anti-GAD Ab Research Articles

Successfully treated anti-GAD limbic encephalitis in a 15-year-old diabetic boy with intravenous immunoglobulin: case report

Introduction and importance: Limbic encephalitides (LE) have symptoms and signs of new-onset seizures accompanied by cognitive impairment and signal changes in the MRI of the limbic system in the brain. Numerous antibodies against the neurons and synapses have been detected so far. Of those, antiglutamic acid decarboxylase antibody (Anti-GAD Ab) impairs the gamma amino butyric acid, one of the primary mediators that naturally prevents abnormal neuronal activity causing seizure. Case presentation: The authors have reported a case of anti-GAD Ab LE in a diabetic male adolescent who responded dramatically to intravenous immunoglobulin and reviewed all similar pediatric cases for 15 years now. Clinical discussion: The symptoms in children suffering from anti-GAD LE in three categories, systemic, psychiatric, and neurological, are heterogeneous. The most common manifestations were seizures followed by altered mental status and behavioral changes, respectively. The two main clinical scenarios described in GAD65-mediated autoimmune epilepsy are (1) an acute/subacute onset of seizures alone or seizures (including new-onset refractory status epilepticus, NORSE) accompanied by some degrees of cognitive and psychiatric manifestations, including amnesia and mesiotemporal inflammatory involvement consistent with LE and (2) epilepsy without clinical or MRI evidence of active central nervous system inflammation. Conclusion: Although rare, the neurologist should consider the potential role of anti-GAD ab-associated encephalitis in the presence of diabetes mellitus.

THU291 Successful Reversal Of Glucose Toxicity After DKA Precipitated By SGLT2 Inhibitor

Abstract Disclosure: H. Abdelrahman: None. B. DeMoranville: None. Case: A 40 year old man with history of NAFLD and type 2 diabetes mellitus with HbA1c 12.2% on metformin 750 mg daily, presented with diabetic ketoacidosis (DKA) with blood glucose 275 mg/dL and anion gap 24 (AG 10-12). He had been started on empagliflozin 25 mg daily four days prior as outpatient. He was treated with IV insulin and hydration per DKA protocol. Labs showed C-peptide 3.0 ng/mL (1.1-4.4 ng/mL), Anti-GAD Ab 0.01 nmol/L (<0.02 mol/L), negative anti-insulin cell Ab. He was discharged on glargine 10u qHS, lispro 2u AC plus corrective scale, and metformin 750 mg BID. On outpatient follow-up, pre-meal glucose remained under 130 mg/dL, not requiring corrective insulin. He was started on semaglutide 0.5mg weekly and insulin was discontinued. At 3 months, his HbA1c improved to 5.8%. Self-monitoring glucose levels were at goal. Discussion: This case illustrates glucotoxicity due to significant hyperglycemia causing beta-cell apoptosis and resulting in insulin deficiency. The initiation of SGLT2 inhibitors (SGLT2i) when insulin deficiency and peripheral resistance are at their peak increases risk of DKA. This patient with type 2 diabetes presented with blood glucose 275 mg/dL in DKA four days after starting empagliflozin, a SGLT2i. SGLT2i increase risk of DKA due to dehydration from glucosuria, inhibiting ketone body excretion by the kidneys, causing a state of carbohydrate deficit and hypovolemia that promotes glucagon release from alpha-cells, an increased glucagon-to-insulin ratio, and thus triggers ketogenesis.1 In glucose toxicity, intra-cellular hyperglycemia-induced molecular dysfunction results in beta-cell apoptosis. Islet cells cultured in a glucotoxic environment (20 mmol/l) had suppressed insulin content, but fully reversed the intra-cellular calcium response after one week of culturing in a euglycemic environment, demonstrating recovery of the molecular steps promoting insulin release. 2 Treatment with insulin close to euglycemic goals promotes the reversal of glucose toxicity. Our patient recovered beta-cell function several weeks after the glucotoxic episode and was able to discontinue insulin therapy. With the addition of semaglutide, a GLP-1 receptor agonist, which potentiates glucose-dependent insulin release to control post-prandial hyperglycemia, he was able to maintain euglycemia and an HbA1c 5.8%. Conclusion Patients with type 2 diabetes mellitus may present in diabetic ketoacidosis due to glucose toxicity which can be reversed with short-term insulin therapy. References 1) Nasa P, et al. Euglycemic diabetic ketoacidosis: A missed diagnosis. World J Diabetes. 2021 May 15;12(5):514-523. 2) Tariq M, et al. Prolonged culture of human pancreatic islets under glucotoxic conditions changes their acute beta cell calcium and insulin secretion glucose response curves from sigmoid to bell-shaped. Diabetologia. 2022 Dec 2. Epub ahead of print. PMID: 36459178. Presentation: Thursday, June 15, 2023

PSUN236 Previously Undiagnosed Hereditary Pancreatitis Presenting as New Onset Type 3c Diabetes Mellitus

Abstract Background Type 3c Diabetes Mellitus (DM3c) or Pancreatogenic Diabetes is defined as diabetes secondary to pancreatic disease. The most common cause of Type 3c Diabetes is chronic pancreatitis, accounting for 80% of cases.1 Hereditary pancreatitis, with mutations such as SPINK1, CFTR, CTRC, is an underdiagnosed cause of chronic pancreatitis leading to Type 3c Diabetes Mellitus.1 The typical disease course for hereditary pancreatitis is recurrent episodes of acute pancreatitis that leads to chronic pancreatitis.1 The average time between hereditary pancreatitis diagnosis and development of DM3c has been shown to be 80 +/- 24 months.1 We present a case of previously undiagnosed hereditary pancreatitis presenting as new onset Type 3c Diabetes Mellitus. Clinical Case A 33-year-old male presents with a two month history of diarrhea, epigastric pain, and weight loss. Vital signs on presentation were blood pressure 105/74, heart rate 59, BMI 13. Physical exam revealed a cachectic appearing male with epigastric tenderness. Lab-work showed blood glucose 819 mg/dL, SOsm 313 mOsm/kg, lipase 21 U/L, bicarbonate 33 mmol/L. A computed tomography (CT) of the abdomen revealed punctate pancreatic parenchymal calcifications, suggestive of chronic pancreatitis. He was admitted to general medicine for management of HHS, where he was treated with IV hydration and insulin therapy. Workup for new onset diabetes revealed a negative anti-GAD Ab <5.0 U/mL, and C peptide level 0.5 ng/mL which suggested β cell dysfunction and decreased endogenous insulin secretion. With these lab values, along with radiographic findings consistent with chronic pancreatitis, the likely driving factor for his diabetes was pancreatic disease and he was diagnosed with DM3c. Severe pancreatic disease was further shown by a reduced fecal elastase level of <50, suggesting exocrine pancreatic insufficiency. Investigating the etiology of his chronic pancreatitis, history revealed no prior episodes of acute pancreatitis or abdominal pain, and no family history of pancreatitis. Workup for common causes of pancreatitis, including alcohol use, hypertriglyceridemia, and gallstones was negative, and genetic workup was pursued. The patient was found to be heterozygous for a SPINK1 mutation, which is a known mutation in hereditary pancreatitis.1 Therefore, hereditary pancreatitis was determined to be the likely cause of his chronic pancreatitis which led to Type 3c Diabetes Mellitus. He was started on daily insulin therapy and pancreatic enzymes for his endocrine and exocrine pancreatic dysfunction respectively, with improvement in symptoms. Conclusion This is a unique case of hereditary pancreatitis presenting as new onset Type 3c Diabetes Mellitus with no prior episodes of acute pancreatitis or established diagnosis of chronic pancreatitis. References Ramalho, G. X., & Dytz, M. G. (2020). Diabetes of the exocrine pancreas related to hereditary pancreatitis, an update. Current Diabetes Reports, 20(6). Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Role of C-Peptide in Relation to Levels of Anti-GAD and Islet Cell Antibodies in Characterizing Types of Diabetes in the Young, in Eastern India

Background: Measuring fasting C-peptide (FCP) and antibodies against Glutamic acid decarboxylase (GADA) and Islet cell antibodies (ICA) are not so commonly explored in children and young adults. Objectives: To assess the levels of FCP, GADA and ICA in subjects below the age of 25 years with DM and compare their levels to differentiate between Autoimmune and Non-Autoimmune Type 1 DM. Methodology: Blood samples of 93 subjects diagnosed with DM, reporting to the tertiary care hospital, were analysed for ICA, GADA and FCP. Receiver operating characteristics (ROC) curves were analysed to check the ability of autoimmune markers, BMI and C-peptide to differentiate between Autoimmune (Ai) and Non-Autoimmune (NonAi) diabetes. Results: 30/93 (32.2%) were positive for anti-GAD ab and/or ICA and categorised as Autoimmune (Ai), the most common antibody being, anti-GAD ab (80%) in them. The level of FCP among Ai compared to NonAi, was significantly low (p 20.75 nmol/l) as a very dependable test for diagnosing Ai, Type 1 DM, in children and young adults. Its sensitivity and specificity are in the range of 86.2% and 96.8% respectively. Low level of C-peptide (<0.36 nmol/l) is a fair indicator for diagnosing Ai diabetes in the same population unlike BMI. Conclusion: This study revealed predominant positivity for anti-GAD ab (80%) among Ai+ patients. ROC analysis shows GADA above 20.75 nmol/l and Fasting C-peptide < 0.36 nmol/l as a good indicator for diagnosing Ai in children and young adults.

Placenta derived Mesenchymal Stem Cells transplantation in Type 1 diabetes: preliminary report of phase 1 clinical trial.

Type 1 Diabetes Mellitus (T1DM) is an auto immune reaction against insulin secreting beta cells. Exogenous insulin administration is the only standard treatment for T1DM. However, despite tight glycemic control many patients will develop chronic life-threatening complications. Recently, stem cell transplantation has been suggested as a novel treatment for eliminating the beta cell damage and promoting their regeneration by modulating auto-immunity. To our knowledge; this is the first preliminary report of placenta derived MSCs (PLMSCs) transplantation in juvenile T1DM. An Open label non-randomized phase 1 clinical trial was designed to evaluate the safety of PLMSCs transplantation in new onset juvenile T1DM (IRCT20171021036903N2). PLMSCs were manufactured in our clean room facility using a Xeno-free/GMP compliant protocol. The first series of patients (n = 4) received one dose of1 × 106 PLMSCs/kg intravenously. Diabetic clinical and laboratory parameters and side effects were evaluated weekly for the first month, monthly for 6 months, and then every 3 month till 1 year. Serious adverse events were not seen during 1 year follow-up. Partial remission and hypoglycemic attacks were happened one month after transplantation in two patients. ZnT8-Ab decreased till month 3 and then increased again in all patients. Anti Gad-Ab decreased till month 3 of follow up then increased. This preliminary report of our phase I clinical trial demonstrated the short term safety of PLMSCs transplantation in juvenile T1DM. To prove the long term safety and probable efficacy of this treatment more investigations are needed. Iranian Registry of Clinical Trials: IRCT20171021036903N2.

Association of stiff-person syndrome with autoimmune endocrine diseases.

BACKGROUNDStiff-person syndrome (SPS) and its subtype, stiff limb syndrome (SLS), are rare neurological disorders characterized by progressive muscular rigidity and spasms. Glutamic acid decarboxylase (GAD) is the enzyme that catalyzes the production of γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter of the central nervous system. SPS is an autoimmune disease triggered by anti-glutamic acid decarboxylase antibody (anti-GAD Ab). Clinically, anti-GAD Ab is associated with SPS, type 1 diabetes mellitus (T1DM), and other autoimmune diseases.AIMTo investigate the link of autoimmune endocrine disorders with anti-GAD Ab in SPS subjects.METHODSThis retrospective study was approved by the Institutional Review Board of Chang Gung Memorial Hospital, Taiwan. We collected the patients with SPS from January 2001 to June 2018. By reviewing 14 patients from medical records, we analyzed the clinical findings with coexisting autoimmune diseases, particularly diabetes mellitus and thyroid disease, which are associated with anti-GAD antibody titers or other immunological test results (anti-thyroid peroxidase and anti-nuclear antibodies). We also evaluated malignancies, major complications, and reported treatment to improve symptoms. Anti-GAD antibodies were measured using radioimmunoassay and enzyme-linked immunosorbent assay (ELISA). The cut-off values of these tests are < 1 U/mL and < 5 U/mL, respectively.RESULTSThe median age of all patients was 39.3 (range, 28.0-54.0) years with a median follow-up period of 6.0 (2.7-13.3) years. Five (35.7%) patients were female; twelve (85.7%) were diagnosed with classic SPS and two (14.3%) with SLS. The median age of onset of symptoms was 35.0 (26.0-56.0) years with a median follow-up duration of 9.0 (2.1-14.9) years in the classic SPS group; the SLS group had a median age of onset of 46.7 years and a shorter follow-up duration of 4.3 years. Among nine classic SPS patients who underwent the anti-GAD Ab test, three were anti-GAD Ab seropositive and each of these three patients also had T1DM, latent autoimmune diabetes in adults, and autoimmune thyroid disease, respectively. In contrast, other rare autoimmune diseases co-existed in six anti-GAD Ab seronegative SPS patients. None of the SLS patients had additional autoimmune diseases.CONCLUSIONWhile typical clinical symptoms are crucial for the diagnosis of SPS, the presence of anti-GAD autoantibody may consolidate the diagnosis and predict the association with other autoimmune diseases.

Anti-glutamate Dehydrogenase Antibody Positive Cerebellar Ataxia and Stiff Person Syndrome Responding to Dual Treatment with Steroids and Intravenous Immunoglobulin: A Case Presentation and Literature Review

Anti-glutamic acid decarboxylase (anti-GAD) antibody syndrome (aGAS) has various presentations including cerebellar ataxia (CA) and stiff person syndrome (SPS). This is a treatable cause of CA and SPS. We present a case of a 49-year-old man who developed blurred vision, slurred speech, difficulty walking, unsteady gait, and clumsiness which had progressed over four months. The patient was found to have anti-GAD ab (+) CA and SPS and experienced significant symptomatic improvements after treatment with intravenous (IV) steroids followed by intravenous immunoglobulin (IVIG). The patient’s improvement persisted when he was reevaluated at follow up one month later. Since anti-GAD ab related diseases, including anti-GAD CA and SPS, are rarely diagnosed, there is limited data regarding the treatment of this condition. As there are only a few cases in the literature similar to this one, highlighting the successful treatment of anti-GAD ab cerebellar ataxia and SPS with dual therapy (steroids followed by IVIG) is important.

A Cut-Off Value for Anti-GAD Ab ELISA Test for Predicting Future Insulin Dependency in SPIDDM May Not Exist

We previously demonstrated that patients initially diagnosed with slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) using a radioimmunoassay (RIA) test for anti-glutamic acid decarboxylase antibody (GADA) (GADA-RIA), who were also positive on a GADA enzyme-linked immunosorbent assay (ELISA) test (GADA-ELISA), showed a reduced insulin secretory capacity early in the SPIDDM disease process [Endocr J. 2017;64:163]. When we used GADA-RIA test, in SPIDDM with non-insulin dependent state, a GADA-RIA value ≥10 U/mL(GADA-RIA-High) was believed to indicate a higher risk for future insulin dependency than a value &amp;lt;10 U/mL(GADA-RIA-Low). In our previous study also, the insulin secretory capacity may be lower in “GADA-RIA-High and GADA-ELISA-positive SPIDDM patients” (A group) than those with “GADA-RIA-Low and GADA-ELISA-positive SPIDDM patients” (B group) early in the disease process, but this point was not yet confirmed. Therefore, we have now performed additional analysis to compare serum C-peptide levels in these two patient groups (group A vs. B). When restricted to a shorter disease duration, &amp;lt;11 years based on our previous study, serum C-peptide levels were 0.73 ± 0.61 ng/mL in group B (n = 9) and 0.68 ± 0.65 ng/mL in group A(n = 15). There was no significant difference between the two measures, but each of these two measurements was significantly lower than those for patients with type 2 diabetes (2.20 ± 0.85 ng/mL; n = 15) and those for “GADA-RIA-Low and GADA-ELISA-NEGATIVE SPIDDM patients” (2.60 ± 1.66 ng/mL; n = 6). These findings suggest that, regardless of their GADA-RIA titer, GADA-ELISA-positive patients with SPIDDM may show a reduced insulin secretory capacity early in the disease process. In conclusion, unlike GADA-RIA test, a cut-off value for GADA-ELISA test for predicting future insulin dependency in SPIDDM may not exist. Disclosure Y. Oikawa: None. T. Katsuki: None. T. Kawai: None. A. Shimada: Speaker's Bureau; Self; Eli Lilly and Company, Sanofi-Aventis, Novo Nordisk A/S.

Subtyping of Type 1 Diabetes as Classified by Anti-GAD Antibody, IgE Levels, and Tyrosine kinase 2 (TYK2) Promoter Variant in the Japanese

ObjectiveType 1 diabetes (T1D) is known to be caused by Th1 cell-dependent autoimmunity. Recently, we reported that TYK2 promoter variant serves as a putative virus-induced diabetes susceptibility gene associated with deteriorated interferon-dependent antiviral response. TYK2 is also related to HIES, that is, Th2 cell-dependent. Therefore, TYK2 promoter variant may be also associated with the pathogenesis of T1D, modulating Th1/Th2 balance. Research Design and MethodsWe assessed the association between anti- GAD Ab, IgE levels, and TYK2 promoter variant among 313 T1D patients, 184 T2D patients, and 264 YH controls in the Japanese. ResultsT1D patients had elevated IgE (median, 56.7U/ml; p<0.0001) compared with T2D patients (22.5U/ml) and controls (43.3U/ml). Contrary to our expectations, there was no correlation between TYK2 promoter variant and IgE levels. We found that T1D could be subtyped as four groups based on anti-GAD Ab and IgE profile: Subtype 1, anti-GAD Ab positive and non-elevated IgE (47.0%); Subtype 2, anti-GAD Ab negative and non-elevated IgE (35.1%); Subtype 3, anti-GAD Ab positive and elevated IgE (10.9%); and Subtype 4, anti-GAD Ab negative and elevated IgE (7.0%). In Subtype 2, a significantly higher incidence was observed in T1D cases carrying the TYK2 promoter variant (OR, 2.60; 95%CI, 1.03–6.97; p=0.032), and also showing a flu-like syndrome at diabetes onset (OR, 2.34; 95%CI, 1.27–4.35; p=0.003). InterpretationAnti-GAD Ab and IgE profiling helps classifying T1D into four groups that recognize variable pathogenic bases of T1D.

Clinical, Endocrinological and Immunological Characteristics of Japanese Patients With Autoimmune Polyglandular Syndrome Type 3a

Background: Autoimmune polyglandular syndrome (APS) is an autoimmune disease that involves multiple organ failure. In APS3, autoimmune thyroid disease occurs with other autoimmune diseases, but not with Addison disease. APS3a is defined as APS3 including autoimmune diabetes. The information about clinical backgrounds of APS3a is very limited. We studied to understand clinical, endocrinological and immunological characteristics of Japanese patients with APS3a. Methods: We reviewed our previously published case reports about APS3a, and picked up patients with type 1 diabetes and autoimmune diabetes, who showed the positivity for anti-glutamic acid decarboxylase antibody (anti-GAD ab) or anti-islet antigen 2 antibody (anti-IA2 ab) or anti-thyroglobulin antibody (anti-TG ab) or anti-thyroid peroxidase antibody (anti-TPO ab) or anti-thyroid stimulating hormone receptor antibody (anti-TR ab) between January 2010 and January 2016. We collected data including age, sex, anti-GAD ab, anti-IA2 ab, HbA1c, serum fasting C-peptide immunoreactivity (CPR), urinary CPR, treatment for diabetes, anti-TPO ab, anti-TG ab, anti-TR ab, thyroid stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), findings of thyroid ultrasonography and treatment for thyroid diseases. Results: Present study revealed a remarkable female predominance in APS3a. Among patients with autoimmune diabetes, slowly progressive insulin-dependent diabetes mellitus (SPIDDM) was the most common type of diabetes, and almost 80% of patients with APS3a showed the positivity for anti-GAD ab. Among patients with autoimmune thyroid diseases, almost 80% of patients had possible Hashimoto thyroiditis. Almost 70% of patients with APS3a showed the positivity for anti-TPO ab. Almost 20% of APS3a patients had possible Grave’s disease, and 83% of patients with possible Grave’s disease showed overt Grave’s disease. In patients with possible Grave’s disease, the positive rate of anti-TR ab was 100%. Conclusion: We revealed clinical, endocrinological and immunological characteristics of patients with APS3a in Japan. J Endocrinol Metab. 2016;6(2):46-51 doi: http://dx.doi.org/10.14740/jem348e

Epilepsy and autoimmunity in pediatric patients.

Our aim was to determine the presence and possible role of autoantibodies in epileptic patients with an undetermined etiology. Eighty epilepsy patients, who were referred to the Pediatric Neurology Department at Ankara University between November 2011 and April 2012, were enrolled in the study. Antinuclear antibodies (ANA), anticardiolipin IgG, antiphospholipid, antithyroid peroxidase, paraneoplastic, glutamic acid decarboxylase (GAD), and N-methyl-d-aspartate (NMDA) receptor antibodies were studied in our university laboratory. In addition, NMDA receptor (NMDAR), voltage-gated potassium channel (VGKC)-complex, leucine-rich, glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2) antibodies were studied at the Oxford University Immunology Laboratory. The study included 35 girls (44%) and 45 boys (56%) with a mean symptom age of 8.6 ± 4.53 years. ANA was detected in 15 (18.8%), antiphospholipid Ab in 3 (3.75%), anticardiolipin Ab in 1 (1.25%), and antithyroid peroxidase in 3 (3.75%) epileptic patients. In addition, anti-GAD Ab was detected in 7 (8.75%), anti-Yo Ab in 3 (3.75%), and anti-Ma2 in 3 (3.75%) epileptic patients. Anti-VGKC was positive in 13 (16.25%) epileptic patients. We performed a pioneer study to investigate the association between autoimmunity and pediatric epilepsy and we conclude that autoimmunity should be considered in epileptic patients with an undetermined etiology.

Viruses Induce Type 1 Diabetes Mellitus in the Presence of HLA-DR3, DR4 Genes

Recently, the increasing of type 1 diabetes (T1DM) was revealed among children in Kurdistan - Iraq that passed through several wars and economic sanctions. It has been demonstrated that virus infection induced T1DM by destruction of beta cells through direct invasion or autoimmune reactions. Genetic factors also lead to immune disorders which induce T1DM. Despite the reports on effects of viral infection and autoimmune disturbance in the presence of HLA genes, there are no enough studies to show the relationship between them in Kurdish race. Therefore, Serum glucose, three viral (CMV, Rubella and Coxsackie virus), two genes (HLA DR3 and HLA DR4) and anti- glutamic acid decarboxylase (GAD) Ab. were studied to evaluate their relationship with T1DM. Study was performed by interviewing 230 samples (122 females and 108 males) of T1DM patients and another 130 non-diabetic individuals as a control group for collecting blood samples and personal and family information related to this study. Indirect Enzyme-Linked Immuno Sorbent Assay (ELISA) used for detection of anti-viruses antibodies and anti-GAD antibody. While, Polymerase Chain Reaction (PCR) - SSP technique were used for detection of HLA-DR3 and DR4. The statistical results revealed that the mean±SD concentration of anti-CMV IgG, rubella, CSV-B antibodies in the sera of patients was (1.22±0.36 IU/ml), (0.80±0.08 IU/ml), (0.81±0.14 IU/ml) respectively when compared with (0.79±0.32 IU/ml), (0.38±0.17 IU/ml), (0.26±0.21 IU/ml) respectively in sera of control group (P-value < 0.05). This means that there is a significant increase in mean concentration of anti-CMV, rubella, CSV-B antibodies in the sera of patients in comparison with control group. The mean of anti-GAD antibody was (89.54±0.43 IU/ml) when compared with (9.73±38 IU/ml) with control group (P-value < 0.05). While, results of the HLA-DR3 and DR4 genes revealed that there are a relationship between these genes and viral infections that induce T1DM and these genes also related with the elevation of anti-GAD Ab in the blood circulation of T1DM patients. This study supports the claims that viruses are responsible for T1DM especially in the presence of HLA-DR3 or/and DR4.

Detection of Type 2 Diabetes Mellitus in Serum from Women with Polycystic Ovarian Syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorder. To determine the metabolic disorders in women with PCOS, (25) women with PCOS ages (15 - 47) years have been investigated and compared with (20) healthy individuals. All the studied groups were carried out to measure fasting blood sugar, (anti-GAD Ab, anti ?-islet cell Ab by IFAT) and measured insulin level by ELISA. There was significant elevation in the concentration of fasting blood sugar than in control groups (p ? 0.05) and there was negative results for anti-GAD Ab and anti ?-islet cell Ab by IFAT test for serum of women with PCOS, while there was significant differences in the insulin level for women with PCOS compared with control groups (p ? 0.05), these indicated that women with PCOS are at high risk for type -2 Diabetes mellitus and reflecting insulin resistance.

Detection of Type 2 Diabetes Mellitus in Serum from Women with Polycystic Ovarian Syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorder. To determine the metabolic disorders in women with PCOS, (25) women with PCOS ages (15 - 47) years have been investigated and compared with (20) healthy individuals. All the studied groups were carried out to measure fasting blood sugar, (anti-GAD Ab, anti ?-islet cell Ab by IFAT) and measured insulin level by ELISA. There was significant elevation in the concentration of fasting blood sugar than in control groups (p ? 0.05) and there was negative results for anti-GAD Ab and anti ?-islet cell Ab by IFAT test for serum of women with PCOS, while there was significant differences in the insulin level for women with PCOS compared with control groups (p ? 0.05), these indicated that women with PCOS are at high risk for type -2 Diabetes mellitus and reflecting insulin resistance.

Comparison of the prevalence of islet autoantibodies according to age and disease duration in patients with type 1 diabetes mellitus.

PurposeThis study investigated the prevalence of islet autoantibodies in children and adults with T1DM according to their age and the duration of disease.MethodsWe measured the levels of islet autoantibodies, including antiglutamic acid decarboxylase antibody (anti-GAD Ab), and combined these with anthropometric measurements and laboratory tests of 137 patients newly diagnosed with T1DM during the last 20 years. The subjects were subdivided into four groups according to their age at the onset of the disease. We then compared the prevalence of islet autoantibodies in the different age groups with the duration of disease.ResultsAmong the 137 patients, 68.9% tested positive for islet autoantibodies (71.4% within 1 year; 67.7% after 1 year of the disease onset). Within 1 year of the onset of the disease, 66.3% of the patients were positive for the anti-GAD Ab, and 35.6% were positive for IAAs. The prevalence of islet autoantibodies was significantly higher in the prepubertal groups than in the postpubertal groups (80.0% vs. 58.3%). The rate of positive islet autoantibodies changed with the duration of disease, and it differed according to the type of autoantibody and the age of the patient.ConclusionThe rates of positive islet autoantibodies were significantly higher in younger than in older patients at the time of the diagnosis of the disease. The positive rates were significantly changed 1 year after the onset of the disease in the preschool and the children groups. So these findings suggest that we need to diagnose type 1B diabetes distinguished T2DM in aldolescent group, carefully.

Exercise in An Islet-Transplanted Amateur Marathon Runner: Effects on Training, Autoimmunity and Metabolic Profile

Introduction: Type 1 diabetes mellitus (T1DM) is a chronically progressive autoimmune disease in which the adverse immune response is induced and promoted by the interaction of genetic and environmental factors. Recent studies have suggested that physical exercise may interfere with immune system function even at low intensity and duration. Methods: An islet-transplanted T1DM patient (M, 44yrs) has been longitudinally monitored for autoimmunity markers, metabolic profile and physical performance, being himself an amateur marathon runner, over a 7-year period since he received an islet allograft. Given his irregular history of training (because of injuries, medical issues etc), we identified 4 phases throughout this period, lasting 2 years each, alternating between phases of rest and training. Results: An ad hoc regime of training (supervised interval training) resulted in an improvement in HbA1c (-9.2%, p< 0.05), C-reactive protein (-16.6%, p< 0.05) and a decrease of exogenous insulin (from 4-8 to 4-6 U/day) during the 2nd phase compared to the 1st phase of rest (recovery after allograft). In the 3rd phase (post-injury resting), Hb1Ac increased by 13.3% (p< 0.05 vs 2nd phase), as did the insulin dose (6-8 U/day). In the 4th phase, exercise training was accompanied by an amelioration of Hb1Ac of 22% compared to the 3rd phase, and the number of required insulin units diminished dramatically vs the 1st phase (2-3 U twice a week), as did the levels of autoimmunity markers (antiGAD and antiINS ab, from 0.5 to 0.0 and from 6.6 to 1.6 AU, respectively). Race time during competition improved by 10.5% vs the 2nd phase of training (p< 0 .05). Also in the 4th phase, aerobic, anaerobic thresholds and heart rates were significantly higher than in the previous phases (p< 0.05). Conclusions: Altogether, these data suggest an association between the alterations in detrimental metabolic and autoimmunity profiles and the successive training/resting periods, evoking a potential role for exercise in the positive immunomodulation against T1DM progression and inflammation.

PO.01 IDDM associated with cerebellar ataxia; drug resistant complex partial seizures and intrathecal synthesis of anti GAD-Ab

High levels of antibodies to glutamic acid decarboxylase (anti GAD-Ab) are an uncommon association in neurological conditions. We describe a patient who initially presented with cerebellar ataxia. Four years later...

Molecular mechanisms supporting a paracrine role of GABA in rat adrenal medullary cells

GABA is known to produce membrane depolarization and secretion in adrenal medullary (AM) cells in various species. However, whether the GABAergic system is intrinsic or extrinsic or both in the adrenal medulla and the role that GABA plays are controversial. Therefore, these issues were addressed by combining a biochemical and functional analysis. Glutamic acid decarboxylase (GAD), a GABA synthesizing enzyme, and vesicular GABA transporter (VGAT) were expressed in rat AM cells at the mRNA and protein levels, and the adrenal medulla had no nerve fibre-like structures immunoreactive to an anti-GAD Ab. The double staining for VGAT and chromogranin A indicates that GABA was stored in chromaffin granules. The alpha1, alpha3, beta2/3, gamma2 and delta subunits of GABA(A) receptors were identified in AM cells at the mRNA and protein levels. Pharmacological properties of GABA-induced Cl(-) currents, immunoprecipitation experiments and immunocytochemistry indicated the expression of not only gamma2-, but also delta-containing GABA(A) receptors, which have higher affinities for GABA and neurosteroids. Expression of GATs, which are involved in the clearance of GABA at GABAergic synapses, were conspicuously suppressed in the adrenal medulla, compared with expression levels of GABA(A) receptors. Increases in Ca(2+) signal in AM cells evoked trans-synaptically by nerve stimulation were suppressed during the response to GABA, and this suppression was attributed to the shunt effect of the GABA-induced increase in conductance. Overall Ca(2+) responses to electrical stimulation and GABA in AM cells were larger or smaller than those to electrical stimulation alone, depending on the frequency of stimulation. The results indicate that GABA functions as a paracrine in rat AM cells and this function may be supported by the suppression of GAT expression and the expression of not only gamma2-, but also delta-GABA(A) receptors.

Anti-GAD monoclonal antibody delays the onset of diabetes mellitus in NOD mice.

Insulin Dependent Diabetes Mellitus (IDDM type I) is the result of autoimmune destruction of insulin producing pancreatic beta-cells by the cellular immune system, specifically, autoreactive T cells. Disease progression is evident by multiple autoantibodies responding to self-antigens in a cascade mechanism, wherein the first self-antigen induces the activation of the immune system, leading to the destruction of beta-cells and consequently, exposure of other antigens. Glutamic Acid Decarboxylase (GAD) is recognized in the literature as a primary autoantigen involved in the cascade. We questioned the immunological involvement of this autoantigen in the overall progression of the disease, specifically if antigen recognition by the cellular immune system (T cells) is necessary for organ specific autoimmunity and cellular toxicity. We tested this hypothesis by isolating, purifying and injecting monoclonal antibodies against GAD (anti-GAD Ab; 0.1 mg or 0.3 mg) into non-obese diabetic (NOD) mice on a weekly basis. We suggest that the anti-GAD Ab will bind to the GAD antigen, or perhaps bind to the epitope presented in association with APC-MHC and prevent T cell recognition, thereby delaying disease onset. Our results demonstrate a delay in the onset of diabetes and a decrease in the severity of insulitis in our test animals, when compared to controls. The mechanism of action of the anti-GAD Ab may be associated with a passive protection mechanism, as evidenced by the fact that splenocytes transferred from anti-GAD Ab treated mice did not prevent or delay diabetes in syngeneic irradiated NOD mice. The mechanism of diabetes prevention by administration of anti-GAD antibody could be associated with an interference in recognition of GAD by T cells, and continuing research will be perform to investigate this hypothesis.