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)

Several islet antigens have been shown to modify the time of onset and severity of spontaneous insulin dependent diabetes mellitus (IDDM) in NOD (non-obese diabetic) mice. Oral, intravenous and intra-nasal administration of insulin and glutamic acid decarboxylase (GAD) or their derived peptides have all been shown to be effective to differing degrees in reducing the incidence and delaying the onset of diabetes in this mouse model of the disease. Incomplete Freund's Adjuvant (IFA) has also played a key role in tolerance when co-administered with insulin peptides subcutaneously. We show that route of administration may be of crucial importance, since although insulin B chain and the B9-23 peptide given in IFA subcutaneously protected (either partially or completely) from IDDM, when given intraperitoneally they completely failed to modify the disease.
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PMID:Protection from insulin dependent diabetes mellitus afforded by insulin antigens in incomplete Freund's adjuvant depends on route of administration. 965 91

Several risk factors for severe non-proliferative and proliferative retinopathy in type 1 diabetes mellitus have been proposed without explaining the rapid progression of retinopathy in some patients. Since GAD65 autoantibodies (GAD65Abs) are detected against glutamic acid decarboxylase (GAD), which is mainly expressed in islets and nervous tissue in type 1 diabetic patients, the aim of the present investigation was to test the hypothesis whether GAD65Abs are associated with rapidly progressing severe retinopathy. Patients with severe non-proliferative or proliferative retinopathy (n = 27) were compared with another group, which in spite of long diabetes duration had no or only mild signs of retinopathy (n = 28). GAD65Abs were analysed in a radioimmunoassay using in vitro translated human GAD65, and the levels were expressed as an index in relation to positive and negative reference samples. Using a cut-off level representing the 99th percentile of normals, 6/27 (22%) with and 9/28 (32%) without severe retinopathy were considered GAD65Ab positive. Although there was no difference in the number of GAD65Ab positive patients, the GAD65Ab levels were lower in patients with (0.30; 0.11-0.64) than without (0.68; 0.34-1.12) severe retinopathy (P = 0.03). The patients were also subjected to HLA-DR and DQ typing by PCR and hybridization with oligospecific probes. DQ2/8 was more common in patients with (56%) than without (29%) severe retinopathy (P = 0.05), but DQ2/8 could not account for the lower GAD65Ab levels in patients with severe retinopathy. It is concluded that GAD65Ab levels are inversely correlated with severe retinopathy in young type 1 diabetic patients.
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PMID:Inverse relationship between GAD65 antibody levels and severe retinopathy in younger type 1 diabetic patients. 969 85

Insulin-dependent diabetes mellitus (IDDM) is characterized by infiltration of T-lymphocytes in the islets of Langerhans. Antigens are presented to Th-lymphocytes which can be divided into Th1- and Th2-lymphocytes, producing interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) respectively. The aim of our study was to determine the messenger-RNA (mRNA) for these cytokines by RT-PCR in antigen-stimulated lymphocytes from children with newly diagnosed IDDM. The expression of mRNA for IL-4, and to a lesser degree IFN-gamma, is increased in lymphocytes stimulated with tetanus toxoid (TT). Loss of activity after freezing and thawing could be compensated for, by increased amplification, while the use of EDTA or sodium heparin in the blood samples did not influence the results. In a pilot application, the lymphocytes from children with newly diagnosed IDDM were stimulated with a peptide of glutamic acid decarboxylase (GAD) (a.a. 247-279) known to have a similar aminoacid sequence as the Coxsackie B virus (a.a. 32-47). Increased IFN-gamma mRNA could be seen in two out of four children, whereas IL-4 showed a less pronounced mRNA expression. No increased mRNA expression for IFN-gamma and IL-4 could be seen in healthy HLA-matched controls. Further studies are needed to confirm whether increased IFN-gamma mRNA in Th1-like lymphocytes stimulated with this specific GAD-peptide play a role in the cell-mediated immune response seen in children early after the onset of IDDM.
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PMID:Determination of mRNA expression for IFN-gamma and IL-4 in lymphocytes from children with IDDM by RT-PCR technique. 969 87

Insulin-dependent diabetes mellitus in humans is linked with specific HLA class II genes, e.g., HLA-DQA1*0301/ DQB1*0302 (DQ8). To investigate the roles of HLA-DQ8 molecules and glutamic acid decarboxylase (GAD) in disease development, we generated DQ8(+)/I-Abo transgenic mice expressing functional HLA-DQ8 molecules and devoid of endogenous mouse class II. DQ8(+)/I-Abo mice produced antigen-specific antibodies and formed germinal centers after immunization with GAD65 peptides. Two GAD peptide-specific (247-266 and 509-528), DQ8 restricted Th1 CD4(+) T cell lines, were generated from immunized DQ8(+)/I-Abo mice. They induced severe insulitis after adoptive transfer into transgene positive (but not negative) mice who were treated with a very low dose of streptozotocin that alone caused no apparent islet pathology. In addition to CD4, islet mRNA from these mice also showed expression of CD8, IFNgamma, TNFalpha, Fas, and Fas ligand. Our data suggest that a mild islet insult in the presence of HLA-DQ8 bearing antigen-presenting cells promotes infiltration of GAD peptide reactive T cells into the islet.
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PMID:Induction of insulitis by glutamic acid decarboxylase peptide-specific and HLA-DQ8-restricted CD4(+) T cells from human DQ transgenic mice. 972 63

To investigate autoimmunity to glutamic acid decarboxylase (GAD) 65 in Japanese patients with insulin-dependent diabetes mellitus (IDDM, type I diabetes), we established seven CD4+ T-cell clones, by stimulating peripheral blood mononuclear cells (PBMC) of six IDDM patients, using a mixture of overlapping human GAD65 peptides. No GAD65 autoreactive T-cell clones were evidenced in four healthy controls. Specificities of T-cell clones were as follows: (a) two clones specific to GAD65 p111-131 (residue 111 to 131) + DR53 (DRB4*0103); (b) one clone specific to GAD65 p413-433 + DR1 (DRB1*0101); (c) two clones specific to GAD65 p200-217 + either DR9 (DRB1*0901) or DR8 (DRB1*0802); and (d) two clones specific to GAD65 p368-388 + DP2 (DPA1*01 or 0201-DPB1*0201). Two DR53-restricted and one DR1-restricted T-cell clones, responded to a recombinant human GAD65 protein, and showed cytotoxicity against B lymphoblastoid cell lines pre-pulsed with the peptides. Six T-cell clones exhibited the Th1-like phenotype. Interestingly, two DR53-restricted T-cell clones killed a Fas-deficient B lymphoblastoid cell line, thereby indicating that cytotoxicity was not completely dependent on a Fas-Fas ligand interaction. Thus, the T-cell epitopes were mapped in a limited portion of GAD65 protein, with a tendency to be restricted by disease-associated HLA-DR, but not DQ molecules.
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PMID:Characterization of self-glutamic acid decarboxylase 65-reactive CD4+ T-cell clones established from Japanese patients with insulin-dependent diabetes mellitus. 975 11

A case of a 29-year-old woman with a multiple autoimmune disorder is reported. She had a history of hypothyroidism since the age of 18. She was admitted to hospital due to hyperglycaemia. At admission she had hyperglycaemia, metabolic acidosis, but no urinary ketone bodies. Further laboratory studies revealed that the acidosis was due to distal renal tubular acidosis rather than diabetic ketoacidosis (although the patient had type 1 diabetes mellitus). Blood tests revealed antibodies to glutamic acid decarboxylase (GAD-65; associated with type 1 diabetes mellitus), thyroid and adrenal tissue, and gastric parietal cells. The patient had not developed pernicious anaemia or Addison's disease. The multiple positive antibody titres in this patient indicate that the diabetes, hypothyroidism and distal renal tubular acidosis are part of an autoimmune syndrome.
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PMID:[A young woman with metabolic acidosis and recently discovered IDDM without ketonuria. A rare autoimmune (?) combination of hypothyroidism, diabetes mellitus and distal renal tubular acidosis]. 977 Oct 61

Autoantibodies to glutamic acid decarboxylase (GAD) are an important marker of the autoimmune-mediated beta-cell destruction in insulin-dependent (Type I) diabetes. However, these autoantibodies are also found in patients with Stiff-man syndrome (SMS) without onset of diabetes and some diabetic patients who initially present as non-insulin dependent (Type II) diabetes later becoming insulin-dependent, called as latent autoimmune diabetes in adults (LADA). To study the immune response to GAD in these LADA patients a competitive radiobinding assay based on murine monoclonal antibodies recognizing three different GAD regions was performed. The monoclonal antibodies against GAD recognize two different linear epitopes localized at the N- (amino acids 4-17) and C-terminus (amino acids 572-585) and one conformation-dependent epitope region (amino acids 221-442 IDDM-E1) known to be immunodominant for diabetes-associated autoantibodies. All LADA sera (20/20) reduced substantially the 125I-GAD binding of the monoclonal antibodies reactive with the conformation-dependent epitope region IDDM-E1 and only 20% of these sera additionally diminished the 125I-GAD65 binding by those monoclonals reactive with the both linear epitopes. The SMS sera completely abolished the GAD binding of all three monoclonals, reflecting a broader repertoire including an immune response against the IDDM-E1, a conformation-dependent GAD65 epitope region, also revealed if the SMS sera are diluted to equivalent antibody concentrations. In summary, our results show that diabetes-associated GAD autoantibodies even in adult patients with a late autoimmune process preferentially recognize a conformation-dependent middle GAD65 region. An immune response to all three GAD epitope regions is seldom in these LADA patients and only detectable in association with high antibody titres.
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PMID:A monoclonal antibody-based characterization of autoantibodies against glutamic acid decarboxylase in adults with latent autoimmune diabetes. 977 77

We report a 79-year-old woman case of slowly progressive IDDM (SPIDDM) with rheumatoid arthritis (RA) and Hashimoto disease. High titer of anti-glutamic acid decarboxylase antibody (GAD) with a value of 16,400 U/ml (normal value: less than 5 U/ml) and deteriorated secretion of insulin, and clinical course led to the diagnosis of SPIDDM. Both anti-islet cell and anti-insulin antibodies were negative. One year prior to the diagnosis, at 78 years of age, she was newly diagnosed with NIDDM and had been medicated with sulfonylurea and voglibose, resulting her glucose levels well-controlled. Four months before admission, a gradual increase of plasma glucose was noticed, while oral hypoglycemic agents were fully administrated. On admission, her glycemic control was revealed as follows; a fasting blood glucose level of 458 mg/dl and an HbA1 C level of 14.3%. Urinary CPR was 22.5 micrograms day. Her insulin secretion was proved not to be induced with intravenous glucagon injection. Hyperinsulinemic euglycemic glucose clamp test showed the normal glucose uptake ratio; 9.5 mg/kg/min. Moderate doses of subcutaneous insulin (20 units daily) were effective on her diabetes control. She was newly diagnosed with Hashimoto disease that required thyroid hormone replacement 50 micrograms per day after having developed NIDDM. High titer of anti-thyroglobulin antibody (46.9 U/ml) and anti-thyroid peroxidase antibody (81.5 U/ml) were observed. The patient had been medicated for RA with anti-inflammatory drugs since her early seventieth. Rheumatoid factor was elevated to 127.7 IU/L and, anti-nuclear antibody (x 80) and anti-DNA antibody (x 80) were present. It may be of interest that a specific phenotype of HLA; A24 (9) and DR9 recognized to be susceptible to IDDM was detected in the high-elderly onset SPIDDM. Taken together HLA typing with her history of both RA and Hashimoto disease, our case may provide the information to the mechanism of pathogenesis of SPIDDM. Furthermore, to out knowledge, this is the first case of SPIDDM in the aged; 75-year-old or more.
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PMID:[Slowly progressive IDDM with rheumatoid arthritis and Hashimoto disease in high elderly]. 977 59

Autoimmune T-cell responses to peptide determinants of several autoantigens have recently been characterized. These data suggest that, in some autoimmune models, such as experimental autoimmune encephalomyelitis, T-cell responses may diversify from a nested set of peptides to include many other peptide regions. A similar immune phenomenon pertaining to autoimmune diabetes (IDDM) is observed in NOD mice. We have explored a similar pattern of T-cell responses related to age and disease status in NOD mice termed epitope dominance, which describes immune responses toward a pronounced subset of determinants of the autoantigen glutamic acid decarboxylase (GAD). Our studies have identified a total of five GAD epitopes between the 65 and 67 kDa isoforms. The magnitude of T-cell responses to these various determinants was dependent on the stage of disease as well as on whether mice were protected from disease. The T-cell responses of these epitopes in NOD mice correlated with the predicted binding of these peptides to the NOD class II molecule I-Ag7. We therefore propose a model which implicates antigen presenting cells as critical entities in the propagation of dominant responses to the presentation of autoantigens to T cells, particularly in the Th 1 environment of the NOD mouse. This hypothesis presents a new framework for the discussion and interpretation of the kinetics of T-cell responses to different peptide epitopes in autoimmune diseases such as IDDM.
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PMID:Epitope dominance: evidence for reciprocal determinant spreading to glutamic acid decarboxylase in non-obese diabetic mice. 979 69

We describe a patient with type 1 diabetes with recurrent diabetic ketoacidosis and severe insulin resistance. Extensive evaluation of the etiology of the insulin resistance did not reveal an etiology, and well over 1000 U of daily insulin did not prevent the ketoacidosis. Her blood glucose and insulin requirements were improved with glucocorticoids and octreotide, but the effects of both of these agents were short-lived. She was given a trial of insulin lispro with immediate and dramatic effects, lowering her HbA1c from 14.6 to 5.1% in 7 months with a decrease in insulin requirements of 1600-100 U per day. Besides her diabetes, she had a history of pain and stiffness affecting numerous muscle groups, and hospitalization was required for pain control. The diagnosis of stiff-man syndrome (SMS) was confirmed with high titers of glutamic acid decarboxylase 65 antibodies in both serum and cerebral spinal fluid. In summary, we describe the first patient with type 1 diabetes, SMS, and severe insulin resistance. Although the etiology of the insulin resistance is unknown, due to the efficacious response to insulin lispro, hydrocortisone, and perhaps octreotide, we propose an immune-mediated etiology. Although rare, this syndrome needs to be considered as an etiology of insulin resistance.
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PMID:Severe insulin resistance in a patient with type 1 diabetes and stiff-man syndrome treated with insulin lispro. 982 49


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