The evaluation of pancreas β-cell autoantibodies in non-diabetic COVID-19 patients

ABSTRACT Objective: This study aims to evaluate potential pancreas endocrine damage due to SARS-CoV-2 by measuring β-cell autoantibodies in COVID-19 patients. Subjects and methods: Between June and July 2020, 95 inpatients with a positive COVID-19 test result after polymerase-chain-reaction (PCR) and who met the inclusion criteria were enrolled in our study. Laboratory parameters that belong to glucose metabolism and β-cell autoantibodies, including anti-islet, anti-glutamic acid decarboxylase, and anti-insulin autoantibodies, were measured. β-cell autoantibodies levels of the patients were measured during COVID-19 diagnosis. Positive results were reevaluated in the 3rd month of control. Results: In the initial evaluation, 4 (4.2%) patients were positive for anti-islet autoantibody. Only one (1.1%) patient was positive for anti-glutamic acid decarboxylase autoantibody. No patient had positive results for anti-insulin autoantibody. FPG, HbA1c, and C-peptide levels were similar in patients who were split into groups regarding the initial positive or negative status of anti-islet and anti-GAD autoantibodies (p>0.05). In the 3rd month after the initial measurements, anti-islet autoantibody positivity of 2 (50%) of 4 patients and anti-glutamic acid decarboxylase positivity of 1 (100%) patient were persistent. Finally, 3 (3.1%) patients in the whole group were positive for anti-islet autoantibody in the 3rd month of control. No difference was determined between the initial and the 3rd month of parameters of glucose metabolism. Conclusion: Following an ongoing autoantibody positivity in the present study brings the mind that SARS-CoV-2 may be responsible for the diabetogenic effect. Clinicians should be aware of autoantibody-positive DM as a potential autoimmune complication in patients with SARS-CoV-2.

Diabetes-Associated Autoantibodies Among Young Diabetes Mellitus Patients in Malaysia

@#Introduction: Diabetes-associated autoantibodies (DAA) is the hallmark of T1DM and LADA which are frequently tested in young diabetes patients. It was noted that up to 10-15% of patients with initial diagnosis of T2DM also exhibit DAA. Regardless of the classification, the presence of DAA suggests an underlying islet autoimmunity which lead to progressive pancreatic β-cell failure. There is limited data reported on DAA in young diabetes patients in Malaysia. This study aims to determine the frequency of DAA positivity and its association with demographic and clinical characteristics among this cohort. Methods: A retrospective study using secondary data obtained from Allergy and Immunology Research Centre, Institute for Medical Research, Malaysia. This study included 194 diabetes patients who were diagnosed before the age of 40 years old and tested for GADA, ICA, IA2A and IAA. Results: From 194 patients, 91 (46.9%) were positive for least one of the following DAA: ICA (79, 40.7%), GADA (61, 31.4%), IA2A (37, 19.1%) and IAA (9, 4.6%). Multiple positivity was higher (73.6%) compared to single positivity. Highest combination of double positivity was ICA+GADA (54, 59.3%) and triple positivity was ICA+GADA+IA2A (25, 27.5%). Simultaneous positivity of four autoantibodies was seen in only one (1.1%) patient. ICA, GADA and IA2A were associated with age group and ethnicity (all p < 0.001). Only IA2A was associated with gender (p = 0.012). Conclusions: GADA, ICA ad IA2A are more significant in young Malaysian diabetes patients. IAA has a very low frequency in this studied population.

Stiff person syndrome: An unusual paraneoplastic neurological phenomenon in Carcinoid tumour

@#Stiff person syndrome is a rare neurologic disorder characterised by rigidity of the truncal and proximal limb muscles with intermittent superimposed spasms. It’s unique because it lacks similarity to any other neurologic disorder. Possibly tetanus is the closest related condition with both inhibiting central gamma-aminobutyric (GABA) systems. Stiff person syndrome is extremely rare with less than 20 cases reported from South Asia which has a population of nearly 2 billion. In its classic form, it is associated with the presence of high titres of glutamic acid decarboxylase (GAD) antibodies. Paraneoplastic stiff person syndrome comprising of around 5% of the patients has been reported with malignancies of the breast, colon, lung, thymus and Hodgkin’s lymphoma. Antibodies against amphiphysin and gephyrin are detected in paraneoplastic stiff person syndrome. We report a 58 year old Sri Lankan male with stiff person syndrome with a high GAD antibody titre and classical electromyographic changes, who was found to have an underlying carcinoid tumour. We postulate that stiff person syndrome was a paraneoplastic phenomenon secondary to the carcinoid in this case. Although neurological syndromes such as sensory neuropathy, limbic encephalitis and, myelopathy have been described as paraneoplastic features in carcinoid, we believe this is the first report of stiff person syndrome associated with carcinoid tumour.

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.

Glutamic acid decarboxylase (anti-GAD) & tissue transglutaminase (anti-TTG) antibodies in patients with thyroid autoimmunity.

Background & objectives: Several autoimmune disorders have been reported to be associated with autoimmune thyroiditis and may coexist with other organ-specific autoantibodies. The aim of the present study was to evaluate the presence of tissue transglutaminase (anti-TTG) and glutamic acid decarboxylase (anti-GAD) antibodies in patients suffering from autoimmune thyroiditis as diagnosed by anti-thyroid peroxidase (anti-TPO) antibodies, which may indicate high risk for developing celiac disease or type 1 diabetes mellitus. Methods: Five thousand children and 2800 adults were screening as part of a general health examination done on a voluntary basis in four different parts of Delhi. A total of 577 subjects positive for anti-TPO antibody constituted the cases. Equal number of age and sex matched anti-TPO antibody negative controls were randomly selected from the same cohort to form paired case control study. The cases and controls were further divided into two groups as follows: group-1 (children and adolescent <18 yr), group-2 (adults >18 yr). Serum samples of cases and controls were analysed for thyroid function test (FT3, FT4, and TSH), anti-TTG and anti-GAD antibodies. Results: A total of 1154 subjects (577 cases and 577 controls) were included in this study. Hypothyroidism was present in 40.2 per cent (232) cases compared to only 4.7 per cent (27) in controls (P<0.001). Anti-TTG and anti-GAD antibodies were present in 6.9 and 12.5 per cent subjects among cases compared to 3.5 per cent (P=0.015) and 4.3 per cent (P=0.001) in controls, respectively. Only anti-GAD antibody were significantly positive in cases among children and adolescents (P =0.0044) and adult (P=0.001) compared to controls. Levels of anti-TTG and anti-GAD antibodies increased with increasing titre of anti-TPO antibody. Interpretation & conclusions: Our findings showed high positivity of anti-GAD and anti-TTG antibodies among subjects with thyroid autoimmunity. It is, therefore, important to have high clinical index of suspicion for celiac disease or type 1 diabetes mellitus in patients with autoimmune thyroiditis.

Neurological disorders associated with glutamic acid decarboxylase antibodies: a Brazilian series / Distúrbios neurológicos associadas a anticorpos anti-GAD (descarboxilase do ácido glutâmico): uma série de casos brasileira

Neurological disorders associated with glutamic acid decarboxylase (GAD) antibodies are rare pleomorphic diseases of uncertain cause, of which stiff-person syndrome (SPS) is the best-known. Here, we described nine consecutive cases of neurological disorders associated with anti-GAD, including nine patients with SPS and three cases with cerebellar ataxia. Additionally, four had hypothyroidism, three epilepsy, two diabetes mellitus and two axial myoclonus.

Distúrbios neurológicos associados com anticorpos anti-GAD são doenças pleomórficas, raras, de causa incerta, das quais a rigidez muscular espasmódica (SPR) é a mais conhecida. Neste estudo, descrevemos nove casos consecutivos de distúrbios neurológicos associados com a presença de anticorpos anti-GAD, incluindo nove pacientes com SPR e três casos com ataxia cerebelar. Adicionalmente, foram encontrados quatro casos com hipotireoidismo, três com epilepsia, dois com diabetes mellitus e dois casos com mioclonia axial.

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.

Measurement of Anti-GAD65 Autoantibodies in Patients with Type 1 Diabetes Mellitus with / without Autoimmune Thyroid Diseases (Immunoblotting followed by Immunoprecipitation) / 대한내분비학회지

BACKGROUND: Type 1 diabetes mellitus is frequently associated with other autoimmune diseases. The broad concept of polyendocrinopathies takes into consideration that patients affected by at least one endocrine disease may have another autoimmune disorder or express specific autoantibodies. Anti-glutamic acid decarboxylase autoantibodies, now recognized as one of the major serological markers for type 1 diabetes has been reported to be higher in type 1 diabetes patients with autoimmune thyroid diseases (ATD) than in those without ATD. The objective of the present study was to evaluate the prevalences of GAD65 antibodies applying a newly developed assay(anti-GAD65) in type 1 diabetes patients with and without ATD. METHODS: We developed a new anti-GAD65 assay after mammalian expression of a recombinant GAD65 antigen. Since the detection of anti-GAD65 is rather complicated and insensitive due to inherent antigenic difference of antibody recognition in conventional assays, we applied this new approach in measuring anti-GAD autoantibodies and compared the result with ICA and anti-GAD measurement using the purified porcine GAD (anti-GAD) in 109 cases of type 1 diabetes, 29 of whom had concomitant ATD (mean age at diagnosis: 7.9 yr, mean duration of type 1 diabetes: 4.5 yrs). RESULTS: The overall prevalence of anti-GAD65 antibodies was 65% (71 of 109) in patients with Korean type 1 diabetes. Prevalences and titers of anti-GAD65 had not changed much after controlling for the duration and the status of concomitant ATD. In contrast, the prevalence of anti-GAD was 56%(61 of 109), while that of ICA(+) WAS 36% in type 1 diabetes patients. We found significant, but not strong association of anti-GAD65 either with anti-GAD(r=0.4, p<0.01) or with ICA(r=0.6, p< 0.001). CONCLUSION: From this, we could assess that autoantibodies are present at comparable sensitivity and specificity in Korean type 1 diabetes patients. This anti-GAD65 assay, another immunologic marker for type 1 diabetes might also confer disease susceptibility among Koreans, but no increase in the prevalence or in the titer in patients with ATD may suggest that this marker is unlikely to give much benefit, for the detection of the overlapping disease of type 1 diabetes and ATD.

Prevalence of Autoimmune Antibodies in Type I Diabetic Children and Their Siblings / 대한소아내분비학회지

Background:Insulin dependent diabetes mellitus(IDDM) is known to be a disease characterized by a deficiency of insulin caused by destruction of the pancreatic beta-cells. It has been suggested that the clinical and immunological characteristics of IDDM in Korean are different from those of Caucasian. This study was undertaken to investigate the clinical characteristics and the prevalence of autoimmune markers in type I diabetic children and their prediabetic siblings in Korea. METHODS:Insulin autoantibody(IAA), antiglutamic acid decarboxylase(Anti-GAD) antibody, thyroid autoantibodies such as antithyroid antibody(ATA) and antimicrosomal antibody(AMA), and rheumatoid facter(RF) in 54 type I diabetic children have been measured. Diabetic autoimmune antibodies were also measured in 48 siblings. RESULTS: 1)Clinical characteristics of type I diabetic children were that age of onset was 8.6+/-4.4 years, duration of diabetes was 4.1+/-3.3 years. C-peptide at onset of diabetes was fasting 0.7+/-0.5ng/ml, and postprandial 1.2+/-0.5ng/ml, and HbA1c was 12.5+/-4.3%. 2)The positivity of IAA and anti-GAD antibody of type I diabetic children was 74% and 50% respectively. ATA and AMA positivity of type I diabetic children was 3.7% and 5.6%. however RF was not detected at all. Among the diabetic siblings, 48 persons for anti-GAD antibody, 21 for IAA, 27 for ICA were measured but 1 case was positive for IAA. 3)Clinical characteristics of type I diabetic children were not specific different between IAA and anti-GAD antibody positivity. But the mean age of onset of type I diabetic children was younger in case of both positivity of IAA and anti-GAD antibody than both negativity(7.8 vs 11.4 years old, P<0.05). 4)A case in whose brothers are diagnosed as IDDM has shown that autoantibody of elder brother was positive in both IAA and anti-GAD antibody, and younger brother was also strongly positive in IAA. Another case in whose sisters were IDDM, has shown that, while elder sister was positive in IAA, younger sister strongly positive in both IAA and anti-GAD antibody. 5)In a case of identical twin brother, the elder is type I diabetic child and the younger is normal, elder brother's onset of age was 6 years and 8 months old, and titer of anti-GAD antibody was measured as strong positive. Both ICA and anti- GAD antibody were negative in normal younger brother. First phase insulin release in IV GTT and the insulin levels in oral GTT showed reduction from the normal level in normal brother, and repeat check up showed normal ranges but on-going study is needed under observation. CONCLUSION: The prevalence of autoantibody positivity of type I diabetic children of Korea in this study were IAA 74%, and anti-GAD antibody 50%. Cases with both IAA and anti-GAD antibody positive were shown to be earlier onset. Though titers of auto-antibody in IDDM twins, brothers and sisters were strongly positive, auto-antibodies in siblings of IDDM patients were detected only one case with IAA positive(0.47%). We suggest that the pathogenesis of IDDM in Korean is different from foreign countries in terms of prevalence of autoimmune antibodies and more numbers of diabetic siblings should be tested for further study.