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)

Nerve growth factor (NGF) and transforming growth factor-beta2 (TGF-beta2) are cytokines which have known immunological effects. An elevated level of NGF has been reported in certain autoimmune diseases, whereas TGF-beta2 is an immunosuppressor which is known to play a role in regulating cell proliferation. A role of this cytokine has been proposed in the pathogenesis of type-1 diabetes mellitus (IDDM), but no clinical studies have yet measured its serum level in this disease. In this study we measured the levels of NGF and TGF-beta2 in the sera of patients with IDDM (n = 26) and values were compared to those of age-matched normal subjects (n = 27) and also to patients with type-2 diabetes mellitus (NIDDM) (n = 26) with similar HbA1c levels and an equal duration of diabetes. Serum NGF levels were significantly elevated in IDDM patients compared to those of age-matched controls (p <.001) and NIDDM controls (p <.01). TGF-beta2 levels were lower in IDDM patients when compared with the healthy control (p <.001) and the NIDDM control (p <.05). There was no correlation between the levels of NGF and TGF-beta2. The duration of diabetes and the level of HbA1c did not affect the NGF and TGF-beta2 levels in the IDDM patients. We conclude that an increase in NGF and a suppression in TGF-beta2 levels are present in patients with type-1 diabetes mellitus and that both cytokines may play independent roles in the pathogenesis of this disease.
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PMID:Altered plasma levels of nerve growth factor and transforming growth factor-beta2 in type-1 diabetes mellitus. 1060 Feb 22

Activated T-cells and macrophages infiltrate pancreatic islets early in the pathogenesis of type 1 diabetes. Their secretion of different pro-inflammatory cytokines such as interleukin (IL)-1beta, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha affects beta-cell function. Here we report that a combination of these cytokines inhibits insulin release, stimulates inducible nitric oxide synthase (iNOS), and upregulates the surface expression of Fas in NIT-1 beta-cells and intact mouse islets. Using iNOS-deficient and Fas-deficient islets, respectively, we investigated the relative contribution of NO and Fas upregulation in cytokine-induced beta-cell damage. Interestingly, inhibition of insulin release did not occur in the absence of NO production. However, de novo expression of Fas-specific mRNA and Fas cell surface expression were detected and thus appear to be NO-independent. The lack of NO production partially protected islets from cytokine-induced apoptosis but had no effect on cell death induced by cell surface cross-linking of Fas with soluble Fas ligand (FasL). The absence of FasL on alpha-cells and the degree of apoptosis observed in Fas-deficient islets exclude the possibility of cytokine-induced fratricide. In conclusion, pro-inflammatory cytokines exert a cytotoxic effect on beta-cells via an NO-dependent pathway and, in parallel, render beta-cells susceptible to Fas:FasL-mediated, NO-independent cell death triggered by activated T-cells.
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PMID:Nitric oxide production and Fas surface expression mediate two independent pathways of cytokine-induced murine beta-cell damage. 1061 48

Nonobese diabetic mice develop type 1 diabetes in an age-related and gender-dependent manner. Th1 (IFN-gamma and TNF-beta) and Th2 (IL-4 and IL-10) cytokine mRNA expression was analyzed in pancreatic islets isolated from female NOD mice with a high incidence of diabetes and male NOD mice with a low incidence of diabetes. The levels were measured at 5 time points from the onset of insulitis until the development of overt diabetes, using a semiquantitative reverse transcriptase PCR (RT-PCR) assay. IFN-gamma mRNA levels were significantly higher in the islets obtained from females than those of males, from 10 weeks of age. TNF-beta mRNA was expressed in both females and males between 5 and 15 weeks of age. However, TNF-beta mRNA levels were decreased in males at 20 weeks of age. In contrast, IL-4 mRNA levels were lower in females than in males. These results suggest that islet beta-cell destruction and diabetes in female NOD mice correlates with IFN-gamma and TNF-beta production in the islets, and that male NOD mice may be protected from autoimmune beta-cell destruction by down-regulation of these cytokines. Furthermore, our findings also suggest that insulitis and beta-cell destruction are independently regulated: TNF-beta is more important in forming and maintaining the insulitis, while IFN-gamma has a more important role in beta-cell destruction.
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PMID:Analysis of cytokine mRNA expression in pancreatic islets of nonobese diabetic mice. 1068 43

The alterations of TGF-beta1 production are believed to contribute to the development of insulin-dependent diabetes mellitus (IDDM) in animal models as well as in humans. There is also increasing evidence about the role of this cytokine in the pathogenesis of diabetic vascular complications. The aim of our study was to evaluate in vitro TGF-beta1 production by peripheral blood of newly diagnosed type 1 diabetes patients and subjects in the pre-clinical stage of the disease in comparison to healthy controls and relatives of IDDM patients with low genetic risk for diabetes development. The study was carried out in three groups of subjects: 22 patients with a recently diagnosed type 1 diabetes, their 24 first degree relatives with a different genetic risk of IDDM development and 18 healthy volunteers (control group). In all studied groups whole blood was taken for morphology parameters. HbA1C and for 72 h cultures with PHA stimulation for the estimation of TGF-beta1 in vitro production. TGF-beta1 concentration in supernatants were quantified by ELISA. In the first degree relatives HLA typing (for DR3, DR4 and DQB1*0602 alleles), measurements of anti-pancreatic antibodies (ICA, GADA, IA-2A, IAA) and intravenous glucose tolerance tests were performed. The levels of TGF-beta1 in the supernatants were significantly higher in diabetic patients (P < 0.0002) and in their first degree relatives (P < 0.05) in comparison to the control group. In the group of first degree relatives TGF-beta1 levels were highest in subjects with the presence of two or more pancreatic autoantibodies and/or with impaired insulin release in IVGTT, but lowest in relatives with protective DQB1*0602 alleles (P < 0.01). There was also a significant positive correlation between the TGF-beta1 levels and HbA1C in the IDDM subjects and first degree relatives (P < 0.03). Our study suggests that the alterations of TGF-beta1 levels could be associated with the activity of autoimmune process leading to pancreatic B cells destruction and may have a role in the pathogenesis of diabetic complications, but further studies in humans are needed.
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PMID:The analysis of in vitro transforming growth factor-beta1 (TGF-beta1) production by peripheral blood in overt and pre-clinical type 1 diabetes mellitus. 1071 34

It is generally accepted that proinflammatory cytokines secreted by macrophages/monocytes as well as cytotoxic T cells are responsible for pancreatic B-cell destruction in animal models of autoimmune diabetes and presumably in insulin-dependent diabetes mellitus (IDDM) in humans. The aim of the present study was to evaluate the production of interleukin (IL)-13-a Th2 cells derived anti-inflammatory cytokine, by peripheral blood of newly diagnosed IDDM patients and their first degree relatives with a low or high risk of IDDM development. The study was carried out in 20 patients with a recent onset of type 1 diabetes, their first degree relatives with high (with DRB1*03 and/or DRB1*04 HLA class II alleles and two or more autoantibodies directed against pancreatic B-cell antigens) (n = 20) or a low (with DQB1*0602 allele) risk of type 1 diabetes development (n = 10) and a control age matched group of healthy volunteers (n = 18). IL-13 concentrations in supernatant of 72 h cultures of peripheral blood after incubation with phytohemagglutinin (PHA) or PHA+ insulin were quantified by enzyme-linked immunosorbent assay (ELISA). The levels of IL-13 in the supernatants were significantly lower in at high risk of IDDM first degree relatives of diabetic patients (P < 0.02), higher in subjects with low genetic risk of diabetes type 1 (P < 0.02), and normal in IDDM patients in comparison to the control group. We have also observed that the adding of human insulin to the cultures resulted in a significant increase of in vitro IL-13 production in prediabetics, but not in the other studied groups. In conclusion our findings suggest that the IL-13 alterations could play an important role in the pathogenesis of type 1 diabetes. We would speculate that IL-13 as an anti-inflammatory cytokine and a mediator of the Th2 pathway could be the potential therapeutic approach in the prevention of type 1 diabetes.
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PMID:In vitro interleukin-13 production by peripheral blood in patients with newly diagnosed insulin-dependent diabetes mellitus and their first degree relatives. 1073 3

To evaluate the effect of antigen-pulsed dendritic cell (DC) transfer on the development of diabetes, 5-week-old female NOD mice received a single iv injection of splenic syngeneic DC from euglycemic NOD mice pulsed in vitro with human y globulin (HGG). Eleven of 12 mice were protected from the development of diabetes up to the age of 25 weeks, and the insulitis score was significantly reduced. In contrast, NOD mice receiving unpulsed splenic DCs showed histological signs of insulitis and course of type 1 diabetes similar to untreated NOD mice. Treatment with HGG-pulsed DC was associated with profound modifications of cytokine secretory capacities within the islets. Thus, supernatants of islets from these mice contained increased levels of interleukin (IL)-4, IL-10, and, to a lesser extent, interferon-gamma and diminished levels of tumor necrosis factor-a compared with controls. Because exogenous IL-4 and IL-10 exert antidiabetogenic effect in NOD mice and early blockade of endogenous tumor necrosis factor-alpha prevents NOD mouse diabetes, these phenomena may be causally related to the antidiabetogenic effect of HGG-pulsed DC treatment.
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PMID:Prevention of spontaneous autoimmune diabetes in NOD mice by transferring in vitro antigen-pulsed syngeneic dendritic cells. 1074 56

In the cascade hormone--second messenger--cellular G-proteins (GTP binding proteins), impairment can occur also at the last step: Mutant G-proteins may amplify the response (e.g. hypophyseal and thyroid adenomas) or reduce it (pseudohypoparathyreosis, testitoxicosis). Other new group of diseases appears to be anexinopathy: Among anexins belong also lippocortins and impairments occur in the hemocoagulation. "Reverse endocrinology" is a process description when the recognition of receptor (called an "orphan receptor") comes earlier than that of the hormone: Such receptors are known for several steroid hormones, retinoids and eicosanoids and it appears they are important also in the metabolism of cholesterol. A single antigen--glutamic acid decarboxylase (GAD), can cause autoimmune disease as the immuno-dependent diabetes (IDDM). Treatment of the skin T-cell lymphoma by some retinoids can result in hypothyroidism. Retrotransposones are example of the human genome modification with yet unknown clinical manifestations. Hepatocytal growth factor reveals to be the hope for treatment of cirrhosis. Search for effective peroral insulin substitutes is at present based on testing of various metabolites of fungi. Antibodies against TNF (tumor necrosis factor) become tested as "anti-cytokine therapy" in patients with rheumatoid arthritis. Some other suggestions for new ways of treatment is also listed, including the intranasal administration of estradiol.
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PMID:[Endocrinology 1998-1999]. 1083 33

Insulin immunization in animal models induces T-helper (Th) 2-like antibody subclass responses to insulin and other beta-cell antigens. The aim of this study was to determine whether exposure to insulin in humans resulted in a similar subclass bias of the humoral immune response. Levels of IgG subclass antibodies to insulin (IAs), GAD, and IA-2 were measured before and after treatment with insulin in the following groups of patients: 29 patients with newly diagnosed type 1 diabetes treated with intravenous and/or subcutaneous insulin; 10 newly diagnosed patients randomized to cyclosporin A (CsA) or placebo plus subcutaneous insulin for 12 months; and 14 islet cell antibody-positive relatives receiving either intravenous and subcutaneous insulin prophylaxis or no treatment. At the onset of diabetes, the major subclass distributions of insulin autoantibodies (IAAs) were IgG1 and, to a lesser extent, IgG4. After insulin treatment in the 29 new-onset patients, IAs were initially of the IgG1 subclass. IgG4-IAs appeared later, but at 12 months, they were at higher levels than IgG1-IAs in 11 patients. Responses were higher in children compared with adults and were higher in subjects with IAAs (P < 0.001). Insulin prophylaxis in relatives showed a similar profile, with a decline in levels of IgG1-IAs after cessation of daily subcutaneous insulin. Patients treated with CsA took longer to develop IAs and showed suppressed levels of IgG4-IAs; however, their levels of high-titer IgG1-IAs persistently rebounded after completion of CsA therapy. Despite the presence of IgG4-IAs in most insulin-treated patients and relatives, a shift to IgG4-anti-GAD or IgG4-IA-2 was not found for up to 3 years after the initiation of insulin therapy. While our findings need to be correlated with T-cell cytokine responses, we suggest that the strong IgG4-IA response in insulin-treated patients is consistent with an enhancement of Th2 immunity, but there is no evidence of subsequent spreading of potentially Th2-associated IgG4 responses to other autoantigens.
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PMID:Exposure to exogenous insulin promotes IgG1 and the T-helper 2-associated IgG4 responses to insulin but not to other islet autoantigens. 1086 43

Engineered insulinoma cell lines may represent an alternative to isolated islets for transplantation therapy of type 1 diabetes. Success of this approach may require development of cell lines that can withstand cytokine-mediated damage. To this end, we have cultured INS-1 insulinoma cells in increasing concentrations of interleukin-1beta (IL-1beta) + gamma-interferon (IFN-gamma), with approximate weekly iterations over an 8-week period. Based on the C,N diphenyl-N'-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium+ ++ bromide (MTT) viability assay, the selected cells, termed INS-1res, were 100% viable after 5 days of treatment with 10 ng/ml of IL-1beta. These cells were also 78 +/- 1.2% viable after 5 days of exposure to the combination of 10 ng/ml IL-1beta and 100 U/ml IFN-gamma, whereas parental INS-1 cells treated in the same manner were only 0.3 +/- 0.03% viable. INS-1res cells were also resistant to treatment with supernatants from activated rat peripheral blood mononuclear cells, whereas only 20% of parental INS-1 cells survived such treatment. The resistance to IL-1beta conferred by this procedure was stable, whereas the partial resistance to IFN-gamma was transient but reinducible by culture in the presence of cytokines. Stable transfection of INS-1res cells with a plasmid containing the human insulin cDNA and expansion of the transfected colonies in the absence of cytokines produced cell lines that were on average more resistant to IL-1beta + IFN-gamma (53 +/- 11%) than similarly transfected clones derived from parental INS-1 cells (15 +/- 7%). Importantly, several INS-1res-derived clones retained the capacity to secrete insulin in response to glucose concentrations over the normal physiological range. With regard to the mechanism by which selection was conferred, we found normal levels of IFN-gamma receptor mRNA, but a 60% reduction in expression of the IL-1 receptor type I (IL-1RI) in INS-1res cells compared with parental INS-1 cells. IL-1beta signaling through p38 MAP kinase was found to be normal in INS-1res cells, suggesting that their expression of IL-1RI is sufficient to maintain cytokine action. However, normal IL-1beta-mediated translocation of NF-kappaB and induction of inducible nitric oxide synthase expression and nitric oxide production was severely impaired in the INS-1res cell lines, suggesting a mechanism for the IL-1beta resistance. In sum, this study defines a strategy for isolation of cytokine-resistant beta-cell lines and provides a new system for studying the mechanisms by which such resistance can be achieved.
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PMID:Selection of insulinoma cell lines with resistance to interleukin-1beta- and gamma-interferon-induced cytotoxicity. 1087 Nov 93

TNF-alpha is a proinflammatory cytokine that has been implicated in the severity of different immune-regulated diseases including autoimmune diseases and transplantation. The gene for TNF-alpha is located within the MHC region on chromosome 6p21.3. This is a highly polymorphic region, and the TNF-alpha itself contains a large number of polymorphisms. Some of these polymorphisms form extended haplotypes with the HLA class I and II alleles. TNF polymorphisms have been investigated in different diseases and most often whenever there is an HLA association with the disease (for example IDDM and RA) association(s) with TNF polymorphisms has been described. There are many studies on the function of the TNF polymorphisms showing the influence of the different alleles on the in vitro and in vivo levels of TNF production. However, recent studies in animal models suggest that not only polymorphisms within the TNF cluster are important in the regulation of TNF production but also the receptors as well (TNF R). This suggests that investigating polymorphisms within the TNF cluster and TNF receptors will be important in understanding the role of TNF regulation in a given disease.
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PMID:TNF-alpha gene polymorphism: clinical and biological implications. 1089 87


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