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

Periodontal disease is the result of a complex interplay of bacterial infection and host responses, and is often modified by various systemic diseases such as diabetes mellitus. Such diseases are capable of affecting the periodontium and/or the treatment of periodontal disease. However, recent research has changed our concept of how periodontal disease should be treated. Here we present several concerns directed towards the periodontal therapy of patients with diabetes mellitus based on our studies. When treating periodontitis patients who have diabetes mellitus it is important to consider the type of diabetes. Patients with non-insulin dependent diabetes mellitus can be further classified according to the degree of insulin resistance, since recent epidemiological studies have suggested that successful anti-microbial therapy might result in improved insulin resistance in highly insulin resistant patients. Because the major contributing factor for insulin resistance is currently considered to be the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), and because periodontal surgery may cause transient bacteremia which may up-regulate the serum TNF-alpha level, which in turn suppresses insulin action, patients should be strictly treated non-surgically and their serum TNF-alpha levels should be periodically monitored. On the other hand, diabetic patients positive for serum anti-glutamate decarboxylase auto-antibody should be examined for the source of this antibody, since 1) gingival and periodontal ligament fibroblasts were found to express glutamate decarboxylase, and 2) some otherwise healthy periodontitis patients develop anti-glutamate decarboxylase antibody. Thus, chronic periodontitis may influence the level of this antibody which is widely used as a predictive marker for slowly progressive insulin dependent diabetes mellitus. Not only is periodontal disease thereby affected by systemic diseases, but carefully managed periodontal therapy may also have a positive effect on the general health of patients with systemic diseases.
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PMID:Negative effects of chronic inflammatory periodontal disease on diabetes mellitus. 1266 61

Latent autoimmune diabetes of adults (LADA) manifested after the age of 35 is characterized by the presence of disease-specific autoantibodies (anti-glutamate decarboxylase GADAb, anti-IA2Ab). However, autoimmunity in Type 1 diabetes mellitus is not targeted only to pancreatic beta-cells. No data have so far been published concerning the antibodies associated with other autoimmune disease in LADA patients. The presence of anti-thyroglobulin (TGAb), anti-thyroid peroxidase (TPOAb), anti-gliadin IgA (AGAAb) and IgG (AGGAb) and endomysial antibodies (EMAb) in sera of 68 diabetics typed as LADA was compared with the antibody presence in sera of 85 patients with Type 2 diabetes. We found a significantly higher occurrence of gliadin antibodies in LADA patients: the rate of AGGAb was 19.1% in comparison with 3.5% in the T2DM group (P = 0.0026), the rate of AGAAb was 13.2% in comparison with 3.5% (P = 0.035). The prevalence of EMAb was very low in both groups (1.5% and 0). The two groups differed significantly in the TPOAb rate: 22.1% in LADA compared to 9.4% in T2DM (P = 0.04), whereas no significant difference was found in the presence of TGAb (8.8% and 3.5%, P = 0.187). In comparison with T2DM patients, LADA patients were found to express higher antibody activity against gluten-related antigens and against TPO.
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PMID:Gliadin, endomysial and thyroid antibodies in patients with latent autoimmune diabetes of adults (LADA). 1282 88

HLA-DM stabilizes peptide-receptive class II alphabeta dimers and facilitates the capture of high affinity peptides, thus influencing the peptide repertoire presented by class II molecules. Variations in DM levels may therefore have a profound effect on the antigenic focus of T cell-mediated immune responses. Specifically, DM expression may influence susceptibility and resistance to autoimmune diseases. In this study the role of DM in HLA-DR4-restricted presentation of an insulin-dependent diabetes mellitus autoantigen, glutamate decarboxylase (GAD), was tested. Presentation of immunodominant GAD epitope 273-285 was regulated by endogenous DM levels in human B lymphoblasts. T cell responses to exogenous GAD as well as an endogenous cytoplasmic form of this Ag were significantly diminished with increasing cellular expression of DM. Epitope editing by DM was observed only using Ag and not small synthetic peptides, suggesting that this process occurred within endosomes. Results with cytoplasmic GAD also indicated that peptides from this compartment intersect class II proteins in endocytic vesicles where DM editing was facilitated. Changes in DM levels within APC may therefore influence the presentation of autoantigens and the development of autoimmune disorders such as type I diabetes.
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PMID:Editing of an immunodominant epitope of glutamate decarboxylase by HLA-DM. 1284 54

Family history of type 1 diabetes and autoantibodies to the islet antigens insulin (IAA), glutamate decarboxylase (GADA), and the protein tyrosine phosphatase-like protein IA-2 (IA-2A) are strong predictors of type 1 diabetes, but the rate of progression to diabetes in multiple islet autoantibody-positive relatives varies widely. We asked whether detailed characterization of islet autoantibodies that included determination of titer, epitope specificity, and IgG subclass would improve diabetes prediction in a large cohort of autoantibody-positive relatives. The study shows a strong association between risk and high titer, broad antibody responses to IA-2 and insulin. The highest risks were associated with high-titer IA-2A and IAA, IgG2, IgG3, and/or IgG4 subclass of IA-2A and IAA, and antibodies to the IA-2-related molecule IA-2beta. Using models based on these antibody characteristics, autoantibody-positive relatives can be classified into groups with risks of diabetes ranging from 7 to 89% within 5 years.
Diabetes 2004 Feb
PMID:Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics. 1474 89

The origin of autoimmunity leading to the destruction of insulin-producing beta-cells is not known. Several studies suggest that a link exists between the gut immune system and the islets infiltrating lymphocytes. Inflamed pancreatic islets express the same adhesion molecules involved with the homing of gut-associated lymphocytes. The manifestation of autoimmune diabetes in the animal models can be modified by dietary factors, which cause changes in the cytokine production by islet-infiltrating lymphocytes. Increased risk of type 1 diabetes has been associated with an early introduction of cows' milk formula in infancy, indicating that triggering of the gut immune system in early infancy may contribute to the later development of beta-cell autoimmunity. Enhanced immune reactivity to cow milk (CM) proteins in the patients with type 1 diabetes suggests aberrant regulation of the gut immune system in this disease. In the patients with newly diagnosed type 1 diabetes, anti-glutamate decarboxylase (GAD)-reactivity was found in the subpopulation of lymphocytes expressing gut-associated homing receptor alpha 4 beta 7. Based on these findings, the hypothesis that aberrant function of the gut immune system would lead to the development of beta-cell autoimmunity and type 1 diabetes has recently received a lot of attention. The possibility that regulation of the gut immune system is not normal in subjects at risk of autoimmune diabetes should be considered when treatments interfering with mucosal immunity for the prevention of type 1 diabetes are planned.
Pediatr Diabetes 2000 Dec
PMID:The role of the gut in beta-cell autoimmunity and type 1 diabetes: a hypothesis. 1501 19

TCR transgenic mice are valuable tools for dissecting the role of autoantigen-specific T cells in the pathogenesis of type 1 diabetes but are time-consuming to generate and backcross onto congenic strains. To circumvent these limitations, we developed a new approach to rapidly generate mice expressing TCR using retroviral-mediated stem cell gene transfer and a novel picornavirus-like 2A peptide to link the TCR alpha- and beta-chains in a single retroviral vector. We refer to these as retrogenic (Rg) mice to avoid confusion with conventional transgenic mice. Our approach was validated by demonstrating that Rg nonobese diabetic (NOD)-scid mice expressing the diabetogenic TCRs, BDC2.5 and 4.1, generate clonotype-positive T cells and develop diabetes. We then expressed three TCR specific for either glutamate decarboxylase (GAD) 206-220 or GAD 524-538 or for hen egg lysozyme 11-25 as a control in NOD, NOD-scid, and B6.H2(g7) mice. Although T cells from these TCR Rg mice responded to their respective Ag in vitro, the GAD-specific T cells exhibited a naive, resting phenotype in vivo. However, T cells from Rg mice challenged with Ag in vivo became activated and developed into memory cells. Neither of the GAD-reactive TCR accelerated or protected mice from diabetes, nor did activated T cells transfer or protect against diabetes in NOD-scid recipients, suggesting that GAD may not be a primary target for diabetogenic T cells. Generation of autoantigen-specific TCR Rg mice represents a powerful approach for the analysis of a wide variety of autoantigens.
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PMID:Diabetes incidence is unaltered in glutamate decarboxylase 65-specific TCR retrogenic nonobese diabetic mice: generation by retroviral-mediated stem cell gene transfer. 1532 70

Previous studies have demonstrated that antigen-specific tolerance could be induced by lipopolysaccharide (LPS)-stimulated B cells retrovirally transduced with an immunoglobulin-antigen (or epitope-containing peptide) fusion construct. To investigate the mechanism of this gene therapy system, we now adapted this approach to immunotherapy of spontaneous diabetes in nonobese diabetic (NOD) mice, a T-cell-mediated autoimmune disease triggered, in part, by a pathogenic response to glutamate decarboxylase (GAD) 65. We demonstrate that LPS-stimulated splenocytes, retrovirally transfected with GAD-IgG fusion construct, induce a significant antigen-specific hyporesponsiveness at both cellular and humoral levels and reduce the incidence of diabetes in female NOD mice. Parallel with disease protection, we observed a prolonged increase of the numbers of CD4+CD25+ T cells in the periphery of GAD-IgG-treated mice, compared to those treated with a control IgG vector, both in the prediabetic period and persisting even 8 months after gene therapy. This increase appeared to be induced by the repeated stimulation of the antigen in the periphery instead of a result of differentiation of T-cell precursor in the thymus. Moreover, CD4+CD25+ T cells induced by GAD-IgG fusion construct were capable of suppressing the proliferative response of CD4+CD25- T cells in vitro; and ablation of the activity of CD4+CD25+ T cells by blocking antibody against CD25 could reverse GAD-specific T-cell hyporesponsiveness. These results suggested that CD4+CD25+ T-cell subset induced in GAD-IgG-treated NOD mice represented the regulatory or suppressive CD4+CD25+ T cells (Treg) and might play an important role in the induction and maintenance of tolerance in NOD mice. Furthermore, the numbers of splenic CD4+CD62L+ regulatory T cells in GAD-IgG-treated mice during the prediabetic period and serum TGF-beta levels in 34-38-week-old GAD-IgG-protected mice were also increased, compared to control IgG-treated ones. Therefore, we propose that the induction of tolerance and the prevention of diabetes incidence in NOD female mice induced by the GAD-IgG fusion construct may require CD4+ regulatory T cells, and the possible mediation of TGF-beta.
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PMID:Retroviral delivery of GAD-IgG fusion construct induces tolerance and modulates diabetes: a role for CD4+ regulatory T cells and TGF-beta? 1534 60

The 65 kDa human isoform of glutamate decarboxylase, GAD65, plays a central role in neurotransmission in higher vertebrates and is a typical autoantigen in several human autoimmune diseases, such as insulin-dependent diabetes mellitus (IDDM), Stiff-man syndrome and autoimmune polyendocrine syndrome type I. In autoimmune diabetes, an attack of inflammatory cells to endocrine pancreatic beta-cells leads to their complete destruction, eventually resulting in the inability to produce sufficient insulin for the body's requirements. Even though the etiology of beta-cell destruction is still a matter of debate, the role and antigenic potency of GAD65 are widely recognized. Herein a model of GAD65 is presented, which is based on the recently solved crystal structures of mammalian DOPA decarboxylase and of bacterial glutamate decarboxylase. The model provides for the first time a detailed and accurate structure of the GAD65 subunit (all three domains) and of its dimeric quaternary assembly. It reveals the structural basis for specific antibody recognition to GAD65 as opposed to GAD67, the other human isoform, which shares 81% sequence similarity with GAD65 and is much less antigenic. Literature data on monoclonal antibody binding are perfectly consistent with the detailed features of the model, which allows explanation of several findings on GAD65 immunogenicity. Importantly, by analyzing the active site, we identified the residues most likely involved in catalysis and substrate recognition, paving the way for rational mutagenesis studies of the GAD65 reaction mechanism, specificity and inhibition.
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PMID:Structural model of human GAD65: prediction and interpretation of biochemical and immunogenic features. 1569 Mar 45

The optimal cutoff point of glutamate decarboxylase antibody (GAD-Ab) titers for differentiating two latent autoimmune diabetes (LADA) subtypes remains unclear. One hundred and forty-five GAD-Ab-positive patients screened from phenotypic type 2 diabetes were diagnosed as LADA. The clinical features were compared among LADA patients with different GAD-Ab titers. The receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic value of GAD-Ab titers and to define the optimal cutoff point. The heterogeneity of clinical features in LADA could be discriminated by five GAD-Ab titers, with maximal differences at the titer of 175 U/mL. The ROC curve analysis showed that the optimal cutoff point for discriminating two LADA subtypes was at the titer of 175 U/mL, with sensitivity and specificity of 54.5% and 92.1%, respectively. These findings demonstrated that the two clinically distinct subtypes of LADA can be optimally discriminated by the GAD-Ab titers.
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PMID:Optimal cutoff point of glutamate decarboxylase antibody titers in differentiating two subtypes of adult-onset latent autoimmune diabetes. 1569 4

An association between thyroid and islet autoantibodies has been reported for patients with type 1 diabetes and their first-degree relatives. However no general agreement on this association has been reached since several studies reported controversial data. In the present study, sera from 429 healthy first-degree relatives of type 1 diabetic patients have been examined for the presence of thyroid and islet autoantibodies. Autoantibodies against glutamate decarboxylase (GAD65Ab) and tyrosine-phosphatase IA-2 (IA-2/ICA512Ab) have been detected by radioimmunoassay techniques with in vitro translated recombinant human 35S-autoantigens. The presence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) has been estimated by commercial radioimmunoassay kits. An increased frequency of TgAb was found in subjects who were positive for GAD65Ab (p=0.0257). However, no significant association between TPOAb and GAD65Ab or IA-2Ab or between TgAb and IA-2Ab could be established. These data indicate an increased rate of coincidence between TgAb and GAD65Ab in healthy first-degree relatives of type 1 diabetic patients. Accordingly a common genetic background leading to the appearance of both TgAb and GAD65Ab may be suggested.
Exp Clin Endocrinol Diabetes 2005 Feb
PMID:Coincidence of high antiislet and antithyroid autoantibody titles in first-degree relatives of patients with type 1 diabetes. 1577 99


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