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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 1 diabetes is believed to be a Th1 lymphocyte-mediated disease, and both environmental and genetic factors play a role in its pathogenesis. It was recently found that interleukin (IL)-18 acts as a proinflammatory cytokine and, in synergy with IL-12, promotes development of Th1 lymphocyte response by induction of gamma-interferon production. The aim of our study was to evaluate the frequency of known polymorphisms in the IL-18 promoter in patients with type 1 diabetes in comparison with healthy control subjects, since higher levels of IL-18 were recently reported in the subclinical stage of type 1 diabetes. We studied two recently described single-nucleotide polymorphisms of the promoter of IL-18 gene at the position -137 and -607, which have been suggested to cause differences in transcription factor binding and have an impact on IL-18 gene activity. The genotype distribution differed significantly between patients with type 1 diabetes and control subjects. The difference reflected an increase in the GC genotypes and a decrease in GG genotypes at position -137 in the promoter of IL-18 gene. AA genotype at position -607 was found only in the control group. The results also demonstrated that the contribution of -137GC genotypes to genetic susceptibility to type 1 diabetes differs depending on the combination of IL-18 promotor gene haplotypes. Our study suggests the first evidence of an association between type 1 diabetes and polymorphisms in the promoter of IL-18 gene.
Diabetes 2002 Nov
PMID:Interleukin-18 promoter polymorphisms in type 1 diabetes. 1240 30

At onset of type 1 diabetes, the islet autoantibody status of patients has been reported to predict progression of the disease. We therefore tested the hypothesis that the systemic immunoregulatory balance, as defined by levels of circulating cytokines and chemokines, is associated with islet autoantibody status. In 50 patients with recent-onset type 1 diabetes, antibodies to GAD and insulinoma-associated antigen 2 (IA-2) were analyzed by radioimmunoassay; cytoplasmic islet cell antibodies were determined by indirect immunofluorescence. Cytokine and chemokine concentrations were measured by rigidly evaluated double antibody enzyme-linked immunosorbent assay. Of four classically defined Th1/Th2 cytokines (gamma-interferon, interleukin [IL]-5, IL-10, IL-13), none showed an association with multiple autoantibody positivity. Of six mediators mainly produced by innate immunity cells, three were associated with multiple autoantibody status (IL-18 increased, MIF and MCP-1 decreased) and three were unaffected (IL-12, MIP-1beta, IP-10). GAD and/or IA-2 antibody titers negatively correlated with systemic concentrations of MIF, MIP-1beta, and IL-12. Combining the data of several cytokine and chemokine levels made it possible to predict islet antibody positivity in individual patients with 85% sensitivity and 94% specificity. These data suggest a close association of islet antibody status with systemic immunoregulation in type 1 diabetes.
Diabetes 2003 May
PMID:An association of autoantibody status and serum cytokine levels in type 1 diabetes. 1271 43

IL-18 is a cytokine structurally and functionally related to IL-1 that, in synergy with IL-12, stimulates the synthesis of IFN-gamma from T lymphocytes and natural killer cells. Because IFN-gamma plays a key pathogenic role in the development of murine immunoinflammatory diabetes induced by multiple low doses of streptozotocin (STZ) we investigated the effect of negating the actions of endogenous IL-18 in this model by administering recombinant IL-18-binding protein:Fc (IL-18 bp:Fc). C57BL/6 mice were injected once daily with 40 mg/kg STZ for 5 consecutive days, day 0 being the first day of STZ challenge. Relative to control animals treated in parallel with either PBS or human IgG, mice treated from day -3 to day 7 with daily doses of 150 microg of IL-18 bp:Fc exhibited lower incidence of diabetes and milder insulitis. In contrast, mice that were treated with IL-18 bp:Fc from day 7 to day 14 exhibited clinical and histological signs of STZ-induced diabetes similar to those of control mice treated with IgG. The protective effect of IL-18 bp:Fc was accompanied by modified ex vivo immune responses, in that spleen cells and peritoneal macrophages contained fewer IFN-gamma secreting cells and released lower amounts of nitrite (an index of nitric oxide production) and IL-1beta. We conclude that intact IL-18 function is essential for the full diabetogenic effect of low dose STZ in C57BL/6 mice.
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PMID:Essential pathogenic role of endogenous IL-18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL-18-binding protein: Fc construct. 1288 3

IL-18 is now identified as a pleiotropic cytokine that acts as a cofactor for both Th1 and Th2 cell development. Type 1 diabetes is considered a Th1-type autoimmune disease, and to date, the suppressive effect of exogenous IL-18 on the development of diabetes has been reported in 10-wk-old nonobese diabetic (NOD) mice. In the present study we administered exogenous IL-18 systemically in 4-wk-old NOD mice using i.m. injection of the IL-18 expression plasmid DNA (pCAGGS-IL-18) with electroporation. Contrary to previous reports, the incidence of diabetes development was significantly increased in NOD mice injected with pCAGGS-IL-18 compared with that in control mice. Systemic and pancreatic cytokine profiles deviated to a Th1-dominant state, and the the frequency of glutamic acid decarboxylase-reactive IFN-gamma-producing CD4(+) cells was also high in the IL-18 group. Moreover, it was suggested that the promoting effect of IL-18 might be associated with increased peripheral IL-12, CD86, and pancreatic IFN-inducible protein-10 mRNA expression levels. In conclusion, we demonstrate here that IL-18 plays a promoting role as an enhancer of Th1-type immune responses in diabetes development early in the spontaneous disease process, which may contribute to elucidating the pathogenesis of type 1 diabetes.
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PMID:Systemic administration of IL-18 promotes diabetes development in young nonobese diabetic mice. 1463 96

Type 1 diabetes is a heterogeneous autoimmune disease and is often associated with other organ-specific autoimmune diseases, including autoimmune thyroid disease (AITD). IL-18 is a potent proinflammatory cytokine capable of inducing IFN-gamma production that is associated with the development of type 1 diabetes and AITD. The gene for IL-18 is located near Idd2 and has been reported to be associated with a susceptibility to type 1 diabetes. To test the putative involvement of IL-18 gene polymorphism in predisposition to type 1 diabetes and AITD, we conducted a case-control study in Japanese population. The SNPs at position -607 (C/A) and -137 (G/C) in the promoter region of the IL-18 gene were analyzed by sequence-specific PCR in 74 nondiabetic patients with AITD, 47 type 1 diabetic patients with AITD, and 114 normal controls. There was no significant increase in the genotype and allele frequencies not only in nondiabetic patients with AITD compared with normal controls, but also in type 1 diabetic patients with AITD compared with normal controls. The distribution of IL-18 gene haplotypes was also similar between both patient groups and normal controls. These results suggest that polymorphisms of the IL-18 gene are not associated with a susceptibility to AITD and type 1 diabetes coexistent with AITD in Japanese population.
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PMID:Association of interleukin-18 gene promoter polymorphisms in type 1 diabetes and autoimmune thyroid disease. 1467 7

Interleukin (IL)-1 beta and IL-18 are two cytokines associated with the immunopathogenesis of diabetes in NOD mice. Both of these cytokines are cleaved by caspase-1 to their biologically active forms. IL-1 is a proinflammatory cytokine linked to beta-cell damage, and IL-18 stimulates production of interferon (IFN)gamma in synergy with IL-12. To examine the effects produced by caspase-1 deficiency on diabetes development in NOD/Lt mice, a disrupted Casp1 gene was introduced by a speed congenic technique. Casp1(-/-) bone marrow-derived macrophages stimulated with lipopolysaccharide produced no detectable IL-18, fourfold lower IL-1 beta, and 20-30% less IL-1 alpha than macrophages from wild-type Casp1(+/+) or Casp1(+/-) controls. Unexpectedly, despite reduced IL-1 and IL-18, there was no change in the rate of diabetes or in total incidence as compared with that in wild-type NOD mice. IL-1 reportedly makes an important pathological contribution in the multidose streptozotocin model of diabetes; however, there was no difference in sensitivity to streptozotocin between NOD mice and NOD.Casp1(-/-) mice at 40 mg/kg body wt or at 25 mg/kg body wt dosage levels. These findings show that caspase-1 processing of IL-1 beta and IL-18 is not absolutely required for mediation of spontaneous or chemically induced diabetes pathogenesis in the NOD mouse.
Diabetes 2004 Jan
PMID:Caspase-1 is not required for type 1 diabetes in the NOD mouse. 1469 3

Recent studies have demonstrated that diabetic retinopathy has several characteristics of a chronic inflammatory disease, such as increased nitric oxide production, intracellular adhesion molecule-1 upregulation, leukostasis and increased vascular permeability. In addition, diabetes leads to the activation of caspase-1, the enzyme responsible for the production of the pro-inflammatory cytokines IL-1beta and IL-18 in the retinae of diabetic animals and diabetic patients. Minocycline, a second-generation tetracycline derivative, was able to prevent the activation of capase-1 in the retinae of diabetic mice. Therefore, this review is focused on discussing the role of caspase-1 as a mediator of chronic inflammation and/or apoptosis inducer in the development of diabetic retinopathy and the suitability of caspase-1 as a new potential therapeutic target.
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PMID:Potential new strategies to prevent the development of diabetic retinopathy. 1501 39

We aimed to evaluate the effect of treatment with sarpogrelate, a serotonin 2A receptor antagonist, on circulating interleukin (IL)-18 levels in patients with diabetes and arteriosclerosis obliterans. Patients received sarpogrelate (100 mg 3 times daily) for 2 months. We evaluated the degree of cryaesthesia (a feeling of cold in the foot and toes) as the clinical outcome, and measured circulating IL-18, IL-6 and lipid protein concentrations. An improvement in clinical outcome occurred after initiation of sarpogrelate therapy; a significant decrease in IL-18 levels was observed after 2 months of therapy. Levels of IL-6 and lipid proteins, including triglyceride, total cholesterol and high-density lipoprotein cholesterol, were not significantly altered by treatment. Our data suggest that by reducing circulating IL-18 levels, sarpogrelate treatment may contribute to the inhibition of arteriosclerosis obliterans progression in patients with diabetes.
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PMID:Effect of the serotonin blocker sarpogrelate on circulating interleukin-18 levels in patients with diabetes and arteriosclerosis obliterans. 1508 20

Autoimmune diabetes mellitus is characterized by selective destruction of beta pancreatic cells and by cellular infiltration with T- (particularly Th1) and B-lymphocytes. The marker of autoimmunity is the presence of autoantibodies (ICA, IAA, GADab, IA2ab). Etiology of the autoimmune process is still unknown. It is suggested that the pathogenesis is activated by genetic and environmental factors. Individual predisposition can influence also the onset and progression of the disease. The most important genetic risk factors of autoimmune diabetes mellitus are the HLA class II alleles (DQB1*0302, 0201; DRB1*0301, 0401; DQA1*0301, 0501) and the risk alleles of INS-VNTR of the promoter region. Recent studies have shown various genetic risk factors for the autoimmune diabetes mellitus. Individual predispositions belong to the genetic polymorphisms in cytokine genes (IL-10, IL-12, IL-18) and the microsatellite polymorphism of MHC class I chain-related gene A (MIC-A).
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PMID:[Genetic risk factors in autoimmune diabetes mellitus, their significance and function]. 1513 33

IL-18 is a type 1 pro-inflammatory cytokine with structural similarities to IL-1 and in synergy with IL-12 stimulates IFN-gamma production from T lymphocytes and polarizes development and function of Th1 cells. Because IL-1, IFN-gamma, and up-regulated Th1-mediated events are involved in the pathogenesis of both human and rodent type 1 diabetes mellitus, we have evaluated the effects of a specific inhibitor of IL-18 (the IL-18bp:FcIg) on the development of accelerated forms of autoimmune diabetes in NOD mice. The data show that prolonged prophylactic treatment with IL-18bp:FcIg significantly reduced the cumulative incidence of diabetes induced in NOD mice either by adoptive transfer of diabetogenic cells or by injection with large doses of cyclophosphamide. These data provide the first in vivo evidence for the diabetogenic role of IL-18 in immuno-inflammatory diabetogenic pathways in NOD mice.
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PMID:IL-18 binding protein fusion construct delays the development of diabetes in adoptive transfer and cyclophosphamide-induced diabetes in NOD mouse. 1587 24


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