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)

Insulin-dependent diabetes mellitus (IDDM) results from the destruction of pancreatic insulin-secreting cells by a T-cell-mediated autoimmune reaction. Distinct types of T helper cells (TH1 and TH2) have been characterised based on their cytokine secretion profiles following activation. Evidence from animal models favours the hypothesis that autoimmune diabetes is a TH1 response. However, there is no clear indication that a primary imbalance between protective TH2 and deleterious TH1 cells at early stages can trigger the autoimmune process. Protective CD4 + cells detected in nondiabetic young non-obese diabetic mice have not been shown to work through TH2 cytokines. In humans, there is little evidence that IDDM results from a TH1 response. Indeed, efficient experimental systems are lacking in humans to study the regulation of the autoimmune response in vitro. Interestingly, several immunotherapy strategies have aimed at inducing a TH2 response, even though TH2 cells have not been implicated in spontaneous disease development. However, recent ongoing trials in humans using oral administration of insulin to prevent diabetes are based on a protective mechanism which seems to depend essentially on transforming growth factor-beta. This cytokine is not dependent on TH1/TH2 dichotomy. Thus, although several attempts have been made to induce a TH1/TH2 switch to obtain a protective effect, a different and more complex mechanism probably (and paradoxically) accounts for the oral protection actually tested in animal models and humans.
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PMID:T-cell regulation in murine and human autoimmune diabetes: the role of TH1 and TH2 cells. 941 29

T cells from NOD mice display an age-dependent, TCR-inducible proliferative hyporesponsiveness that may be causal to IDDM. Exogenous IL-4 completely restores this hyporesponsiveness in vitro and prevents IDDM in vivo when administered to NOD mice. We therefore tested the hypothesis that stimulation of a Th2 response by either IL-4 or CD28 costimulation may block progression to IDDM. Low-dose IL-4 treatment beginning at 2 weeks of age (pre-insulitis) protects NOD mice from insulitis, sialitis, and thyroiditis, indicating that IL-4 modulates T cell migration to these inflammatory sites. Cytokine secretion profiles of stimulated T cells and assays of intrapancreatic cytokine concentrations revealed that IL-4 treatment prevents IDDM by stabilizing a protective Th2-mediated environment in the thymus, spleen, and pancreatic islets. Whereas treatment of NOD mice with an anti-CD28 mAb between 2 to 4 weeks of age inhibits destructive insulitis and protects against IDDM by enhancing IL-4 production by T cells, anti-CD28 treatment between 5 to 7 weeks of age does not prevent IDDM. Simultaneous anti-IL-4 treatment abrogates the protective effect conferred by anti-CD28 treatment. Our data demonstrate that stimulation of a Th2-cell-enriched environment in the pancreas during the inductive phase of disease development blocks progression to IDDM in NOD mice.
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PMID:Cytokine- and costimulation-mediated therapy of IDDM. 941 41

Insulin-dependent diabetes mellitus is caused by an autoimmune destruction of the beta-cells in the islets of Langerhans. The cytokine interleukin 1 inhibits insulin release and is selectively cytotoxic to beta-cells in isolated pancreatic rat islets. The antigen(s) triggering the immune response as well as the intracellular mechanisms of action of interleukin 1-mediated beta-cell cytotoxicity are unknown. However, previous studies have found an association of beta-cell destruction with alterations in protein synthesis. Thus, two-dimensional (2-D) gel electrophoresis of pancreatic islet proteins may be an important tool facilitating studies of the molecular pathogenesis of insulin-dependent diabetes mellitus. 2-D gel electrophoresis of islet proteins may lead to (i) the determination of qualitative and quantitative changes in specific islet proteins induced by cytokines, (ii) the determination of the effects of agents modulating cytokine action, and (iii) the identification of primary islet protein antigen(s) initiating the immune destruction of the beta-cells. Therefore, the aim of this study was to create databases (DB) of all reproducibly detectable protein spots on 10% and 15% acrylamide 2-D gels of neonatal rat islets (10% and 15% DB), labeled under standardized culture conditions. 1235 and 557 spots were present in 5 of 5 gels in the 15% isoelectric focusing (IEF) and nonequilibrium pH gradient electrophoresis (NEPHGE) DB, respectively, whereas 995 and 378 spots were present in 5 of 5 gels in the 10% IEF and NEPHGE DB, respectively, yielding a reproducibility of spot detection between 75.2% and 91.7%. In both DBs, the average coefficient of variation of the percentage of integrated optical density (CV% of %IOD) for spots present in all gels was between 42.4% and 45.7%. When the same sample was analyzed in consecutive sets of gels on different days (interassay analysis), the average CV% of %IOD was 35.5%-36.1%. When the same sample was analyzed repeatedly in one set of gels (intra-assay analysis), the average CV% of %IOD was 30.2% in the IEF gels, while the average CV% of %IOD was 45.7% in the NEPHGE gels. Addition of interleukin-1beta (IL-1beta) to the cultures resulted in statistically significant modulation or de novo synthesis of 105 proteins in the 10% gels. In conclusion, we present the first 10% and 15% acrylamide 2-D gel protein databases of neonatal rat islets of Langerhans and demonstrate its usage to identify proteins altered in expression by IL-1beta.
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PMID:Interleukin-1beta induced changes in the protein expression of rat islets: a computerized database. 942 Jan 75

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by the destruction of insulin-producing beta-cells in the pancreatic islets. A single administration of CFA prevents clinical hyperglycaemia in non-obese diabetic (NOD) mice. We have previously shown that CFA administration does not eliminate insulitis in the pancreas of the treated animals, but diverts the disease process from a destructive to a non-destructive pathway. We provide evidence that this phenomenon may be under cytokine control. Neutralizing monoclonal antibodies against IL-4 and IL-10 were injected, singularly or in combination, into CFA-treated NOD mice. Antibody treatment did not lead to the development of overt diabetes; however, a marked impairment of glucose tolerance was shown in about one half of the mice treated with a combination of the two antibodies at the end of the study. This functional abnormality correlated with the histological loss of pancreatic islet tissue. These studies suggest a role for IL-4 and IL-10 in CFA-induced protection from diabetes in the NOD mouse. They also suggest that, in this animal model, the nature of the autoimmune response to islet tissue (either destructive or non-destructive) may reflect the relative proportion of Th1- and Th2-type cytokines produced in the lesions.
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PMID:Protection from autoimmune diabetes by adjuvant therapy in the non-obese diabetic mouse: the role of interleukin-4 and interleukin-10. 942 94

In order to study cytokine production profile (IFN-gamma, IL-4 and TNF-alpha) and TCRBV-gene usage of peripheral autoreactive T cells from IDDM patients, we have generated antigen-specific T cell lines with either tetanus toxoid, insulinoma membranes or a single beta-cell protein, recombinant ICA69, which has been shown to be a target of both autoantibodies and T cells in IDDM. By semi-quantitative polymerase chain reaction (PCR) analysis, we have determined the composition of the T cell receptor repertoire of these T cell lines and compared this with the general peripheral repertoire. T cell responses against beta-cell antigens and tetanus toxoid (TT) were shown to be associated with IFN-gamma and TNF-alpha production, suggestive of a Th1-like phenotype of the T-cell lines. The production of IFN-gamma was significantly higher in T-cell lines generated with ISG compared to those generated with TT. The cytokine production profiles of the T-cell lines generated with ICA69 did not provide an obvious explanation for the inverse relation between cellular and humoral responses to this protein observed earlier. Upon stimulation with beta-cell antigens, outgrowth of T cells using a restricted set of TCRBV elements was observed in newly diagnosed IDDM patients. However, this skewing in TCRBV-gene expression was patient-specific rather than antigen-associated, since the T-cell repertoire that is used for the recognition of these antigens was, overall, heterogeneous.
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PMID:Th1-like cytokine production profile and individual specific alterations in TCRBV-gene usage of T cells from newly diagnosed type 1 diabetes patients after stimulation with beta-cell antigens. 945 99

The cytokine interleukin-1beta (IL-1beta) has been postulated to be involved in beta-cell destruction in IDDM. It has also been suggested that this action by IL-1beta is mediated by nitric oxide (NO) generation. Recently it has been reported that Th2-cell promoting cytokines e.g. interleukin-4 (IL-4) and interleukin-13 (IL-13) can reduce NO formation from activated macrophaghes after cytokine activation. In the present study we examined the effect of IL-13 on IL-1beta suppression of islet function. For this purpose rat pancreatic islets were cultured in medium RPMI 1640 + 10% fetal calf serum and exposed for 42 h to human IL-13 (0. 0.1, 1 and 10 ng/ml) in the presence or absence of human IL-1beta (25 U/ml) during the last 24 h of culture. IL-13 alone did not affect any islet functions during prolonged exposure. The highest concentration of IL-13 counteracted IL-1beta suppression of islet glucose oxidation, but not insulin release. Moreover, IL-13 failed to reduce IL-1beta stimulated NO production, as measured by medium nitrite levels. Acute exposure to IL-13 caused a slight stimulation of islet insulin secretion. When IL-4 (10 ng/ml) was combined with IL-13 no synergistic action of the two cytokines was observed in the counteraction of IL-1beta mediated changes. In conclusion, the present study showed that IL-13 could partially prevent IL-1beta induced inhibition of the glucose metabolism, and this effect appeared to be unrelated to NO levels. So far it has not been possible to demonstrate in vitro that Th2-cell promoting cytokines such as IL-4 and IL-13 can effectively reduce cytokine-induced NO from islet cells, as has been reported for macrophages. However, it cannot be excluded that Th2-cell promoting cytokines can be effective in reducing a Th1-cell mediated anti-beta-cell response in vivo.
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PMID:Interleukin-13 counteracts suppression induced by interleukin-1beta of glucose metabolism but not of insulin secretion in rat pancreatic islets. 955 Feb 83

A number of cytokines have been shown to alter the function of pancreatic beta-cells and thus might be involved in the development of type 1 diabetes. Interferon-beta (IFN-beta) expression is induced in epithelial cells by several viruses, and it has been detected in islets of type 1 diabetic patients. Here we show that treatment of isolated mouse islets with this cytokine was able to alter insulin secretion in vitro. To study whether IFN-beta alters beta-cell function in vivo and leads to diabetes, we have developed transgenic mice (C57BL6/SJL) expressing IFN-beta in beta-cells. These mice showed functional alterations in islets and impaired glucose-stimulated insulin secretion. Transgenic animals presented mild hyperglycemia, hypoinsulinemia, hypertriglyceridemia, and altered glucose tolerance test, all features of a prediabetic state. However, they developed overt diabetes, with lymphocytic infiltration of the islets, when treated with low doses of streptozotocin, which did not induce diabetes in control mice. In addition, about 9% of the transgenic mice obtained from the N3 back-cross to outbred albino CD-1 mice spontaneously developed severe hyperglycemia and hypoinsulinemia and showed mononuclear infiltration of the islets. These results suggest that IFN-beta may be involved in the onset of type 1 diabetes when combined with either an additional factor or a susceptible genetic background.
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PMID:Evidence from transgenic mice that interferon-beta may be involved in the onset of diabetes mellitus. 957 86

Diabetic mastopathy is a recently described collection of radiographical and histological features found in dense fibrous masses of the breast in long standing Type I diabetes. We describe the first case of bilateral disease with the alternate progression and regression of the disease over a 5 year period. A 45-year-old woman has been affected of insulin dependent diabetes mellitus (IDDM) for 21 years. She developed palpable mass retromamillar of the right side, indistinguishable radiographically from cancer. The histology showed a diabetic mastopathy (DMP) with B-lymphocytic ductitis and lobulitis, a discrete monocellular vasculitis and a keloid-like fibrosis. After 22 months she developed a suspicious palpable mass contralateral on the left side. The FNAB presented an identical morphology on histology. Additionally 10 months later there were no palpable masses of both mammae. Mammographically no suspect alterations were observed. One year later the clinical and mammographical examination showed similar findings, mentioned before. The pathogenesis is still obscure and includes the hypothesis of extracellular accumulation, secondary to prolonged hyperglycemia in IDDM, production of alternated non-enzymatic glycosylated end products with neoantigen formation, B cell predominant inflammation with autoimmune response against neoantigens and cytokine release secondary to the autoimmune response.
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PMID:Bilateral, tumorlike diabetic mastopathy-progression and regression of the disease during 5-year follow up. 958 50

IDDM results from a progressive loss of pancreatic beta-cells that, in humans, may be triggered by a combination of genetic and environmental factors. Recently, attention has been focused on the hypothesis that the loss of beta-cells is initiated by inappropriate induction of apoptosis. We now demonstrate that human islets of Langerhans undergo apoptosis upon exposure to interleukin-1beta. The cytokine also sharply increases the number of cells that enter apoptosis on treatment with a stimulatory anti-Fas antibody. Western blotting and immunocytochemistry clearly show for the first time that human pancreatic beta-cells normally express Fas ligand. The results suggest that human islet cells are primed to undergo apoptosis by interleukin-1beta and that this involves the close association between cell-surface Fas and its ligand.
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PMID:Human islets of Langerhans express Fas ligand and undergo apoptosis in response to interleukin-1beta and Fas ligation. 958 43

IDDM is a T-cell-mediated autoimmune disease in which the insulin-producing beta-cells are destroyed. The disease process is complex, involving the recognition of several beta-cell autoantigens. One of these, GAD65, appears to have a critical and not fully defined role in IDDM in humans and in the NOD mouse. We provide evidence that an ongoing diabetogenic response in NOD mice can be suppressed after intravenous administration of GAD65, but not by other beta-cell autoantigens. Furthermore, suppression of the diabetogenic response is mediated by the induction of GAD65-specific CD4+ regulatory T-cells. Finally, cytokine analysis indicates that these CD4+ regulatory T-cells have a T-helper 2 phenotype.
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PMID:Induction of GAD65-specific regulatory T-cells inhibits ongoing autoimmune diabetes in nonobese diabetic mice. 960 65


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