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)

Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in an immune-mediated demyelinating disease (TMEV-IDD) similar to human multiple sclerosis (MS). Although the etiology of MS remains unknown, a role of an infectious agent has been implicated in its onset. Previously we have shown the ability of bacterial lipopolysaccharide (LPS) to alter susceptibility to TMEV-IDD in genetically resistant C57BL/6 mice. In this study, the potential of LPS to alter pathogenicity of a low/non-pathogenic variant of TMEV was investigated. After intraperitoneal treatment of genetically susceptible SJL/J mice with LPS before and during viral infection, 80-100% of the mice developed clinical symptoms, while without LPS treatment none of the mice were affected. However, clinical severity in these LPS-treated mice was much milder than the level induced by the wild type pathogenic virus. Increased susceptibility to the disease after LPS treatment did not correlate with splenic T cell proliferative responses against viral antigens. However, by reverse transcriptase polymerase chain reaction (RT-PCR) analyses, an early increase in the production of Th1-type proinflammatory cytokine messages (e.g., interferon-gamma [IFN-gamma] and enhancement of viral persistence was observed in the CNS of LPS-treated, virus-infected animals as compared to mice infected with the variant virus alone. These results indicate that environmental factors such as a bacterial infection (e.g., LPS) promoting proinflammatory cytokine production can significantly enhance the pathogenicity of demyelination induced by a normally non-pathogenic virus.
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PMID:Treatment with lipopolysaccharide enhances the pathogenicity of a low-pathogenic variant of Theiler's murine encephalomyelitis virus. 889 89

IL-4 has been shown to protect against diabetes development in rodent models of insulin-dependent (type I) diabetes mellitus (IDDM). To study IL-4 production in human IDDM, PBMC from IDDM patients and controls were stimulated in vitro with PHA, anti-CD3 mAb, or PMA and ionophore. IL-4 production by PBMC or T cells was strongly impaired in IDDM patients at diabetes onset (p < 0.0001). The mean IL-4 response of patients in the honeymoon stage was higher than the mean of the new onset patients, but significantly lower than the control group (p = 0.01). Patients with IDDM of longer duration (>2 yr) showed a wide range of IL-4 responses and their mean IL-4 response was lower than the controls; however, the difference was not statistically significant. IL-4 mRNA levels were measured using competitive reverse transcription PCR. The results showed greatly reduced mRNA levels in new onset IDDM. In contrast, IL-1 production (measured by ELISA) and IFN-gamma mRNA (measured by reverse transcription PCR) were not significantly different in IDDM. The results suggest an imbalance of inflammatory vs anti-inflammatory cytokine production at the onset of IDDM. Deficient IL-4 production as seen at the onset of IDDM may play a role in the development of diabetes by allowing the inflammatory/autoimmune process in pancreatic islets to progress.
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PMID:Decreased IL-4 production in new onset type I insulin-dependent diabetes mellitus. 890 50

Recently, the synthetic immunomodulator Linomide (quinoline-3-carboxamide, LS 2616) was reported to prevent IDDM and insulitis in NOD mice. The mechanism for this protective effect is not known. The cytokine interleukin 1 (IL-1) may be a pathogenetic factor in the initial destruction of the beta-cells leading to IDDM. This study was undertaken to investigate the influence of Linomide on IL-1beta induced diabetogenic and hormonal changes in the rat in vivo, and on IL-1beta mediated synthesis of NO and inhibition of insulin secretion in isolated islets of Langerhans ex vivo. Normal male Wistar Kyoto rats received 4.0 microg/kg of recombinant human IL-1beta (rhIL-1beta) i.p. daily for 5 days with or without Linomide (8-9 mg/kg/day) in the drinking water. Litters of neonatal Wistar rats were pretreated for 3 days with injections of 10 mg/kg of Linomide i.p., and pancreatic islets of Langerhans were isolated for ex vivo studies. Linomide alone caused significant hypercorticosteronemia, hypoglucagonemia, lymphopenia and neutrophilia. Linomide had no effect on IL-1beta induced hyperglycemia, hyperglucagonemia, lymphopenia, neutrocytosis, or hypercorticosteronemia on day three and hypocorticosteronemia on day five. Further, Linomide did not prevent rhIL-1beta mediated reduction in insulin secretion or increase in NO synthesis ex vivo. In conclusion, Linomide does not seem to exert its protective effect on IDDM development via inhibition of interleukin 1 action on islet insulin release or NO production, but the increase in plasma corticosterone may contribute to the understanding of the immunomodulatory effects of Linomide.
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PMID:Linomide increases plasma corticosterone in normal rats, but does not prevent the inhibitory action of IL-1 on beta-cells in vivo or ex vivo. 891 32

Disturbed immune regulation has been postulated to be crucial in the pathogenesis of IDDM and other autoimmune or allergic diseases. We therefore tested the hypothesis of a general bias in the peripheral immune system in patients with recent-onset IDDM or Graves' disease in comparison to healthy control subjects by studying whole blood cultures stimulated with phytohemagglutinin. Cells from IDDM patients (n = 53) produced significantly higher amounts of Th1 cytokines gamma-interferon (IFN-gamma) (P = 0.028) and tumor necrosis factor alpha (TNF-alpha) (P = 0.007) than normal control subjects (n = 56), while Th2 cytokine levels (interleukin [IL]-4, IL-10) were similar. Low levels of islet cell antibodies (ICAs) in IDDM patients were associated with high levels of Th1 and Th2 cytokines. Antibodies to GAD, ICA512, or insulin did not correlate with individual cytokine profiles. Also, HLA-DQ types did not significantly correlate with either Th1 or Th2 cytokine production. Conversely, whole blood cultures from patients with Graves' disease (n = 18) produced significantly less TNF-alpha and IL-4 than normal subjects (P = 0.001-0.006). However, when the balance between Th1 and Th2 cytokine production was analyzed in individuals, the ratio between IFN-gamma or TNF-alpha and IL-4 or IL-10 was clearly biased toward Th1 reactivity in patients with IDDM (P = 0.0001), while a dominance of Th2 cytokine production was seen in Graves' disease (P = 0.0001). The ratio of counterregulatory cytokines appeared to be the most reliable marker of the individual disease process. This study provides first evidence of a systemic bias in the immune regulation of humans, which might be either toward cell-mediated immunity (Th1) in IDDM or humoral immunity (Th2) in Graves' disease.
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PMID:Systemic bias of cytokine production toward cell-mediated immune regulation in IDDM and toward humoral immunity in Graves' disease. 900 Jul

Insulin-dependent diabetes mellitus (IDDM) is an immunopathological condition involving loss of beta cell function, but views of how this arises are confusing and contradictory. For example, studies with non-obese diabetic mice implicate abnormal cytokine production in disease pathogenesis, but give little insight into how this arises. Many genetic and environmental risk factors have been described, but no single factor predicts the development of disease. Moreover, the prevalence of auto-antibodies suggests an autoimmune aetiology, but no antigen is recognized by all individuals. As an aid to understanding how IDDM develops, this review considers the risk factors as distinct starting points on a journey, and reviews current literature in search of the point where the roads from each origin merge into a highway to diabetes.
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PMID:Autoimmunity and the highway to diabetes. 904 27

Certain diets can have major effects on the development of IDDM in DP-BB rats, but data are scant on the timing, dose, and mechanisms involved. We therefore determined the dose response, timing, and duration of exposure required to induce diabetes, and characterized the effects of nutritionally adequate diets with widely different diabetogenicity on the pancreatic islet area and cytokines. DP-BB rats were fed a diabetogenic, cereal-based, NIH-07 (NIH) diet or a protective, casein or hydrolyzed casein (HC)-based, semipurified diet. Rats were fed from weaning to 50 or 100 days with the HC diet and then switched to the NIH diet, or fed the NIH diet from weaning to 50 days and switched to the HC diet. Pancreas histology and diabetes outcome were determined. Semiquantitative morphometric analyses of hematoxylin and eosin-stained sections of pancreas from 41-day-old rats were also carried out. Diet-induced effects on pancreatic cytokine levels were measured at 70 days using reverse transcriptase-polymerase chain reaction analysis of gamma-interferon (IFN-gamma), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-beta). Long-term daily exposure, particularly around the beginning of puberty to late adolescence (50-100 days), was important for development of diabetes. DP-BB rats could be rescued from diabetes development by feeding them a low-diabetogen HC diet as late as 50 days. Diabetes frequency was highest in rats fed 70% and 100% NIH diets. By age 41 days, before classic insulitis, the islet area in HC-fed DP-BB rats was 65% greater than in NIH-fed rats. By 70 days, when mononuclear cells were visible in the islets of most NIH-fed, but not HC-fed rats, the more pronounced inflammatory process in NIH-fed rats was associated with a Th1 cytokine pattern (high IFN-gamma and low IL-10 and TGF-beta), whereas the pancreases of HC-fed rats showed fewer infiltrating cells, low levels of IFN-gamma, and high levels of TGF-beta, typical of a Th2 cytokine pattern. Thus dietary modification can occur as late as puberty. Further, long-term exposure to sufficient amounts of food diabetogens between 50 and 100 days was required for maximum diabetes induction. The islet area was modified by diet before signs of classic insulitis. Pancreatic inflammation in NIH-fed animals is a Th1-dependent phenomenon. The HC diet inhibited insulitis and was associated with a Th2 cytokine pattern in the pancreas, protecting diabetes-prone rats from developing diabetes.
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PMID:Potential mechanisms by which certain foods promote or inhibit the development of spontaneous diabetes in BB rats: dose, timing, early effect on islet area, and switch in infiltrate from Th1 to Th2 cells. 907 98

Previous studies have shown that type I diabetes (IDDM) increases the risk of developing periodontitis by 2-3-fold. IDDM patients exhibit destruction of the pancreatic beta cells, most probably caused by an autoimmune reaction. Evidence is accumulating to support the role of the autoimmune response in periodontal pathogenesis. A cytokine, interleukin (IL)-10, has been reported to selectively promote the expansion of a B lymphocyte lineage (CD5/LY1/B1) which has the propensity for secreting high levels of autoantibody. Therefore, the purpose of this project was to evaluate IL-10 production, percentage of CD5 B cells and the frequency of anti-collagen secreting cells in peripheral blood mononuclear cells of age, gender and race matched IDDM patients and controls. IL-10 production was evaluated by an ELISA using the supernatant of adherent peripheral blood cells cultured for 24 h in the presence of Porphyromonas gingivalis lipopolysaccharide (LPS). In 8 of 31 patients, IL-10 levels were significantly increased in IDDM compared to controls and a higher percentage of CD5 B cells was also observed by flow cytometry. In addition, these patients exhibited a higher frequency of anti-collagen secreting cells as elucidated by an ELISPOT. Moreover, treatment with a neutralizing anti-IL-10 antibody diminished the anti-collagen antibody response by 70%. These findings support the concept that a subset of IDDM patients possess an extremely robust IL-10 response following exposure to Gram-negative LPS, which could predispose them to the development of periodontitis through a heightened autoimmune mechanism.
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PMID:Interleukin-10 promotes anti-collagen antibody production in type I diabetic peripheral B lymphocytes. 908 33

Insulin-dependent (type I) diabetes mellitus (IDDM) is the consequence of a chronic cell-mediated immune attack upon the insulin-producing beta-cells. Progressive insulinopenia is characteristic of individuals who eventually develop IDDM. Autoimmunity develops because of a failure in self-nonself discrimination. Autoimmunity is usually detected when autoantibodies are present in the patient's serum. However, autoantibodies are not synonymous with disease, as many autoantibody-positive individuals show no evidence of clinical disease. Studies initiated in the early 1980s demonstrated that short term remission from IDDM could be induced or lengthened with immunosuppressive therapy. However, no long term remissions were achieved. Current prevention strategies use a combination of autoantibody marker testing and beta-cell function testing to identify individuals with 'prediabetes'. The most useful autoantibodies for prediabetes screening include islet cell autoantibodies, insulin autoantibodies, glutamic acid decarboxylase autoantibodies and IA-2 autoantibodies. Immunointervention techniques have focused on protecting beta-cells from oxidative damage and developing tolerance to beta-cell autoantigens. Environmental manipulation may also be of benefit but its effectiveness is unproven. The pharmacist of the future may be involved in dispensing autoantigens, cytokines, anti-cytokine antibodies, anti-cytokine receptor antibodies, vaccines or viral vectors for gene therapy in the prevention of IDDM.
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PMID:Pharmacological approaches to the prevention of autoimmune diabetes. 917 26

Insulin-dependent diabetes mellitus (IDDM) is a chronic disorder that results from autoimmune destruction of the pancreatic beta-cells. Recent evidence suggests that oxidative damage, resulting from both cytokine-induced production of toxic free radicals and low antioxidant capacity of the beta-cell plays a significant role in the pathogenesis of IDDM. Islet cell antibodies (ICA) have been the best validated marker of risk for the development of IDDM in predisposed individuals, i.e. first-degree relatives of patients with IDDM. We investigated the total plasma antioxidant status (TAS) in both ICA-positive and ICA-negative first-degree relatives of patients with IDDM, to assess the level of overall protection against oxidative damage. TAS was significantly lowered in ICA-positive when compared to both ICA-negative and healthy subjects (p < 0.001), while no significant difference was found in comparison to recently diagnosed patients with IDDM. TAS values were not significantly influenced by gender, age and smoking habits in all groups, as well as by ICA titers in the group of ICA-positive subjects. Results indicate that prediabetic condition, apart from well-established immunological and metabolic alterations, could be associated with biochemical changes revealing complex disturbances of the antioxidative defence system. Although TAS is a functional rather than specific marker, its measurement is likely to be a valuable tool for understanding the mechanisms of specific beta-cell injury.
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PMID:Total plasma antioxidants in first-degree relatives of patients with insulin-dependent diabetes. 928 8

1. Insulin-dependent diabetes mellitus is an autoimmune disease leading to pancreatic beta-cell destruction, an event that may, at least partially, be induced by the formation of nitric oxide. 2. Under the influence of cytokines, the enzyme nitric oxide synthase is induced. 3. Blockage of the inducible form of nitric oxide synthase has been found to protect against insulin-dependent diabetes mellitus in some animal models. 4. Aminoguanidine has been found to be a fairly specific inhibitor of cytokine-inducible nitric oxide synthase. 5. Aminoguanidine may reduce the blood flow to the pancreatic islets in vivo and, at higher concentrations, also impair insulin secretion by the beta-cells,--which may make the compound less useful in attempts to prevent insulin-dependent diabetes mellitus.
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PMID:Inhibition of nitric oxide formation by aminoguanidine: an attempt to prevent insulin-dependent diabetes mellitus. 934 12


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