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)

Glutamic acid decarboxylase (GAD) is the enzyme that synthesizes the neurotransmitter gamma-aminobutyric acid (GABA) in neurons and in pancreatic beta cells. It is a major target of autoimmunity in Stiff-Man syndrome (SMS), a rare neurological disease, and in insulin-dependent diabetes mellitus. The two GAD isoforms, GAD-65 and GAD-67, are the products of two different genes. GAD-67 and GAD-65 are very similar to each other in amino acid sequence and differ substantially only at their NH2-terminal region. We have investigated the reactivity of autoantibodies of 30 Stiff-Man syndrome patients to GAD. All patient sera contained antibodies that recognize strongly GAD-65, but also GAD-67, when tested by immunoprecipitation on brain extracts and by immunoprecipitation or immunocytochemistry on cells transfected with either the GAD-65 or the GAD-67 gene. When tested by Western blotting, all patient sera selectively recognized GAD-65. Western blot analysis of deletion mutants of GAD-65 demonstrated that autoantibodies are directed predominantly against two regions of the GAD-65 molecule. All SMS sera strongly recognized a fragment contained between amino acid 475 and the COOH terminus (amino acid 585). Within this region, amino acids 475-484 and 571-585 were required for reactivity. The requirement of these two discontinuous segments implies that the epitope is influenced by conformation. This reactivity is similar to that displayed by the monoclonal antibody GAD 6, suggesting the presence of a single immunodominant epitope (SMS-E1) in this region of GAD-65. In addition, most SMS sera recognized at least one epitope (SMS-E2) in the NH2-terminal domain of GAD-65 (amino acids 1-95). The demonstration in SMS patients of a strikingly homogeneous humoral autoimmune response against GAD and the identification of dominant autoreactive target regions may help to elucidate the molecular mechanisms of GAD processing and presentation involved in GAD autoimmunity. Moreover, the reactivity reported here of GAD autoantibodies in SMS partially differs from the reactivity of GAD autoantibodies in insulin-dependent diabetes mellitus, suggesting a link between the pattern of humoral autoimmunity and the clinical condition.
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PMID:Identification of a dominant epitope of glutamic acid decarboxylase (GAD-65) recognized by autoantibodies in stiff-man syndrome. 824 84

Glutamic acid decarboxylase (GAD) catalyzes the synthesis of gamma-aminobutyric acid (GABA), which is known as a major inhibitory neurotransmitter in the central nervous system (CNS), but is also present outside the CNS. Recent studies showed that GAD is the major target of autoantibodies associated with the development of insulin-dependent diabetes mellitus and of the rare stiff man syndrome. Studies of GAD expression have demonstrated multiple transcripts, suggesting several isoforms of GAD. In this study, three different genes were mapped by in situ hybridization to both human and mouse chromosomes. The GAD1 gene was mapped to human chromosome 2q31 and to mouse chromosome 2D in a known region of conservation between human and mouse. GAD2, previously mapped to human chromosome 10p11.2-p12, was mapped to mouse chromosome 2A2-B, which identifies a new region of conservation between human and mouse chromosomes. A potential GAD3 transcript was mapped to human chromosome 22q13 and to mouse chromosome 15E in a known region of conservation between human and mouse. It is concluded that the GAD genes may form a family with as many as three related members.
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PMID:Mapping of glutamic acid decarboxylase (GAD) genes. 840 75

Glutamic acid decarboxylase (GAD) is the enzyme responsible for synthesis of the neurotransmitter gamma-aminobutyric acid in neurons and pancreatic beta cells. It is represented by two isoforms, GAD-65 and GAD-67, which are the products of two different genes and differ substantially only at their N-terminal regions. GAD-65 is a dominant autoantigen in stiff-man syndrome and insulin-dependent diabetes mellitus. In neurons and beta cells, GAD is concentrated around synaptic vesicles and synaptic-like microvesicles, respectively, as well as in the area of the Golgi complex. The mechanisms responsible for specific targeting of GAD to these organelles are not yet understood. The elucidation of the mechanism of subcellular targeting of GAD may be relevant to understanding its role as an autoantigen. In this study, the cloned genes for GAD-65 and GAD-67 were expressed separately in Chinese hamster ovary (CHO) cells and COS cells. While GAD-67 had a diffuse cytoplasmic localization, GAD-65 had a punctate distribution, with most of the immunoreactivity being concentrated in the area of the Golgi complex. A chimeric protein in which the 88 N-terminal amino acids of GAD-67 were replaced by the 83 N-terminal amino acids of GAD-65 was targeted to the Golgi complex, indicating that the N-terminal region of GAD-65 contains a targeting signal sufficient for directing the remaining portion of the molecule, highly similar in GAD-65 and GAD-67, to the Golgi complex-associated structures.
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PMID:Association of GAD-65, but not of GAD-67, with the Golgi complex of transfected Chinese hamster ovary cells mediated by the N-terminal region. 846 26

Glutamic acid decarboxylase (GAD) catalyzes formation of gamma-aminobutyric acid from glutamic acid and is a major autoantigen in insulin-dependent diabetes mellitus. Its two isoforms, GAD65 and GAD67, are encoded by two separate genes. We prepared human islet cDNA library and screened it with cDNA probes of rat brain GAD67. We cloned the cDNA for GAD67, the large isoform of glutamic acid decarboxylase, and determined its nucleotide sequence. Sequencing of the resulting clone identified a 1,785 residue open-reading frame encoded a 594 amino acid polypeptide that showed a 99.4% similarity with GAD67 from human brain. The bacterially expressed human islet GAD67 protein was enzymatically active and immunoreactive. The isolation of cDNA for this additional islet GAD isoforms will be important in studying the etiology and pathogenesis of IDDM.
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PMID:Cloning and expression of large isoform of glutamic acid decarboxylase from human pancreatic islet. 850 3

In rats, beta-endorphin (beta-END) and gamma-aminobutyric acid (GABA) suppress LH secretion by hypothalamic mechanisms involving the preoptic area (POA). Systemic injection of naloxone (NAL) increases LH secretion in male rats, an effect which can be prevented by coadministration of GABA agonists. Application of NAL into the POA of ovariectomized (ovx), progesterone substituted sheep modulates preoptic GABA release. These findings have been interpreted such that the endogenous opioids act via the preoptic GABAergic system to regulate LH release. To evaluate this hypothesis we implanted ovx rats with push pull cannula into the POA and measured GABA secretion prior to and during the preoptic application of either NAL or beta-END. Blood samples were collected to assess the effects of the drugs on LH secretion. In addition, ovx rats were substituted with estradiol (E2) to induce a negative feedback effect on LH release. Intrapreoptic application of beta-END caused a rapid decline of LH release in ovx rats which was completely reversible after termination of beta-END perfusion. Though LH levels were clearly suppressed, no change of GABA release in the POA was observed. During preoptic NAL perfusion both LH secretion and GABA release remained unaffected. Likewise, during beta-END perfusion into the POA of E2 treated rats neither LH nor GABA secretion changed. In contrast, NAL perfusion rapidly increased LH release but again this action of the opioidergic drug was not accompanied by alterations of GABA release. We conclude from these data: 1) Intrapreoptically applied beta-END inhibits LH release only in the absence of steroids. In turn, blockade of opioid receptors is effective only in the presence of steroids. Both findings indicate that in the POA opioidergic activity is low in ovx rats, but high during negative feedback of E2. 2) No changes of GABA secretion were observed during manipulations of the opioidergic tonus in the POA suggesting that both beta-END and GABA do not interact to regulate LH release. Thus, beta-END may directly inhibit the activity of GnRH neurons located in the POA or acts via a neurotransmitter other than GABA.
Exp Clin Endocrinol Diabetes 1995
PMID:The inhibitory effect of beta-endorphin on LH release in ovariectomized rats does not involve the preoptic GABAergic system. 853 61

Glutamic acid decarboxylase (GAD), among other potential autoantigens, is thought to play a crucial role in type I diabetes, particularly in a spontaneous model of the disease, the nonobese diabetic (NOD) mouse. In the pancreas, the presence of GAD and gamma-aminobutyric acid (GABA), the decarboxylation product of GAD and a putative neurotransmitter in the islets of Langerhans, is well documented in the beta-cells. This is particularly true in rats, in which another GABAergic structure exists near the islets, the neuronal bodies. In this study, first the GABA content was measured in isolated islets from NOD and C57BL/6 mice (controls), and a decrease was found in NOD females as their insulitis progressed. Second, for the first time in mice, confocal analysis of immunofluorescent-labeled pancreatic sections revealed near the islets neuronal structures in which GAD and neuropeptide Y were colocalized, as they are in the brain. These structures were always observed in the pancreata of both sexes of C57BL/6 mice at the various ages investigated. In NOD mice, however, these neuronal structures were only detected in young females ( < 10 weeks old) and in males until an intermediate age. Moreover, patches of T cells surrounding GAD-containing fibers were seen in the vicinity of the islets with incipient periinsulitis.
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PMID:Localization of gamma-aminobutyric acid and glutamic acid decarboxylase in the pancreas of the nonobese diabetic mouse. 875 79

In type I (insulin-dependent) diabetes, destruction of pancreatic beta cells has been associated with the presence of circulating antibodies against glutamate decarboxylase (GAD), a GABA (gamma-aminobutyric acid) synthesizing enzyme which is located in the beta cells. We examined whether destruction of islet beta cells can lead to discharge of GAD in the extracellular medium, making it a potential autoantigen. Rat islet beta cells were first exposed for 1 hour to streptozotocin and then cultured for 4 to 24 hours before cellular and medium GAD activities were measured. After 24 hours culture, 70 percent of streptozotocin-treated beta cells were disintegrated whereas the number of control cells remained unchanged. Control cells exhibited a stable cellular GAD activity over the 24 hour period with no enzyme activity detectable in their culture medium. The cells recovered 24 hours after streptozotocin treatment exhibited 10-fold lower levels of GAD-activity and of GABA; their culture medium contained GAD, its enzymatic activity reaching peak values after 10 hours. The beta-cell enzymes glutamate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase were not detectable in the medium of control or streptozotocin-treated cells. Similar observations were made when beta cells had been exposed to cytotoxic concentrations of alloxan. It is concluded that damage to rat islet beta cells results in transient discharge of GAD in the extracellular medium making this enzyme a candidate extracellular marker for beta cell toxic processes and a potential autoantigen for immune reactivity.
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PMID:Damaged rat beta cells discharge glutamate decarboxylase in the extracellular medium. 892 Sep 8

Free amino acid levels and high affinity uptake of glutamate, aspartate, gamma-aminobutyrate, glycine and taurine were studied in retina and retinal pigment epithelium of streptozotocin diabetic rats. Results show that experimental diabetes produces a generalized fall in the content of free amino acids in both retina and retinal pigment epithelium. With regard to the high affinity uptake, in the two tissues of diabetic animals showed decreased aspartate uptake, enhanced taurine and gamma-aminobutyrate uptake, whereas that of glycine and glutamate was unchanged. These results might suggest that diabetes causes alterations of specific amino acid transport systems and/or alterations of some cell populations.
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PMID:Effect of diabetes on levels and uptake of putative amino acid neurotransmitters in rat retina and retinal pigment epithelium. 892 76

Ten patients, eight males and two females with a mean age of 51.20 +/- 8.23 (SD) were seen in ABU Teaching Hospital, Zaria from 1985 to 1994 with either myocardial infarction or angina. Three patients were Asians and Lebanese. Seven had myocardial infarction and two had angina and one patient had ischaemic cardiomyopathy. There were four patients with anterior-lateral, two with inferior lateral and one anterior septal myocardial infarction. The diagnosis of acute myocardial infarction was based on symptoms and electrocardiograph. Five patients had angiogram with evidence of severe coronary disease. The risk factors identified were hypertension, hyperlipidaemia, smoking, Diabetes mellitus and male sex. Laboratory evidence was minimal because CK-MB is not a routine investigation in our centre, this might compromise the diagnosis.
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PMID:Ischaemic heart disease and myocardial infarction in ABU Teaching Hospital, Zaria: a 10 year review (1985 to 1994); a short report. 893 88

We report the case of a female patient, who died at the age of 66 years. Besides an insulin-dependent diabetes mellitus (IDDM) she had developed the clinical symptoms of stiff-man-syndrome (SMS) and harbored autoantibodies against glutamate-decarboxylase (GAD) in blood and liquor. GAD catalyzes the biosynthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The autopsy revealed typical alterations observed in diabetes mellitus including an incomplete fibrosis of pancreatic Langerhans islets. A decrease of GABA-ergic cells in the cerebellar cortex was observed, and a size reduction of Renshaw cells in the spinal cord. Furthermore, a dilution series of a polyclonal GABA antibody delivered a reduced immunofluorescence in the cerebellum. In skeletal muscle a neurogenic atrophy was observed. As described in literature, the clinical symptoms decayed following clonazepam administration. We suggest that this case including GAD autoantibodies, dramatic loss of GAD-expressing pancreatic cells, and loss or atrophy of GABA secretory neurons, supports the hypothesis that SMS may be an autoimmune disease directed against GABA-ergic cells. Furthermore, we suggest a neuronal hypersensitivity at the spinal cord level caused by the atrophic Renshaw cells.
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PMID:Stiff-man syndrome: possible autoimmune etiology targeted against GABA-ergic cells. 926 48


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