID:Oral epithelial hyperplasia in diabetes mellitus. 2006 71

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

Diabetes and high glucose (HG) increase the generation of NADPH oxidase-derived reactive oxygen species and induce apoptosis of glomerular epithelial cells (podocytes). Loss of podocytes contributes to albuminuria, a major risk factor for progression of kidney disease. Here, we show that HG inactivates AMP-activated protein kinase (AMPK), up-regulates Nox4, enhances NADPH oxidase activity, and induces podocyte apoptosis. Activation of AMPK blocked HG-induced expression of Nox4, NADPH oxidase activity, and apoptosis. We also identified the tumor suppressor protein p53 as a mediator of podocyte apoptosis in cells exposed to HG. Inactivation of AMPK by HG up-regulated the expression and phosphorylation of p53, and p53 acted downstream of Nox4. To investigate the mechanism of podocyte apoptosis in vivo, we used OVE26 mice, a model of type 1 diabetes. Glomeruli isolated from these mice showed decreased phosphorylation of AMPK and enhanced expression of Nox4 and p53. Pharmacologic activation of AMPK by 5-aminoimidazole-4-carboxamide-1-riboside in OVE26 mice attenuated Nox4 and p53 expression. Administration of 5-aminoimidazole-4-carboxamide-1-riboside also prevented renal hypertrophy, glomerular basement thickening, foot process effacement, and podocyte loss, resulting in marked reduction in albuminuria. Our results uncover a novel function of AMPK that integrates metabolic input to Nox4 and provide new insight for activation of p53 to induce podocyte apoptosis. The data indicate the potential therapeutic utility of AMPK activators to block Nox4 and reactive oxygen species generation and to reduce urinary albumin excretion in type 1 diabetes.
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PMID:AMP-activated protein kinase (AMPK) negatively regulates Nox4-dependent activation of p53 and epithelial cell apoptosis in diabetes. 2086 Oct 22

In type 1 diabetes mellitus (T1D) p53 pathways are up-regulated and there is an increased susceptibility to apoptosis. The hypothesis is that p53 codon 72 polymorphism could be associated with T1D. A total of 286 children with T1D and a control sample of 730 subjects were studied. p53 codon 72 polymorphism was analysed by polymerase chain reaction. A large increase of p53 *Arg/*Arg was observed in T1D patients with age at onset < 6 years. A strong linear correlation between *Arg/*Arg genotype and age at onset was observed in females. The involvement of the *Arg/*Arg genotype in apoptosis suggests that during the autoimmune process leading to T1D, genetic factors that favor apoptosis may contribute to the onset of overt disease.
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PMID:Genotypes of p53 codon 72 correlate with age at onset of type 1 diabetes in a sex-specific manner. 2193 78


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