GAD autoantibodies in IDDM, stiff-man syndrome, and autoimmune polyendocrine syndrome type I recognize different epitopes

Bjork, E.; Velloso, L. A.; Kampe, O.; Karlsson, F. A.

doi:10.2337/diabetes.43.1.161

Cited by 67 publications

(44 citation statements)

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“…In the present case, anti-GAD-specific IgG index (1.62), an assessment index for intrathecal production of anti-GAD antibody (8), was greater than 1.0, thus lending a strong support for its intrathecal production (8,19). In addition, it has been shown that the characteristics of anti-GAD antibodies are different between type 1 diabetes and SPS: anti-GAD65 antibodies in type 1 diabetes may recognize conformational epitopes in the middle and C-terminus of the protein, whereas in SPS they recognize both the linear and conformational epitopes at Nterminus and C-terminus of GAD65 molecules (9,18,20, and 21). Although we have not examined the characteristic of anti-GAD antibodies in the present case, it is possible to assume that the variation of polyclonal properties of anti-GAD antibodies in different cases might account for the initiation of different clinical manifestations.…”

Section: Discussionmentioning

confidence: 99%

Type 1 Diabetes Mellitus and Drug-resistant Epilepsy: Presence of High Titer of Anti-Glutamic Acid Decarboxylase Autoantibodies in Serum and Cerebrospinal Fluid

Yoshimoto¹,

Doi²,

Fukai³

et al. 2005

Intern. Med.

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A 55-year-old man who was diagnosed as having type 1 diabetes mellitus (DM) at the age of 50 years was started on insulin therapy. At 54 years old of age, he suddenly developed complex partial seizures, which frequently occurred despite intensive anti-epileptic drug therapy. Neurological examination on admission revealed hyporeflexia in bilateral upper and lower extremities without any muscle rigidity, painful spasm or cerebellar ataxia. Laboratory examination showed poor glycemic control with increased glycated hemoglobin levels. Positive anti-thyroglobulin antibodies and anti-thyroid peroxidase (TPO) antibodies and slight elevation of TSH levels are consistent with subclinical hypothyroidism due to Hashimoto's thyroiditis. A high titer of anti-glutamic acid decarboxylase (GAD) antibodies was detected in the patient's serum and cerebrospinal fluid (CSF). Electroencephalography showed temporal spikes, consistent with complex partial seizure. This is a very rare case presenting with concomitant type 1 diabetes and drugresistant epilepsy associated with high titers of circulating and CSF anti-GAD antibodies.

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Section: Discussionmentioning

confidence: 99%

Type 1 Diabetes Mellitus and Drug-resistant Epilepsy: Presence of High Titer of Anti-Glutamic Acid Decarboxylase Autoantibodies in Serum and Cerebrospinal Fluid

Yoshimoto¹,

Doi²,

Fukai³

et al. 2005

Intern. Med.

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“…The presence of GADA or ICA in Type II diabetes implicates an autoimmune process, although it is associated with T-cells, which induce beta-cell destruction. Autoantibodies are not always indicative of progressive autoimmune destruction, since patients with autoimmune polyendocrine disease with autoantibodies to beta-cell antigens do not always progress to diabetes [38,39].…”

Section: Discussionmentioning

confidence: 99%

Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43)

Horton

Stratton

Bottazzo³

et al. 1999

Diabetologia

104

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Aims/hypothesis. Juvenile-onset, insulin-dependent diabetes is associated with islet cell antibodies and with specific ªhigh-riskº HLA-DRB1 and HLA-DQB1 genotypes. Patients with Type II (non-insulin-dependent) diabetes mellitus can have islet-related antibodies, but the genotypic associations at different ages of onset have not been evaluated. Our aim was to determine (i) the prevalence of DRB1 and DQB1 genotypes in patients at diagnosis of Type II diabetes at different ages from 25 to 65 years compared with the general population, and (ii) whether the presence of islet cell antibodies (ICA) or glutamic acid decarboxylase antibodies (GADA) or both by age is associated with different DRB1 and DQB1 genotypes. Methods. The antibodies to islet cells and those to glutamic acid decarboxylase were measured in 1712 white Caucasian diabetic subjects at diagnosis of diabetes and they were genotyped for HLA DRB1*03 and DRB1*04 and the high-risk DRB1*04-DQB1* 0302 haplotype. To assess over-representation of high-risk alleles for Type I (insulin-dependent) diabetes mellitus, the prevalence of high-risk alleles in diabetic patients was expressed relative to the prevalence of low-risk alleles, non-DR3/non-DR4, that provided a reference denominator in both the diabetic patients and in 200 non-diabetic control subjects. The prevalence of ICA or GADA or both in patients with different HLA genotypes was assessed in those diagnosed in four age groups, 25±34 years, 35±44 years, 45±54 years and 55±65 years. Results. In Type II diabetic patients presenting at ages 25±34, 35±44 and 45±54 years, there was an increased prevalence of DR3/DR4 compared with the general population with approximately 6.5-fold, 2.9-fold, 2.1-fold over-representation, respectively (p < 0.0001, < 0.01, < 0.05) but this was not found in those aged 55±65 years old. In the group aged 25±34 years, 32 % of patients with ICA or GADA or both had DRB1*03/DRB1*04-DQB1*0302 compared with 10 % in those aged 55±65 years and expected 3 % prevalence. Conversely, only 14 % of those aged 25±34 years with antibodies had non-DR3/non-DR4, compared with 35 % in those aged 55±65 years. There was thus pronounced age heterogeneity in DRB1 and DQB1 predisposition to Type II diabetes. The antibodies displaced DRB1 or DQB1 genotypes in the multivariate model for requiring insulin therapy by 6 years of follow-up. Conclusion/hypothesis. The age of presentation of Type I diabetes in adulthood was in part dependent on the DRB1/DQB1 genotype. Islet cell antibodies and glutamic acid decarboxylase antibodies were strongly associated with DRB1*03/DRB1*04-DQB1*0302 in early adulthood but showed little relation with specific HLA genotypes after the age of 55 years. [Diabetologia (1999) 42: 608±616]

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“…Islets were isolated by hand picking following the collagenase digestion method [5,18]. To measure insulin secretion groups, five islets were pre-incubated for 45 min at 37°C in Krebs-bicarbonate buffer.…”

Section: Insulin Tolerance Test (Itt)mentioning

confidence: 99%

Peroxisome proliferator-activated receptor γ coactivator-1-dependent uncoupling protein-2 expression in pancreatic islets of rats: a novel pathway for neural control of insulin secretion

et al. 2003

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Aims/hypothesis. Sympathetic inputs inhibit insulin secretion through α2-adrenergic receptors coupled with Gi protein. High adrenergic tonus generated by exposure of homeothermic animals to cold reduces insulin secretion. In this study we evaluate the participation of UCP-2 in cold-induced regulation of insulin secretion. Methods. Static insulin secretion studies, western blotting and immunohistochemistry were used in this investigation. Results. Exposure of rats to cold during 8 days promoted 60% (n=15, p<0.05) reduction of basal serum insulin levels concentration accompanied by reduction of the area under insulin curve during i.p. GTT (50%, n=15, p<0.05). Isolated islets from cold-exposed rats secreted 57% (n=6, p<0.05) less insulin following a glucose challenge. Previous sympathectomy, partially prevented the effect of cold exposure upon insulin secretion. Islets isolated from cold-exposed rats expressed 51% (n=6, p<0.5) more UCP-2 than islets from control rats, while the inhibition of UCP-2 expression by antisense oligonucleotide treatment partially restored insulin secretion of islets obtained from cold-exposed rats. Cold exposure also induced an increase of 69% (n=6, p<0.05) in PGC-1 protein content in pancreatic islets. Inhibition of islet PGC-1 expression by antisense oligonucleotide abrogated cold-induced UCP-2 expression and partially restored insulin secretion in islets exposed to cold. Conclusion/interpreatation. Our data indicate that sympathetic tonus generated by exposure of rats to cold induces the expression of PGC-1, which participates in the control of UCP-2 expression in pancreatic islets. Increased UCP-2 expression under these conditions could reduce the beta-cell ATP/ADP ratio and negatively regulate insulin secretion. [Diabetologia (2003[Diabetologia ( ) 46:1522[Diabetologia ( -1531 Keywords Insulin, uncoupling protein, PGC-1, islet, sympathetic. Acetylcholine (Ach) mediates parasympathetic signals and acts upon pancreatic beta cells activating muscarinic M3 receptor subtype [4,5], which in turn promotes phospholipase β (PLCβ) stimulation with subsequent diacylglycerol (DAG) and inositol 1,4,5 triphosphate (IP3) accumulation [6]. The net result is the elevation of cytosolic Ca 2+ and increased insulin secretion. In contrast, norepinephrine (NE) released by sympathetic terminals stimulates beta-cell α2 adrenergic receptors that acting through G i or G 0 proThe role played by neural inputs on beta-cell function has been a matter of intense investigation over the latest forty years [1]. The highest effect is believed to be exerted by parasympathetic fibres originated at the

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GAD autoantibodies in IDDM, stiff-man syndrome, and autoimmune polyendocrine syndrome type I recognize different epitopes

Cited by 67 publications

References 0 publications

Type 1 Diabetes Mellitus and Drug-resistant Epilepsy: Presence of High Titer of Anti-Glutamic Acid Decarboxylase Autoantibodies in Serum and Cerebrospinal Fluid

Type 1 Diabetes Mellitus and Drug-resistant Epilepsy: Presence of High Titer of Anti-Glutamic Acid Decarboxylase Autoantibodies in Serum and Cerebrospinal Fluid

Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43)

Peroxisome proliferator-activated receptor γ coactivator-1-dependent uncoupling protein-2 expression in pancreatic islets of rats: a novel pathway for neural control of insulin secretion

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