Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Pancreatic beta cell function and antibodies to glutamic acid decarboxylase (anti-GAD) in Chinese patients with clinical diagnosis of insulin-dependent diabetes mellitus. 880 79

We evaluated the frequency of antibodies to glutamic acid decarboxylase (GAD-Ab) in Japanese patients diagnosed initially as having non-insulin-dependent diabetes mellitus (NIDDM) and investigated a possible link between the presence of GAD-Ab and development of the insulin-dependent (ID) state. The population sample consisted of 583 Japanese NIDDM patients (age at onset > 30 years) who were initially non-ketotic and did not require insulin treatment during at least 6 months of observation. GAD-Ab were measured using radioimmunoassay. The clinical characteristics of GAD-Ab+ patients were carefully examined at four-year intervals from the onset of diabetes. We also examined the ID state by measuring the level of postprandial serum C-peptide and i.v. glucagon-stimulated serum C-peptide. The overall prevalence of GAD-Ab in Japanese NIDDM patients was 3.8%. The frequency of GAD-Ab+ did not significantly decrease with a long history of diabetes. GAD-Ab+ patients had a lower body mass index, compared with GAD-Ab- (20.8 +/- 2.9 vs 23.0 +/- 3.7, P < 0.005), lower postprandial C-peptide levels (0.7 +/- 0.6 vs 1.4 +/- 1.2, P < 0.01), and an early commencement of insulin therapy (3.6 +/- 4.7 vs 8.3 +/- 6.6, P < 0.01). GAD-Ab+ patients who had already developed the ID state had characteristically higher titers of GAD-Ab (421.4 +/- 359.1) and a higher frequency of islet cell antibodies (ICAs) (77.8%), compared with GAD-Ab+ NID patients (titer: 60.2 +/- 86.9, P < 0.005, 23.1%, P < 0.05, respectively). GAD-Ab+ ICAs+ patients showed higher frequencies of ID state at any diabetic duration compared with GAD- ICAs-, while GAD-Ab+ ICAs- patients did not differ in the frequency of the ID state from GAD- ICAs-. Our results suggest that the presence of both GAD-Ab and ICAs represents a high risk for IDDM in GAD-Ab+ NIDDM patients.
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PMID:Clinical evaluation of non-insulin-dependent diabetes mellitus patients with autoantibodies to glutamic acid decarboxylase. 893 85

Persistent humoral autoimmunity to the enzyme glutamic acid decarboxylase (GAD) has been described in a substantial proportion of patients with insulin-dependent diabetes mellitus (IDDM) of long duration. The source of the stimulus for this autoimmune reactivity is still unknown. Because the GAD 65 isoform is mainly expressed in pancreatic beta-cells and in the nervous system we investigated in the present study of the largest number of well characterized patients with longstanding IDDM (n = 105; median duration: 21 years; range: 10-46 years) the presence of autoantibodies to GAD 65 and their relationship to a residual C-peptide response or peripheral and autonomic neuropathy. Additionally we studied the HLA-DR status relative to GAD 65 antibodies in 86 out of the 105 individuals. One hundred healthy control subjects and 100 recent onset IDDM patients were also studied for GAD 65 antibodies. GAD 65 antibodies were detected in a radioligand-binding-assay with recombinant human GAD 65 and were present in 32% of the long-term diabetic patients, 82% of the recent onset IDDM patients and in 3% of the healthy control subjects. A preserved C-peptide response to i.v. glucagon (Hendriksen criteria) was observed in 23% of the long-term IDDM patients. Autonomic neuropathy and peripheral neuropathy was identified using criteria based on both symptoms and formal testing giving a frequency of 67% vs 79%. The HLA specific DR 4/X was observed in 47% and HLA-DR 3/X in 22% of the long-term IDDM patients. Patients who were heterozygous for DR3/DR4 were found in 23% of the cases. GAD 65 antibodies were significantly less frequent in the long-term IDDM patients compared to recent onset IDDM (p < 0.001), and diabetes duration showed a significant negative correlation with GAD 65 antibody index levels (r = 0.22, p < 0.01). Interestingly, GAD 65 antibodies were not significantly correlated either with residual beta-cell function or neuropathy and no particular HLA-DR status was associated with persistent GAD 65 antibodies. In conclusion neither residual beta-cell function nor diabetic neuropathy or a certain HLA-DR specificity are exclusively associated with persistent autoimmunity directed to GAD 65 in longstanding IDDM. The stimulus for the persistent humoral immune response and its significance for the disease process and its complications remain to be established.
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PMID:Persistent GAD 65 antibodies in longstanding IDDM are not associated with residual beta-cell function, neuropathy or HLA-DR status. 940 79

A single, large dose of N-methyl-D-aspartate (NMDA) or quisqualic acid (QA) injected into the chick eye has been shown previously to destroy many retinal amacrine cells and to induce excessive ocular growth accompanied by myopia. The purpose of this study was to identify distinct populations of retinal cells, particularly those believed to be involved in regulating ocular growth, that are sensitive to NMDA or QA. Two pmol of NMDA or 0.2 micromol of QA were injected unilaterally into eyes of 7-day-old chicks, and retinas were prepared for observation 1, 3, or 7 days later. Retinal neurons were identified by using immunocytochemistry, and cells containing fragmented DNA were identified by 3'-nick-end labelling in frozen sections. NMDA and QA destroyed many amacrine cells, including those immunoreactive for vasoactive intestinal polypeptide, Met-enkephalin, and choline acetyltransferase, but they had little effect upon tyrosine hydroxylase-immunoreactive cells. Other cells affected by both QA and NMDA included those immunoreactive for glutamic acid decarboxylase, gamma-aminobutyric acid, parvalbumin, serotonin, and aminohydroxy methylisoxazole propionic acid (AMPA) receptor subunits GluR1 and GluR2/3. Cells largely unaffected by QA or NMDA included bipolar cells immunoreactive for protein kinase C (alpha and beta isoforms) and amacrine cells immunoreactive for glucagon. DNA fragmentation was detected maximally in many amacrine cells and in some bipolar cells 1 day after exposure to QA or NMDA. We propose that excitotoxicity caused by QA and NMDA induces apoptosis in specific populations of amacrine cells and that these actions are responsible for the ocular growth-specific effects of QA and NMDA reported elsewhere.
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PMID:Immunocytochemical characterization of quisqualic acid- and N-methyl-D-aspartate-induced excitotoxicity in the retina of chicks. 952 96

To compare the clinical usefulness of commercial radioimmunoassay (RIA) kits based on recombinant and pig brain GAD, we measured glutamic acid decarboxylase autoantibody (GADAb) titers in 125 non-obese (body mass index < 24) Japanese diabetics without insulin therapy using two commercial RIA kits based on recombinant human (rh) GAD65 (GADAb Cosmic) and purified pig brain native GAD (RIP Anti-GAD Hoechst). The frequencies of GADAb positivity using these two RIA kits (normal ranges; < 1.3 and < 4.0 U/ml, respectively) were about 4.8 (6/125) and 3.2% (4/125), respectively. The six patients found to be positive with RIA using GADAb Cosmic demonstrated significantly higher prevalence of NIDDM in their parents (P = 0.04), lower beta-cell function estimated by intravenous glucagon loading tests (P = 0.03) and higher prevalence of progression to insulin therapy (P = 0.0001). Five of these six patients slowly progressed to insulin-requiring status within 34 +/- 11 months of follow-up evaluation, and one of these five patients progressed to a completely insulin-dependent status within 30 months from the onset of diabetes. Of these six patients, two demonstrated chronic pancreatitis, three had chronic thyroiditis, and five showed HLA DR4. Interestingly, two of the six patients demonstrated very low GADAb titers (2.3 and 2.9 U/ml), while RIP Anti-GAD Hoechst showed no positivity with the same sera. Based on the binding study after pre-incubation of unlabeled GADs, these low titrated GADAb were elucidated to be true specific reactions to rh GAD65 alone. Moreover, one of the two patients with chronic thyroiditis and HLA DR4 slowly progressed to insulin-requiring status over a period of 45 months. These findings suggest that the measurement of GADAb using a commercial assay kit with rh GAD65 may be more useful to detect non-insulin-dependent type I diabetics among non-obese patients than using a commercial kit with purified pig brain native GAD, especially among those with low GADAb titers.
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PMID:Antibodies to glutamic acid decarboxylase (GAD) in non-obese Japanese diabetics without insulin therapy: a comparison of two commercial RIA kits based on recombinant and pig brain GAD. 976 69

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

The role of the thymus in the induction of tolerance to peripheral antigens is not yet well defined. One impending question involves how the thymus can acquire the diversity of peripheral nonthymic self-Ags for the process of negative selection. To investigate whether peripheral Ags are synthesized in the thymus itself, we have determined the expression of a panel of circulating and cell-bound peripheral Ags, some of which are targets of autoimmune diseases, at the mRNA level in total thymic tissue and in its main cellular fractions. Normalized and calibrated RT-PCR experiments demonstrated the presence of transcripts of nonthymic self-Ags in human thymi from 8 days to 13-yr-old donors. Out of 12 glands, albumin transcripts were found in 12; insulin, glucagon, thyroid peroxidase, and glutamic acid decarboxylase (GAD)-67 in six, thyroglobulin in five, myelin basic protein and retinal S Ag in three, and GAD-65 in one. The levels of peripheral Ag transcripts detected were age-related but also showed marked interindividual differences. Cytokeratin-positive stromal epithelial cells, which are a likely cellular source for these, contained up to 200 transcript copies of the most expressed peripheral Ags per cell. These results implicate the human thymus in the expression of wide representation of peripheral self-Ags and support the view that the thymus is involved in the establishment of tolerance to peripheral Ags. The existence of such central mechanism of tolerance is crucial for the understanding of organ-specific autoimmune diseases.
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PMID:Transcription of a broad range of self-antigens in human thymus suggests a role for central mechanisms in tolerance toward peripheral antigens. 983 72

Antibodies to glutamic acid decarboxylase (GAD) are a useful autoimmune marker for type 1 diabetes mellitus in Caucasians. We examined antibodies to GAD and their relationships with clinical features and pancreatic beta cell function in 140 young Chinese diabetic patients. Over an 18-month period beginning in 1995, 140 young Chinese diabetic subjects with age of onset of disease < or = 35 years and age < 40 years were recruited consecutively, irrespective of their modes of presentation. Clinical features, antibodies to GAD and pancreatic beta cell function (using a glucagon stimulation test) were examined. Increased levels of antibodies to GAD (> 18 units) were detected in 12.1% (n = 17) of these subjects. Forty-three (31%) patients had a classical type 1 presentation and 65 (46%) patients were insulin-deficient based on post-glucagon plasma C-peptide levels. Patients who were insulin-deficient and had a type 1 presentation had the highest prevalence of antibodies to GAD (29.0%) compared with patients who had a type 2 presentation and were non-insulin deficient (6.4%, P = 0.003). Patients who had antibodies to GAD had lower body mass index and waist-hip ratio, earlier onset of disease, lower blood pressure, plasma triglyceride and C-peptide, and higher concentrations of plasma high-density lipoprotein cholesterol and glycated haemoglobin, and were more likely to require drug treatment, compared with those without antibodies to GAD. In conclusion, there was a low prevalence of antibodies to GAD in Chinese young diabetic patients although such antibodies remained a relatively specific marker for insulin deficiency and acute presentation. Causes other than autoimmunity should be sought to explain the high prevalence of insulin deficiency in these young Chinese patients.
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PMID:Antibodies to glutamic acid decarboxylase in young Chinese diabetic patients. 983 90

This study determined the prevalence of glutamic acid decarboxylase antibodies (GAD Ab) in a group of 926 young Malaysian diabetics of three ethnic groups, Malay, Chinese, and Indian. Patients were clinically diagnosed to be Type 1 or Type 2 before the age of 40 years. The overall GAD Ab positivity was 17.4% (161/926), significantly higher in the Type 1 than the Type 2 diabetics (35.5%, 116/329 vs. 7.5%, 45/597, P=0.0001). Compared to GAD Ab negative patients, seropositive diabetics were diagnosed at younger age (21.2+/-0.9 vs. 27.4+/-0.3 y, P=0.0001), had lower fasting (289+/-27.4 vs. 640+/-17.6 pmol/l, P=0.0001) and post-glucagon C-peptide levels (527+/-51.8 vs. 1030+/-28.9 pmol/l, P=0.0001). There were no racial differences in the prevalence of GAD Ab; of the total Type 1, 30.8, 36.4, and 39.4% were Malay, Chinese, and Indian diabetics, respectively and of the total Type 2, 8.8, 8.2, and 4.4% were Malay, Chinese, and Indian diabetics respectively. There was a curvilinear relationship between GAD Ab and the post-glucagon C-peptide levels, suggesting that GAD Ab do play a role in the beta-cells destruction and could be an important immune marker for the LADA group. This study reconfirmed previous reports that the autoimmune mechanisms in the Type 1 Asian diabetics are indeed different from the Caucasians, and further investigations should be carried out to explain the differences.
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PMID:Prevalence of glutamic acid decarboxylase antibodies amongst young Malaysian diabetics. 1019 89

The present study was conducted to determine the extent of insulin deficiency and glucagon excess in the hyperglycemia of type 2 diabetes in children. The incidence of type 2 diabetes mellitus in children and adolescents has increased substantially over the past several years. Because insulin and glucagon action both regulate blood glucose concentration, we studied their responses to mixed meals in children with type 2 diabetes. Subjects were 24 patients with type 2 diabetes compared with 24 controls, aged 9--20 yr (predominantly African-Americans), matched for body mass index and sexual maturation. All of those with diabetes were negative for antibodies to glutamic acid decarboxylase. Plasma glucose, glucagon, and serum C-peptide concentrations were measured at 0, 30, 60, 90, and 120 min after a mixed liquid meal (Sustacal) ingestion (7 mL/kg body weight; maximum, 360 mL). The area under the curve (AUC) was calculated by trapezoidal estimation. The incremental C-peptide (Delta CP) in response to the mixed meal was calculated (peak -- fasting C-peptide). The plasma glucose AUC was significantly greater in patients than in controls (mean +/- SEM, 1231 +/- 138 vs. 591 +/- 13 mmol/L x min; P < 0.001). The Delta CP was significantly lower in those with diabetes than in controls (1168 +/- 162 vs. 1814 +/- 222 pmol/L; P < 0.02). Glucagon responses did not differ between the two groups. Hyperglycemia is known to inhibit glucagon secretion. Therefore, our patients with substantial hyperglycemia would be expected to have decreased glucagon responses compared with controls and are thus relatively hyperglucagonemic. Patients were divided into poorly and well controlled subgroups (glycosylated hemoglobin A(1c), > or =7.2% and <7.2%, respectively). There were no significant differences in the Delta CP and glucagon responses between these two subgroups. We next analyzed the data in terms of duration of diabetes (long term, > or =1 yr; short term, <1 yr). The CP was significantly lower in long- vs. short-term patients (768 +/- 232 vs. 1407 +/- 199 pmol/L; P < 0.05). The plasma glucagon AUC was significantly higher in the long- vs. short-term patients (9029 +/- 976 vs. 6074 +/- 291 ng/L x min; P < 0.001). Hemoglobin A(1c) did not differ between long- vs. short-term patients. Our results indicate that relative hypoinsulinemia and hyperglucagonemia represent the pancreatic beta- and alpha-cell dysfunctions in children with type 2 diabetes. The severity of both beta- and alpha-cell dysfunctions appears to be determined by the duration of diabetes.
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PMID:C-peptide and glucagon profiles in minority children with type 2 diabetes mellitus. 1129 91


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