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PubMed1997

Measurement of antibodies against glutamic acid decarboxylase 65 (GADA): two new 125I assays compared with [35S]GAD 65-ligand binding assay.

Recently, 65-kDa glutamic acid decarboxylase (GAD 65) antibodies (GADA) have been introduced as autoimmune markers in blood to confirm the diagnosis of insulin-dependent diabetes mellitus (IDDM). In this study, to evaluate two new assays that use 125I-labeled GAD 65, we assayed samples from 100 children with recent onset of diabetes and 100 control children, the results were compared with those of a [35S]GADA assay and with results for islet cell antibodies (ICA), the conventional autoimmune marker. Receiver operating characteristic (ROC) curve analysis showed one of the new assays (from RSR) to be more sensitive (P = 0.01) than the comparison ([35S]GADA) assay, whereas the second new assay (from Elias) was less sensitive (P < 0.001). The GADA frequency at 97.5% specificity was greatest in the comparison assay: 63 of 100 vs 41 of 100 (P < 0.01) and 53 of 100 (P = 0.16) in the RSR and Elias assays, respectively. Almost all GADA-positive patients had ICA, but one-third of the ICA-positive patients was GADA-negative. Accordingly, adding GADA analysis results to ICA testing increased the frequency of detection of autoimmune markers only slightly (from 81% to 85%). In conclusion, at 97.5% specificity the [35S]GADA assay seemed to be more efficient than the 125I assays, although the difference was significant only for the Elias 125I assay. Antigen-specific antibodies other than GADA may explain the difference in GADA and ICA frequencies.

Adolescent↗
PubMed1993

Antibodies to glutamic acid decarboxylase in Australian children with insulin-dependent diabetes mellitus and their first-degree relatives.

Antibodies to glutamic acid decarboxylase (GAD), previously known as the 64-kD pancreatic islet cell autoantigen, are an important serologic marker of insulin-dependent diabetes mellitus (IDDM). Antibodies to GAD (anti-GAD) were examined in sera from Australian children with newly diagnosed IDDM (within 1 mo of diagnosis), IDDM of longer duration (mean +/- SD, 4.8 +/- 3.3 y), and in first-degree relatives, using a radioimmuno-precipitation assay with purified porcine brain GAD as antigen. Antibodies to islet cell cytoplasmic antigens (ICAb) were tested concurrently. The frequency of anti-GAD was not significantly different in children with newly diagnosed IDDM (31 of 42, 74%) and with IDDM of longer duration (14 of 21, 67%), whereas ICAb were present more frequently in children with newly diagnosed IDDM (64%) than in those with longer duration IDDM (14%). In all, 90% of children with newly diagnosed IDDM had either anti-GAD or ICAb, whereas only 48% had both. For the 77 first-degree relatives, the frequency of anti-GAD was 2% (one of 44) in parents and 6% (two of 33) in siblings; ICAb were not detected in any of these relatives. The presence of anti-GAD in the majority of children with IDDM, irrespective of the duration of their disease, represents a useful diagnostic marker for IDDM, and should be of value in ascertaining individuals at risk for developing IDDM.

Adolescent↗
PubMed2000

[Diagnostic efficacy of glutamic acid decarboxylase antibody and islet cell antibody in type I diabetes mellitus].

OBJECTIVE: To investigate the diagnostic efficacy of glutamic acid decarboxylase antibody (GAD65-Ab) and islet cell antibody (ICA) in type I diabetes mellitus. METHODS: 104 cases of type I diabetes mellitus and 102 normal controls were recruited, GAD65-Ab was determined with radioligand assay and ICA with ELISA. The diagnostic efficacy of GAD65-Ab and ICA was analysed by receiver-operating characteristic (ROC) curve with sensitivity, specificity and curve area. RESULTS: (1) The optimal cut-off point of GAD65-Ab was at 0.30, while that of ICA was at 0.45. The area under the curve of GAD65-Ab and ICA were 0.835 and 0.715 respectively. Compared with 0.5, the area under curve of GAD65-Ab and ICA was higher (P < 0.0001). The area under curve of GAD65-Ab was higher than that of ICA(P < 0.01). (2) In type I diabetes mellitus patients, the positivity of GAD65-Ab was not correlated to the age of onset and duration of the disease, while the positivity of ICA was correlated to the age of onset and duration. CONCLUSION: Type I diabetes mellitus can be diagnosed with GAD65-Ab and ICA. The diagnostic efficacy of GAD65-Ab is higher than that of ICA. In patients of type I diabetes mellitus with adult-onset and duration more than one year, the diagnostic efficacy of GAD65-Ab is higher than that of ICA, while in patients of type I diabetes mellitus with adolescent-onset and duration less than one year, the diagnostic efficacy of ICA is higher than that of GAD65-Ab.

Adolescent↗
PubMed2000

Immune reactivity to glutamic acid decarboxylase 65 in stiffman syndrome and type 1 diabetes mellitus.

BACKGROUND: The immune response to an isoform of glutamic acid decarboxylase (GAD), GAD65, is associated with two clinically distinct diseases, stiff-man syndrome (SMS) and type 1 (insulin-dependent) diabetes mellitus. We sought to identify differences in the cellular and humoral immune responses to GAD in these two diseases. METHODS: We compared T-cell responses in 14 SMS patients with axial disease and 17 patients with type 1 diabetes. FINDINGS: Peripheral blood T cells of eight SMS patients recognised different immunodominant epitopes of GAD65 compared with T cells from 17 patients with type 1 diabetes. GAD regions 81-171 and 313-403 induced a dominant T-cell response in six of eight patients with SMS but in only one of 17 patients with type 1 diabetes (p=0.001). No SMS patients responded dominantly to GAD fragments 161-243 and 473-555 compared with ten patients with type 1 diabetes (p=0.008). GAD antibodies were detected in 11 of 14 SMS patients (seven with diabetes) and 11 of 17 patients with type 1 diabetes; IgG1 was dominant in both groups. SMS patients, however, were more likely than patients with diabetes to have isotypes other than IgG1 (p=0.03), in particular, IgG4 or IgE isotypes, which were not detected in patients with type 1 diabetes (p=0.012). INTERPRETATION: Our findings indicate differences between patients with SMS and type 1 diabetes in cellular (epitope recognition) and humoral (isotype pattern) responses to GAD65. Thus the same autoantigen can elicit distinct immune responses in patients with SMS, even when associated with diabetes, compared with patients with type 1 diabetes.

Adolescent↗
PubMed2000

Distribution of autoantibodies to glutamic acid decarboxylase across the spectrum of diabetes mellitus seen in South Africa.

AIMS: This study investigated the association between glutamic acid decarboxylase antibodies (GAD-AB) and Type 1, Type 2, pancreatic and lipoatrophic diabetes mellitus (DM) in South African patients. METHODS: Four groups were selected: group A, 100 Black Type 1 DM patients (age at onset < 35 years, body mass index (BMI) < 27 kg/m2 and insulin dependent within 1 year of presentation); group B, 80 Black Type 2 DM patients (age at onset > 35 years, BMI > 27 kg/m2 and controlled on oral hypoglycaemic agents for at least 1 year after presentation); group C, 10 patients of varying ethnicity with DM or impaired glucose tolerance secondary to chronic pancreatitis; group D, five patients of varying ethnicity with DM associated with total lipodystrophy. Fifty healthy Black control subjects were also studied (group E). Serum GAD-AB and random C-peptide levels were measured by radioimmunoassay. RESULTS: Mean C-peptide concentration was significantly lower in Type 1 DM patients than Type 2 DM patients (P < 0.00001). Forty-four patients with Type 1 DM were GAD-AB-positive compared to two patients with Type 2 DM. Two control subjects were also GAD-AB-positive. No patient in the other groups had a titre > 1 U/ml. Type 1 DM patients who were GAD-AB-positive did not differ from those who were GAD-AB-negative for age at onset, duration of DM or C-peptide concentrations. CONCLUSIONS: Auto-immune beta-cell destruction has an important role in the pathogenesis of Type 1 DM amongst African patients. However, Type 2 African DM patients and other diabetes subtypes are largely GAD-AB-negative.

Adult↗
PubMed1996

Pancreatic beta cell function and antibodies to glutamic acid decarboxylase (anti-GAD) in Chinese patients with clinical diagnosis of insulin-dependent diabetes mellitus.

Antibodies to glutamic acid decarboxylase (anti-GAD) and pancreatic beta cell secretory function were measured in 39 consecutive Chinese patients with a clinical diagnosis of insulin-dependent diabetes mellitus (IDDM) (19 males, mean +/- SD age. 37 +/- 15 years; body mass index (BMI), 22 +/- 4 kg/m2; mean duration of disease, 6.7 +/- 5.6 years). IDDM was defined on the basis of acute symptoms with heavy ketonuria (> 3+) or ketoacidosis at diagnosis, or requirement for continuous insulin treatment within one year of diagnosis. Insulin deficiency was defined as a post-glucagon stimulated plasma C-peptide concentration < or = 0.6 nmol/l. Overall, anti-GAD antibodies were positive (> 18 units) in 23% (n = 9) of these patients. Of the 39 patients, 29 (74%) were insulin deficient and 10 (26%) were non-insulin deficient. Anti-GAD antibodies were positive in 31% of the insulin-deficient patients but in none of the non-insulin-deficient group. Insulin deficiency and anti-GAD positivity were associated with younger age, earlier age of clinical onset and lower BMI. There were independent negative relationships between levels of anti-GAD antibodies and blood pressure and a positive relationship between insulin dosage and albuminuria. This study emphasises the difficulty in differentiating clinically between IDDM and NIDDM in Chinese patients. Despite the acute presentation, these patients had variable pancreatic beta cell secretory function. The varying duration of disease may partly explain the low prevalence of positive anti-GAD antibodies in these patients, but seems unlikely to explain fully the difference from Caucasian IDDM patients.

Adult↗
PubMed2006

The prevalence of the 65-kilodalton isoform of glutamic acid decarboxylase autoantibodies by glucose tolerance status in elderly patients from the cardiovascular health study.

CONTEXT: Autoantibodies (AA) to glutamic acid decarboxylase (GAD65), a determinant of risk for autoimmune diabetes, have been found in up to 10% of patients with type 2 diabetes. In older adults, this marker may also serve as a determinant of risk for autoimmune diabetes and enhance diabetes classification. OBJECTIVE: The objective of this study was to evaluate the relationship between GAD65AA and glucose tolerance status, current diabetes treatment, and clinical measures in older adults. DESIGN: GAD65AA were measured at baseline in 3318 participants from the Cardiovascular Health Study, a cohort study of 5888 individuals 65 or older. SETTING: The population-based cohort was recruited from four U.S. sites. PATIENTS: Patients included all Cardiovascular Health Study participants with known diabetes, newly diagnosed diabetes, impaired fasting glucose, impaired glucose tolerance, and a sample of normal glucose-tolerant participants. MAIN OUTCOME MEASURES: GAD65AA, body mass index, fasting glucose and insulin levels, blood pressure, lipid levels, and diabetes treatment at baseline were measured. RESULTS: The prevalence of GAD65AA increased with decreasing glucose tolerance in both Blacks (n = 560) and Whites (n = 2730), being more pronounced in known diabetic individuals. GAD65AA were found in 2.3, 5.8, 7.8, and 8.3% of diabetic participants, reporting use of no diabetes medication, oral hypoglycemic agents, insulin only, and both oral hypoglycemic agents and insulin, respectively (P = 0.02, linear trend). Among diabetic participants, GAD65AA positivity was associated with diabetes treatment, higher fasting glucose, and lower body mass index. CONCLUSIONS: Even among older individuals with diabetes, GAD65AA may be a useful marker in identifying a subgroup of autoimmune diabetes, serve as a marker of insulin requirement, and remain stable over years.

Aged↗
PubMed1983

Immunocytochemical and autoradiographic methods to demonstrate the coexistence of neuroactive substance: cerebellar Purkinje cells have glutamic acid decarboxylase, cysteine sulfinic acid decarboxylase, and motilin immunoreactivity.

Evidence is presented from immunocytochemical experiments that Purkinje cells in the mammalian cerebellum of a number of species contain gamma aminobutyric acid (GABA), taurine and the peptide motilin. Purkinje neurons show immunoreactivity to antibodies against glutamic acid decarboxylase (GAD), the synthetic enzyme for GABA, cysteine sulfinic acid decarboxylase (CSADC ase), the synthetic enzyme for taurine and motilin. Single neurons have either unique localization for GAD or motilin or CSADC ase or two substances in combination providing evidence for coexistence of these neuroactive agents. Functional studies with iontophoresis of GABA, taurine, and motilin into rabbit lateral vestibular nucleus elicited strong depressant effect on neuronal firing. The interactions of motilin and GABA were additive and inhibitory. Thus, Purkinje neurons of the cerebellum use multiple chemical messengers in their interactions. These chemical messengers coexist in single neurons. Their effects as far as our studies indicate are inhibitory and consistent with previous demonstrations of the physiological actions of Purkinje cells.

Animals↗
PubMed2003

A novel PEPP homeobox gene, TOX, is highly glutamic acid rich and specifically expressed in murine testis and ovary.

The homeobox gene superfamily has been highly conserved throughout evolution. These genes act as transcription factors during several important developmental processes. To explore the functional roles of homeobox genes in spermatogenesis, we performed a degenerate oligonucleotide polymerase chain reaction (PCR) screening of a testis cDNA library and isolated a novel mouse homeobox gene. This gene, which we named Tox, encodes a homeodomain protein distantly related to members of the Paired/Pax (Prd/Pax) family. A phylogenetic analysis revealed Tox to be a member of the recently defined PEPP subfamily of Paired-like homeobox genes. Tox was mapped to chromosome X, with its homeodomain organized into three exons. A special feature of Tox is that the encoded protein sequence contains two poly-glutamic acid (poly E) stretches, which make Tox highly acidic. Tox transcripts were detected predominately in the testis and ovary of mice. Tox expression in testes was initiated soon after birth, mainly in Sertoli cells and spermatogonia; however, in adult mice, Tox expression shifts to the spermatids and spermatozoa. Tox expression in ovaries was detected in somatic cells of follicles, early on in theca cells, and in both granulosa and theca cells at the later stages of follicular development. Based on these results, Tox may play an important role during gametogenesis.

Amino Acid Sequence↗
PubMed2000

In Situ Observation of Growth Process of alpha-L-Glutamic Acid with Atomic Force Microscopy.

The growth kinetics of the (111) and (001) faces of an alpha-L-glutamic acid crystal was investigated from the measurements of the growth rates, coupling with in situ surface observation using atomic force microscopy (AFM). The data of the growth rates were examined by applying the theoretical equations of the BCF and NaN models. The results indicate that the growth mechanism is not due to the screw dislocation but to the two-dimensional nucleation, i.e., the NaN model. It was confirmed by AFM observation that both the (111) and (001) faces grew with the "nucleus above nucleus" (NaN) mechanism. However, the difference of the two-dimensional nucleation behavior was observed between the faces. The growing surface of the (111) face was also observed in the presence of L-phenylaline (L-Phe) and the pinning effect by L-Phe on the growing step on the (111) face was confirmed. This result supports the mechanism of the additive effect, which was proposed previously. Copyright 2000 Academic Press.

Journal Article↗
PubMed1976

Radiation effects of poly(L-glutamic acid) and poly(L-lysine) in the helix-coil transitional state.

The degradation of poly(L-glutamic acid) and poly(L-lysine) by X-rays and ultraviolet radiation has been studied at various pH values, including the helix-coil transition region. It was found that X-rays cause maximum degradation in the transition region for both polypeptides, indicating that the efficiency of degradation is affected not only by the secondary structure but also by some other factors related to the transition. On the contrary, the degradation by monochromatic ultraviolet 2537 A radiation showed a strong dependence on helix content of PLGA, suggesting that degradation occurs more effectively in the helical form than in the coil form. Theoretical calculations were made to approximate the pH dependence of degradation, assuming different cross sections for the peptide bonds in helix, coil, and junctions between helical and coil regions.

Molecular Conformation↗
PubMed1991

Comparative study of in vitro inhibition of activation of the classical and alternative pathways of human complement by the magnesium and sodium salts of the anti-inflammatory peptide N-acetyl-aspartyl-glutamic acid (NAAGA).

The inhibitory activity of the sodium salt of the anti-inflammatory peptide N-acetyl-aspartyl-glutamic acid (NAAGA) on activation of the classical and alternative pathways of human complement was compared with that of the clinically used magnesium salt of NAAGA (NAAGA-Mg). Sodium salt of NAAGA (NAAGA-Na) inhibited both pathways of activation in a dose-dependent manner at concentration ranging from 1 to 10 mM by acting on formation and/or function of the C3 convertases as shown by the inhibitory capacity of the peptide on the release of the C3 cleavage fragment C3b and C3a. NAAGA-Na was as effective as NAAGA-Mg in inhibiting classical pathway activation at concentration above 10 mM. NAAGA-Na was more effective than NAAGA-Mg in inhibiting the alternative pathway since the sodium salt did not interfere with Mg-dependent formation of the alternative pathway C3 convertase.

Animals↗
PubMed2006

Optimal production of poly-gamma-glutamic acid by metabolically engineered Escherichia coli.

Metabolically-engineered Escherichia coli strains were developed by cloning poly-gamma-glutamic acid (gamma-PGA) biosynthesis genes, consisting of pgsB, pgsC and pgsA, from Bacillus subtilis The metabolic and regulatory pathways of gamma-PGA biosynthesis in E. coli were analyzed by DNA microarray. The inducible trc promoter and a constitutive promoter (P(HCE)) derived from the D-amino acid aminotransferase (D-AAT) gene of Geobacillus toebii were employed. The constitutive HCE promoter was more efficient than inducible trc promoter for the expression of gamma-PGA biosynthesis genes. DNA microarray analysis showed that the expression levels of several NtrC family genes, glnA, glnK, glnG, yhdX, yhdY, yhdZ, amtB, nac, argT and cbl were up-regulated and sucA, B, C, D genes were down-regulated. When (NH(4))(2)SO(4 )was added at 40 g/l into the feeding solution, the final gamma-PGA concentration reached 3.7 g/l in the fed-batch culture of recombinant E. coli/pCOpgs.

Bacterial Proteins↗
PubMed2005

Preparation of nanoparticles composed of poly(gamma-glutamic acid)-poly(lactide) block copolymers and evaluation of their uptake by HepG2 cells.

In the study, poly(gamma-glutamic acid) (gamma-PGA) and poly(lactide) (PLA) were used to synthesize block copolymers via a simple coupling reaction between gamma-PGA and PLA to prepare self-assembled nanoparticles. For the potential of targeting liver cancer cells, galactosamine was further conjugated on the prepared nanoparticles as a targeting moiety. gamma-PGA, a water-soluble, biodegradable, and non-toxic compound, was produced by microbial fermentation (Bacillus licheniformis, ATCC 9945a) and then was hydrolyzed. The hydrolyzed gamma-PGA with a molecular weight of 4 kDa and a polydispersity of 1.3 was used, together with PLA (10 kDa, polydispersity 1.1), to synthesize block copolymers. The prepared nanoparticles had a mean particle size of about 140 nm with a zeta potential of about -20 mV. The results obtained by the TEM and AFM examinations showed that the morphology of the prepared nanoparticles was spherical in shape with a smooth surface. In the stability study, no aggregation or precipitation of nanoparticles was observed during storage for up to 1 month, as a result of the electrostatic repulsion between the negatively charged nanoparticles. With increasing the galactosamine content conjugated on the rhodamine-123-containing nanoparticles, the intensity of fluorescence observed in HepG2 cells increased significantly. Additionally, the intensity of fluorescence observed in HepG2 cells incubated with the nanoparticles with or without galactosamine conjugated increased approximately linearly with increasing the duration of incubation. In contrast, there was no fluorescence observed in Hs68 cells (without ASGP receptors) incubated with the nanoparticles with galactosamine conjugated. The aforementioned results indicated that the galactosylated nanoparticles prepared in the study had a specific interaction with HepG2 cells via ligand-receptor recognition.

Cell Line, Tumor↗
PubMed2002

Chemoenzymatic synthesis and application of glycopolymers containing multivalent sialyloligosaccharides with a poly(L-glutamic acid) backbone for inhibition of infection by influenza viruses.

Highly water-soluble glycopolymers with poly(alpha-L-glutamic acid) (PGA) backbones carrying multivalent sialyl oligosaccharides units were chemoenzymatically synthesized as polymeric inhibitors of infection by human influenza viruses. p-Aminophenyl disaccharide glycosides were coupled with gamma-carboxyl groups of PGA side chains and enzymatically converted to Neu5Acalpha2-3Galbeta1-4GlcNAcbeta-, Neu5Acalpha2-6Galbeta1-4GlcNAcbeta-, Neu5Acalpha2-3Galbeta1-3GalNAcalpha-, and Neu5Acalpha2-3Galbeta1-3GalNAcbeta- units, respectively, by alpha2,3- or alpha2,6-sialytransferases. The glycopolymers synthesized were used for neutralization of human influenza A and B virus infection as assessed by measurement of the degree of cytopathic inhibitory effect in virus-infected MDCK cells. Among the glycopolymers tested, alpha2,6-sialo-PGA with a high molecular weight (260 kDa) most significantly inhibited infection by an influenza A virus, strain A/Memphis/1/71 (H3N2), which predominantly binds to alpha2-6 Neu5Ac residue. The alpha2,6-sialo-PGA also inhibited infection by an influenza B virus, B/Lee/40. The binding preference of viruses to terminal sialic acids was affected by core determinants of the sugar chain, Galbeta1-4GlcNAcbeta- or Galbeta1-3GalNAcalpha/beta- units. Inhibition of infection by viruses was remarkably enhanced by increasing the molecular weight and sialic acid content of glycopolymers.

Animals↗
PubMed2005

The detection properties of ammonia SAW gas sensors based on L-glutamic acid hydrochloride.

This study has investigated an improved surface acoustic wave (SAW) ammonia gas sensor based on L-glutamic acid hydrochloride. It presents an excellent reversibility, sensitivity, and repeatability to ammonia. The frequency shift versus ammonia concentration above 40 degrees C was a monotonic function, and the limit of detection of the sensor at 50 degrees C was 80 ppb.

Letter↗
PubMed2004

Deregulation of estrogen receptor coactivator proline-, glutamic acid-, and leucine-rich protein-1/modulator of nongenomic activity of estrogen receptor in human endometrial tumors.

Proline-, glutamic acid-, and leucine-rich protein-1)PELP1/MNAR [modulator of nongenomic activity of estrogen receptor (ER)], a novel coregulatory protein, modulates genomic as well as nongenomic activity of ERs. We characterized the expression and localization of PELP1 in both benign and cancerous endometrium. Our results suggest that PELP1 is expressed in all stages of endometrium; however, this protein exhibits distinct localization depending on the phase. PELP1 is expressed in both the stroma and epithelial cells. Using the Ishikawa endometrial cancer model cell line and ER subtype-specific ligands, we found that PELP1 functionally interacts with both ERalpha and ERbeta and enhances their transcriptional responses. However, in endometrial cancer cells, endogenous PELP1 is also required for optimal ligand-mediated transcription and proliferation responses. PELP1 promoted a tamoxifen-mediated agonistic action in endometrial, but not in breast cancer cells. PELP1 expression and localization are widely deregulated in endometrial cancers. In addition, PELP1 and ERbeta were localized predominantly in the cytoplasm of high-grade endometrial tumors. Our results suggest that PELP1 plays an essential role in the proliferation of cancerous endometrial cells.

Antineoplastic Agents, Hormonal↗