Prevalence of pancreatic autoantibodies in non-diabetic patients with autoimmune thyroid disease and its relation to insulin secretion and glucose tolerance

ABSTRACT Objective We evaluated the prevalence of glutamic acid decarboxylase (GADA) and tyrosine phosphatase-protein antibodies (IA2A), their titers and their relation to first phase insulin response (FPIR) and glucose tolerance in autoimmune thyroid diseases (ATDs) patients. Subjects and methods Graves' disease (GD; n = 181) and Hashimoto's thyroiditis (HT; n = 143) patients in addition to healthy controls (n = 93) were studied. Secondly, FPIR and oral glucose tolerance tests (OGTT) were performed in 11 anti-pancreatic islet-cell (+) and in 20 anti-pancreatic-cell (-) patients. Results There was a non significant trend for higher prevalence of GADA positivity in GD vs HT (7.2% vs 2% p = 0.06), but the GADA titers were higher in HT. We also did not find a significant difference in IA2 prevalence (0.7% vs 0.0%) between these two groups or compared to the control group. In the subsequent analysis, low FPIR was found in 10% of these patients but without statistical difference for OGTT between pancreatic antibody-positive and -negative patients. Conclusion A trend for greater prevalence of GADA was observed for GD patients than for HT or control. However, the titers of these autoantibodies were higher in HT patients, but there was no significant relation to insulin secretion and glucose tolerance at that moment and stage of autoimmune diseases.

Clinical characteristics of patients with cerebellar ataxia associated with anti-GAD antibodies / Características clínicas de pacientes com ataxia cerebelar associada a anticorpos anti-GAD

ABSTRACT The enzyme glutamic acid decarboxylase (GAD), present in GABAergic neurons and in pancreatic beta cells, catalyzes the conversion of gamma-aminobutyric acid (GABA). The cerebellum is highly susceptible to immune-mediated mechanisms, with the potentially treatable autoimmune cerebellar ataxia associated with the GAD antibody (CA-GAD-ab) being a rare, albeit increasingly detected condition. Few cases of CA-GAD-ab have been described. Methods This retrospective and descriptive study evaluated the clinical characteristics and outcomes of patients with CA-GAD-ab. Result Three patients with cerebellar ataxia, high GAD-ab titers and autoimmune endocrine disease were identified. Patients 1 and 2 had classic stiff person syndrome and insidious-onset cerebellar ataxia, while Patient 3 had pure cerebellar ataxia with subacute onset. Patients received intravenous immunoglobulin therapy with no response in Patients 1 and 3 and partial recovery in Patient 2. Conclusion CA-GAD-ab is rare and its clinical presentation may hamper diagnosis. Clinicians should be able to recognize this potentially treatable autoimmune cerebellar ataxia.

RESUMO A enzima ácido glutâmico descarboxilase (GAD), presente nos neurônios GABAérgicos e células beta do pâncreas, catalisa a conversão do ácido gama-aminobutírico (GABA). O cerebelo é altamente susceptível a mecanismos imunomediados, sendo a ataxia cerebelar associada ao anticorpo anti-GAD (CA-GAD) uma doença potencialmente tratável. Embora rara, sua frequência é crescente, com poucos casos descritos. Métodos Estudo retrospectivo e descritivo avaliando características clínicas e desfechos da CA-GAD. Resultados Três pacientes com CA-GAD, altos títulos de anti-GAD e doença endócrina autoimune foram identificados. Os pacientes 1 e 2 tinham síndrome da pessoa rígida em forma clássica e apresentação insidiosa da ataxia cerebelar, enquanto o paciente 3 tinha ataxia cerebelar pura e apresentação subaguda. Os pacientes 1 e 3 não melhoraram com imunoglobulina intravenosa e o paciente 2 teve recuperação parcial. Conclusão A CA-GAD é rara e pode ter apresentação clínica desafiadora. Os médicos devem ser capazes de reconhecer essa forma potencialmente tratável de ataxia cerebelar autoimune.

Ataxia, ophthalmoplegia and laryngeal stridor related to glutamic acid decarboxylase antibodies / Ataxia, oftalmoplegia e estridor laríngeo relacionados a anticorpos antidescarboxilase do ácido glutâmico

Glutamic acid decarboxylase (GAD) is the enzyme responsible for the conversion of glutamate to gamma-aminobutyric acid (GABA) in the central nervous system. The presence of anti-GAD antibody in cerebrospinal fluid and high levels in blood have been described in some neurological disorders, such as stiff person syndrome and cerebellar ataxia. It is postulated that African descent with anti-GAD may exhibit more severe neurological impairment. We report a case of a young adult African descent with cerebellar syndrome associ-ated with ophthalmoplegia and laryngeal stridor. We found in the literature relationship of ophthalmoplegia plus ataxia with anti-GAD, but no reports of these symptoms with laryngeal stridor, apparently being the first reported case.

Descarboxilase do ácido glutâmico (GAD) é a enzima responsável pela conversão do glutamato em ácido gama-aminobutírico (GABA) no sistema nervoso central. A presença do anticorpo anti-GAD no líquido cefalorraquidiano e em altos níveis no sangue tem sido descrita em alguns distúrbios neurológicos, tais como a síndrome da pessoa rígida e ataxia cerebelar. Postula-se que pacientes afrodescendentes podem apresentar comprometimento neurológico mais severo. Relatamos o caso de um adulto jovem afrodescendente com síndrome cerebelar associada a oftalmoplegia e estridor laríngeo. Encontramos na literatura relação entre a oftalmoplegia com ataxia e anti-GAD, mas nenhum relato desses sintomas com estridor laríngeo, sendo aparentemente o primeiro caso reportado.

Implicações clínicas da persistência de anti-GAD positivo e peptídeo C detectável em pacientes com diabetes melito tipo 1 de longa duração / GADA persistence and detectable C peptide in patients with long standing diabetes mellitus type 1

OBJETIVO: Avaliar se anti-GAD positivo e PC detectável se correlacionam com a presença de outras doenças autoimunes, com controle glicêmico e com risco de retinopatia no diabetes melito tipo 1 (DMT1) > 3 anos de duração. PACIENTES E MÉTODOS: Cinquenta sujeitos com DMT1 foram entrevistados, realizaram fundoscopia e dosaram PC pré e pós-glucagon, HbA1C e anti-GAD. RESULTADOS: Pacientes anti-GAD+ (n = 17) apresentaram maior frequência de doenças autoimunes em relação aos demais (p = 0,02). PC detectável (n = 11) também foi associado ao aumento dessa prevalência (p = 0,03), porém nenhum dos dois parâmetros influenciou na presença de retinopatia diabética. PC detectável não influenciou no controle glicêmico (HbA1C média) (p = 0,28), porém as doses diárias de insulina foram mais baixas (0,62 vs. 0,91 U/kg/dia; p = 0,004) neste grupo. CONCLUSÃO: Apesar de não ser um marcador para outras doenças autoimunes, o anti-GAD+ parece ser não só um sinalizador de autoimunidade pancreática. PC detectável também parece ter papel promissor na detecção dessas comorbidades. Ambos não interferiram na presença de retinopatia, entretanto, o PC detectável se relacionou a menores necessidades de insulina.

OBJECTIVE: The aim of this study was to evaluate if GADA+ and detectable CP had any influence in other autoimmune diseases, glycemic control, and risks of retinopathy in diabetes mellitus type 1 (T1DM) lasting longer than 3 years of duration. SUBJECTS AND METHODS: Fifty T1DM subjects were interviewed, performed fundoscopic examination, and measured CP before and after glucagon, HbA1C, and GADA. RESULTS: GADA+ (n = 17) had a higher frequency of other autoimmune diseases when compared to GADA (p = 0.02). Detectable CP was also associated with a higher prevalence of these diseases (p = 0.03), although, retinopathy was not influenced by either one. Detectable CP had no influence in the glycemic control (mean HbA1C) (p = 0.28). However, insulin daily doses were lower in this group (0.62 vs. 0.91 U/kg/day; p = 0.004). CONCLUSION: Although not recommend as a marker of other autoimmune diseases, GADA+ seems to be not only a pancreatic autoimmunity signal. Detectable CP may also have some promising influence in detecting these diseases. Neither influenced the presence of retinopathy, but insulin daily requirements were smaller when CP was present.

Dysregulation of immune system in diabetic child

Diabetes is a chronic disease associated with selective destruction of the pancreatic B-cells. The exact etiology of the disease is unclear; however, insulin deficiency results from autoimmune destruction of B-cells. The appearance of auto antibodies to beta cell antigen, such as those against the 65-KDA isoform of glutamic acid decarboxylase GAD65 and the protein tyrosine phosphates in the peripheral circulation is a predictive sign of clinical disease in non diabetic individuals. Although GAD65 and IA-2 [insulin auto antibodies] may not be directly involved in the pathogenic processes in beta-cell destruction. They are good markers in assessing the risk of disease manifestation. This study aimed to evaluate GAD65 [glutamic acid decarboxylase] and ICA [islet cell auto antibodies] and IA-2 [insulin auto antibodies] auto antibodies as a disease markers and their relationship to certain residual beta cell function and glycemic control in type I diabetes and risk group, and assess the relation between CD4 [+] CD25 [+] [T-regulatory cells] and immune mediated diabetes. This study was conducted on 50 subjects randomly selected from those attending pediatrics outpatients clinics in the period of 2008. The subjects were classified into 3 groups: 1-Group A [patient group]: This group included 20 patients diagnosed as type I DM according to WHO classifications. Their ages ranging from 3-16 years with a mean age of 10.6 +/- 4.0. They were 11 males and 9 females. 2-Group B: [Risk group]: included 20 sibling of diabetic [type I DM] father, mother or both. They were 9 females and 11 males their ages ranging from 18 years to 25 years with a mean of age 21 +/- 2.5. 3-Group C: Control group, included 10 healthy children; they were 5 females and 5 males, their ages ranging from 5-16 years with a mean age of 10.8 +/- 2.8, with no family history of diabetes mellitus. All subjects are subjected to: Complete history taking, Full clinical examination, Complete blood picture, Glycosylated Hb using ion-exchane chromatography, C-peptide of insulin by-ELISA, determination of GAD 65, ICA and IA-2 auto antibodies by ELISA technique, Flowcytometric measurement of the expression of the CD4 [+] /CD25 [+] of T-regulatory cell. The most frequently encountered antibody in children group was GAD65 in 60% of cases, followed by ICA, 40%. When taken together, both GAD65 and ICA were detected in 30%. IA-2 was detectable only in 30% of cases. When both GAD65 and IA-2 were taken together, they were detected in 25% of cases also ICA and IA-2 were detected in 15% of cases. When GAD, ICA and IA-2 were taken together, they were detectable in 5% of cases. The most frequently encountered antibody in risk group was ICA in 15% of cases, followed by GAD, in 10%. When taken together, both GAD65 and ICA were detected in 10%. IA-2 was detectable only in 10% of cases. When both GAD65 and IA-2 were taken together. they were detected in 5% of cases also ICA and IA-2 were detected in 15% of cases. When GAD, ICA and IA-2 were taken together, they were detectable in 5% of cases. There was highly significant difference between 3 groups for prevalence of GAD65 autoantibody [p<0.001] and significant difference between 3 groups for prevalence of ICA autoantibody [p<0.005] and significant difference between 3 groups for prevalence of IA-2 autoantibody [p<0.003]. There were highly significant differences in the level of fasting C-peptide of insulin between patient and control groups. [p value<0.001]. There were significant difference between level of fasting Cpeptide and single and multiple autoantibody positivity [p<0.05]. In the children group the mean and SD of the percentage of CD4 [+] CD25 [+] from CD4 cells were 0.96, 0.46 respectively. In the control group the mean and SD of the percentage of CD4 [+] CD25 [+] from CD4 cells were 2.85, 0.92 respectively. The difference between control and study group according to the mean and SD of the percentage of CD4 [+] CD25 [+] from CD4 cells was statistically highly significant [p<0.001]. In the Risk group the mean and SD of the percentage of CD4 [+] CD25 [+] from CD4 cells were 0.99, 0.7 respectively. In the control group the mean and SD of the percentage of CD4 [+] CD25 [+] from CD4 cells were 2.96, 0.62 respectively. The difference between control and risk group according to the mean and SD of the percentage of CD4 [+] CD25 [+] from CD4 cells was statistically non significant. There was highly sig relation [p<0.001] between percent of CD4 [+] CD25 [+] out of CD4 cells and the presence and absence of auto antibodies in the children group. There was no sig relation between percent of CD4 [+] CD25 [+] out of CD4 cells and the presence and absence of auto antibodies in the in risk group. At the time of diagnosis almost all patients with type I diabetes have auto antibodies that are reactive to islet antigens and auto antibodies GAD, ICA, lA-2 are of' value for predicting IDDM in sibling of diabetic parents type I also CD4[+] CD25[+]T-regulatory cells actively suppress activation of the immune system and prevent pathological self-reactivity

Electrophysiological study and glutamic acid decarboxylase 65 in detection of subclinical neuropathy in type 1 diabetes mellitus

To evaluate the role of electrophysiological studies and serum glutamic acid decarboxylase [GAD65Ab] in the detection of subclinical neuropathy, in Type 1 diabetes mellitus [TIDM]. This study was conducted on 30 patients of Type 1 diabetes mellitus within the first year of diagnosis and 20 controls. All subjects were evaluated for subjective neuropathy symptoms, neurological examination, electrophysiological findings, GAD65Ab, glycosylated hemoglobin [HbA1], cholesterol and triglyceride in serum. At least two abnormal independent neurophysiological nerve parameters were accepted as the criteria of peripheral nervous system involvement. Electrophysiological study showed peripheral nervous system involvement in 93.3% of patients. The percentages of affection were 90% in sural nerve, 82.4% in peroneal motor nerve, 68.5% in posterior tibial motor nerve, 62.2% in median motor nerve, 59.9% in ulnar motor nerve, 65.2% in median sensory nerve, and 60.5% in ulnar sensory nerve. Antibodies to GAD65 were detected in 18 of 30 patients [60%]. Patients with positive GAD65Ab had slower motor nerve conduction velocities in the median, ulnar, and peroneal nerves and prolonged sural nerve latency. There is a positive correlation between HbA1 levels and peripheral nerve dysfunction in the lower extremity. Highly significant correlation between HhA1 and GAD65 in patients group was noticed. Subclinical diabetic peripheral neuropathy can be detected by electrophysiological tests, especially for nerves of lower extremity. The poor glycemic control and GAD65Ab have an impact on peripheral nerve function

Frequency Of Pancreatic Beta-Cell Autoimmunity Markers In Patients With Autoimmune Thyroid Disease / Frecuencia de marcadores de autoinmunidad beta pancreática en pacientes con enfermedad tiroidea autoinmune

A total of 305 ambulatory patients recruited at the Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, with autoimmune thyroid disease (AITD) were studied to search for associations between autoimmune thyroid disease and presence of serum markers of autoimmune diabetes mellitus. Screening for markers of pancreatic beta-cell autoimmunity was performed by radioligand binding assays (RBA) as follows: autoantibodies to glutamic acid decarboxylase (GADA) and proinsulin (PAA) were determined in all sera, whereas autoantibodies to protein tyrosine phosphatase (IA-2A) and insulin (IAA) were additionally measured in 200 sera randomly selected from the total collection. In addition, every GADA positive serum among the remaining 105 sera was systematically tested for the presence of IA-2A and IAA. In the cohort of 305 AITD patients 22 (7.2%) were previously diagnosed as type 1, type 2 or insulin-requiring type 2 diabetics. Ten of these patients presented serum marker positivity specific for β-cell autoantigens and 12 were marker negative. On the other hand, considering the majority of non-diabetic AITD patients (n=283), β-cell marker positivity was detected in 17 individuals (6.0%). The prevalence of autoimmune diabetes markers was much higher in the studied population than in the general population utilized as a control group, and GADA was the most frequent marker.

Se investigó la asociación entre enfermedad tiroidea autoinmune y la presencia de marcadores séricos de diabetes mellitus en 305 pacientes ambulatorios con enfermedad tiroidea autoinmune reclutados en la División Endocrinología. La búsqueda de marcadores de autoinmunidad contra las células beta pancreáticas se realizó por la técnica de unión de radioligandos (RBA) como se detalla a continuación: se determinaron autoanticuerpos contra la decarboxilasa del ácido glutámico (GADA) y proinsulina (PAA) en todos los sueros, mientras que los anticuerpos contra la proteína tirosina fosfatasa (IA-2A) e insulina (IAA) fueron medidos en 200 de estos sueros tomados al azar de la colección total. Además, en los restantes 105 pacientes, la presencia de IA-2A y IAA fue evaluada en todos los sueros positivos para GADA. Del grupo de 305 pacientes con enfermedad tiroidea autoinmune 22 (7.2%) fueron diagnosticados previamente como diabéticos tipo 1, tipo 2 o tipo 2 insulino-requirientes. Diez de ellos presentaron positividad para marcadores específicos de autoantígenos de célula β, en tanto 12 fueron negativos. Por otra parte, en 17 de los 283 pacientes (6.0%) con enfermedad tiroidea autoimmune y sin diagnóstico previo de diabetes, se detectó positividad para marcadores de célula β. La prevalencia de marcadores de autoinmunidad asociados a diabetes fue mayor en la población estudiada que en la población general usada como grupo control, siendo GADA el marcador más frecuente.

Glutamic acid decarboxylase [GAD65] and thyroid autoantibodies in Omani patients with type 2 diabetes

Autoimmunity is a common feature in type 1 diabetes mellitus [DM]. Little is known of the role of autoimmunity in type 2 diabetes. Antibodies to glutamic acid decarboxylase [GAD65] and thyroid antigens have been reported with various frequencies in diabetic patients. In this study, we investigated the prevalence and association of antibodies to GAD65, anti-thyroglobulin [A-TG-A], anti-thyroid microsomal [ATMA] antibodies, haemoglobin A[1c] [HbA[1c]] and fasting serum C-peptide in Omani patients with type 2 diabetes mellitus. We studied 100 Omani patients with type 2 diabetes for the presence of serum antibodies to GAD65, A-TG-A and ATMA by the use of commercially available kits. Results were compared with those from fifty patients with type 1 diabetes mellitus [DM] and fifty unaffected individuals who were used as controls. Results showed that type 2 DM had significantly high positivity levels [24%] of anti-GAD65 antibodies than the control group [4% - p < 0.05] though less than that found in type 1 DM [38%]. GAD65 antibodies were more commonly found in older females [> 40 years] with type 2 diabetes [p < 0.05]. A higher prevalence of ATMA was noted in both type 2 and type 1 diabetes [20 and 26% respectively] compared to the levels in the control group [8%]. There was a low prevalence and little difference in A-TG-A values among the three groups studied [9%, 14% and 4%]. Both A-TG-A and ATMA were more often expressed in older females with type 2 diabetes. HbA[1c] did not differ between groups with the duration of disease less or more than three years. When the same groups were tested for fasting serum C-pepticle, those with disease of more than three years duration had significantly higher prevalence [p < 0.05] as compared to those less than three years. This study confirms the presence and association of thyroid and GAD65 antibodies in some Omani patients with clinical diagnosis of type 2 DM

Frequency of islet cell autoantibodies (IA-2 and GAD) in young Brazilian type 1 diabetes patients

Type 1 diabetes, as an autoimmune disease, presents several islet cell-specific autoantibodies such as islet cell antibody (ICA), anti-insulin, anti-glutamic acid decarboxylase (GAD) and the antibody (Ab) against tyrosine phosphatase (PTP)-like protein known as ICA-512 (IA-2). In order to determine the frequency of the anti-GAD and anti-IA-2 autoantibodies in Brazilian type 1 diabetes patients we studied 35 diabetes mellitus (DM) type 1 patients with recent-onset disease 12 months and 37 type 1 diabetes patients with long-duration diabetes 12 months who were compared to 12 children with normal fasting glucose. Anti-GAD65 and anti-IA-2 autoantibodies were detected with commercial immunoprecipitation assays. The frequency of positive results in recent-onset DM type 1 patients was 80.0 percent for GADAb, 62.9 percent for IA-2Ab and 82.9 percent for GADAb and/or IA-2Ab. The long-duration type 1 diabetes subjects presented frequencies of 54.1 percent for GADAb and IA-2Ab, and 67.5 percent for GAD and/or IA-2 antibodies. The control group showed no positive cases. Anti-GAD and IA-2 assays showed a high frequency of positivity in these Brazilian type 1 diabetes patients, who presented the same prevalence as a Caucasian population