Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 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.
Diabetes Res Clin Pract 1998 Sep
PMID:Severe insulin resistance in a patient with type 1 diabetes and stiff-man syndrome treated with insulin lispro. 982 49

GAD65 (glutamic acid decarboxylase) is an important autoantigen in both type 1 (insulin-dependent) diabetes mellitus (IDDM) and the neurological autoimmune disease stiff-man syndrome (SMS), and is expressed in pancreatic islets as well as the nervous system. Still, only 30% of SMS patients also have type 1 diabetes. To study regulation of T cell responsiveness to GAD65, we investigated a non-diabetic SMS patient with HLA-DR3/7 (predisposing to type 1 diabetes) and high levels of type 1 diabetes-associated autoantibodies against GAD65 and islet cells, and compared the results with those of her diabetic son and two other SMS patients. T cell responses to GAD65 were repeatedly absent in primary stimulation, whereas IA-2, islet antigen and tetanus toxoid induced significant T cell proliferation. However, after in vitro restimulation, GAD65 reactive T cell lines and clones were obtained that were HLA-DR3 restricted, and cross-reactive with a homogenate of purified human pancreatic islets. These T cells produced the immunoregulatory cytokine IL-10 in combination with IFN-gamma and IL-4 (Th0). The dominant T cell epitope was mapped to the central region of GAD65. Although no primary response to whole GAD65 was detectable, the naturally processed GAD65 peptide epitope was recognized vigorously in the primary stimulation assay. The lack of detectable primary T cell responses to GAD65, together with the GAD65-specific cytokine production of restimulated T cells, suggest that GAD65-specific cellular autoimmunity in this patient is suppressed and may be related to the absence of diabetes despite humoral autoreactivity and genetic predisposition.
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PMID:GAD65-Reactive T cells in a non-diabetic stiff-man syndrome patient. 1033 Mar

Autoantibodies to GAD, an important marker of the autoimmune process in type I or insulin-dependent diabetes mellitus (IDDM), are also found in non-diabetic individuals with autoimmune polyendocrine syndrome type 1 (APS1), APS2, and stiff man syndrome (SMS). Most IDDM sera contain two distinct GAD antibody specificities, one of which targets an epitope region in the middle-third of GAD65 (IDDM-E1; amino acids 221-359) and one of which targets the carboxy-third of GAD65 (IDDM-E2; amino acids 453-569). Using 11 chimeric GAD65/GAD67 proteins to maintain conformation-dependent epitopes of GAD65, we compared the humoral repertoire of IgG antibodies from an individual with APS2-like disease (b35, b78, and b96) and MoAbs from an IDDM patient (MICA-2, MICA-3, and MICA-4). Neither the APS2 IgG antibodies nor the IDDM MoAbs bind the amino-terminal third of GAD65, but instead target the carboxy-terminal two-thirds of GAD65. Amino acids 270-359 (IDDM-E1) are targeted by one APS2 IgG antibody and MICA-4, while two other APS2 IgG antibodies, MICA-2 and MICA-3, target amino acids 443-585 (IDDM-E2). Using GAD65/67 chimera that span the IDDM-E2 region, we found that MICA-2 binds amino acids 514-528 of GAD65, but two APS2 IgG antibodies require this region and amino acids 529-570. In contrast, the binding of MICA-3 requires two discontinuous amino acid segments of GAD65 (452-513 and 528-569), but not amino acids 514-528. These results indicate that there are both similarities and differences in the humoral response to GAD65 in APS2 and IDDM.
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PMID:Comparative analysis of epitope recognition of glutamic acid decarboxylase (GAD) by autoantibodies from different autoimmune disorders. 1059 51

Some beta-cell-specific autoantigens also are present in the central nervous system. Furthermore, stiff man syndrome, an autoimmune neurological disease, is frequently associated with diabetes and shares with this one an anti-GAD and IA-2 humoral immunoreactivity. We wondered whether these autoantibodies could be found in other neurological diseases with a present or supposed autoimmune origin. So, anti-GAD65 (GAD65A) and anti-IA-2 (IA-2A) autoantibodies were assayed in various neurological diseases. There was a higher prevalence of such antibodies in Lambert-Eaton myasthenic syndrome (LEMS) (GAD65A, 35%; IA-2A, 21%; double positivity, 18%) compared to amyotrophic lateral sclerosis (18%, 12%, and 12%, respectively) and multiple sclerosis (10%, 3%, and 3%, respectively). In LEMS, the humoral reaction was more frequent and/or appeared earlier in the paraneoplastic forms. The detection of such autoantibodies in patients with small-cell lung carcinoma (SCLC) without LEMS suggests that these autoantigens, GAD65 and IA-2, could be produced by SCLC tissue.
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PMID:Humoral immunity against glutamic acid decarboxylase and tyrosine phosphatase IA-2 in Lambert-Eaton myasthenic syndrome. 1093 16

Stiff man syndrome (SMS), an uncommon neurological disease, is characterised by symmetrical muscle stiffness and spasms that often lead to skeletal deformity. Variants of the syndrome may involve one limb only (stiff leg syndrome), a variety of additional neurological symptoms and signs such as eye movement disturbances, ataxia, or Babinski signs (progressive encephalomyelitis with rigidity and myoclonus), or be associated with malignant disease (paraneoplastic SMS). Antineuronal autoimmunity and accompanying autoimmune diseases, most often insulin-dependent diabetes mellitus, are characteristic features of SMS and its variants. The condition is frequently misinterpreted as psychogenic movement disturbance, but electromyographic abnormalities and the presence of autoantibodies against glutamic acid decarboxylase (GAD) in both serum and cerebrospinal fluid help to establish the correct diagnosis. The aetiology of SMS is obscure. However, several features suggest that SMS is an autoimmune-mediated chronic encephalomyelitis. In line with this hypothesis, immunomodulation with a front-loaded methylprednisolone regimen reduces stiffness and spasms and improves other neurological symptoms in the majority of patients. Plasmapheresis or intravenous immunoglobulins are effective less frequently. For symptomatic treatment, the benzodiazepines are drugs of first choice. An alternative of last resort is baclofen administered intrathecally via an implanted pump device.
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PMID:Stiff man syndrome. 1151 Jun 22

Stiff-Person Syndrome (SPS) is a very rare disorder characterised by progressive fluctuating muscle rigidity and episodic spasm. So far, only two reports have demonstrated a significant clinical improvement in the patients with SPS when muscle were injected with Botulinum Toxin A (BTA). We investigated the effectiveness of intramuscular injections of BTA in a patient with clinical, biochemical and electrophysiological evidence of SPS. A 41-year-old woman with coexisting epilepsy and insulin-dependent diabetes mellitus was hospitalised in our Department because of stiffness and paroxysmal spasm of trunk and proximal limbs muscles. Because of not sufficient results of the pharmacological treatment the injections of BTA into involved muscles were done. Clinical observations included measure of pain, frequency of spasm, well-being and selection's activities were performed at baseline and in 1, 2, 7, 11, 16, 20, weeks. Significant improvement started one week after injections and lasting about 4 months was observed. Using BTA injections into involved muscles for the treatment of SPS can be followed by marked functional improvement and reducing the need for systemic drugs.
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PMID:[Botulinum toxin A in the treatment of stiff man syndrome]. 1509 44

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

Our laboratories have developed several technologies to accelerate drug discovery process on the basis of structural chemoproteomics. They include SPS technology for the efficient determination of protein structures, SCP technology for the rapid lead generation and SDF technology for the productive lead optimization. Using these technologies, we could determine many 3D structures of target proteins bound with biologically active chemicals including the structure of phosphodiesterase 5/Viagra complex and obtain highly potent compounds in animal models of obesity, diabetes, cancer and inflammation. In this paper, we will discuss concepts and applications of structural chemoproteomics for drug discovery.
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PMID:Structural chemoproteomics and drug discovery. 1581 88

Glutamic acid decarboxylase (GAD) catalyzes the conversion of glutamic acid to gamma-aminobutyric acid (GABA). Autoantibodies directed against GAD (antiGAD-Ab) have been described in patients with insulin-dependent diabetes mellitus, stiff-man syndrome, and in a few patients with progressive cerebellar ataxia. The presence of these autoantibodies suggests an autoimmune pathophysiological mechanism for the neurological manifestations in these disorders. However, the exact role of antiGAD-Ab and GABAergic neurotransmission in the pathogenesis of the neurological manifestations, particularly in progressive cerebellar ataxia, is not fully understood. The cases of two patients with subacute cerebellar ataxia associated with antiGAD-Ab presenting with abnormal eye movements are reported. One patient presented a periodic alternating nystagmus (PAN), whereas the other presented a downbeat nystagmus (DBN) and slow vertical saccades. The potential role of antiGAD-Ab and the resultant GABAergic neurotransmission deficit in oculomotor manifestations is discussed.
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PMID:Potential role of anti-GAD antibodies in abnormal eye movements. 1582 97


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