Glutamic Decarboxylase Antibodies Research Articles

Detection of Glutamate Decarboxylase Antibodies and Simultaneous Multi-Molecular Translocation Exploration by Glass Nanopores.

Glutamic acid decarboxylase antibody (GADAb) has emerged as a significant biomarker for clinical diagnosis and prognosis in type 1 diabetes (T1D). In this study, we investigated the potential utilization of glass capillary solid-state nanopores as a cost-effective and easily preparable platform for the detection of individual antigens, antibodies, and antigen-antibody complexes without necessitating any modifications to the nanopores. Our findings revealed notable characteristic variations in the translocation events of glutamic acid decarboxylase (GAD65) through nanopores under different voltage conditions, discovered that anomalous phenomenon of protein translocation events increasing with voltage may potentially be caused by the crowding of multiple proteins in the nanopores, and demonstrated that there are multiple components in the polyclonal antibodies (GADAb-poly). Furthermore, we achieved successful differentiation between GAD65, GADAb, and GADAb-GAD65 complexes. These results offer promising prospects for the development of a rapid and reliable GADAb detection method, which holds the potential to be applied in patient serum samples, thereby facilitating a label-free, cost-effective, and early diagnosis of type I diabetes.

Data-Driven Patient clusters of Type 2 Diabetes May Help to Identify Patients at Risk and Predict Metabolic Surgery Outcomes on Diabetes Remission and NAFLD Pregression

Abstract Background Precision medicine and customized medicine have gained enormous attention in recent years, especially in the treatment of type 2 diabetes (T2D). Different subgroups of diabetes have been identified by research employing data-driven cluster analysis, each with a unique diabetes progression and complication risk (Ahlqvist et al., Lancet Diabetes Endocrinol. 2018). Aims We aimed to apply the proposed cluster analysis to a patent population post metabolic surgery and investigate the association with T2D remission and presence of NAFLD. Methods We retrospectively linked newly defined clusters to metabolic surgery outcomes in 53 T2D patients. Utilizing k-means and hierarchical clustering, three clusters emerged based on glutamate decarboxylase antibodies, age, BMI, HbA1c, and homoeostatic model assessment estimates of β-cell function (HOMA2-B%) and insulin resistance (HOMA2-IR). Intraoperative liver biopsies assessed nonalcoholic fatty liver disease (NAFLD) presence differentiating between simple steatosis (NAFL) and steatohepatitis (NASH). Clinical and biochemical data were collected over two years, focusing on T2D remission and NAFLD improvement. Results Cluster 1, characterized by the lowest BMI, highest NASH rate, impaired beta-cell function, and increased insulin resistance, displayed a favorable response to surgery, indicating robust regeneration of beta-cells. Despite increased insulin production, T2D remission was surprisingly low at 44.0% after one year, in contrast to 75.00% in Cluster 2 and 100.00% in Cluster 3. Metabolic surgery notably reduced insulin resistance and promoted NASH remission, evidenced by a significant reduction in a non-invasive NASH detection score and liver enzyme levels across all three clusters. Conclusion Our findings suggest that patients in Cluster 1 already show a lack of beta-cell compensation being associated with a higher prevalence of NAFLD and poorer diabetic control and therefore especially might benefit from an earlier intervention. Data-driven classification might help to customize treatment plans and identify patients at higher risk of problems at diagnosis.

Risk predictors of glycaemic control in children and adolescents with type 1 diabetes: A systematic review and meta-analysis.

To conduct systematic evaluation of the risk predictors of glycaemic control in children and adolescents with type 1 diabetes mellitus. Cohort studies on risk predictors of glycaemic control in children and adolescents with type 1 diabetes were retrieved from CNKI, PubMed, Web of Science, Embase databases, etc. from the construction of the repository to 3 February 2023. Literature screening was conducted according to inclusion and exclusion criteria, then data extraction of region, sample size, age, follow-up time, risk predictors, outcome indicators, etc., and quality evaluation of The Newcastle-Ottawa Scale were conducted by two researchers while the third researcher makes decisions if there are disagreements. Finally, Revman5.4 and StataMP17 were used for meta-analysis. A total of 29 studies were included, and the results showed that insulin pump [Weighed mean difference (WMD) = -.48, 95% CI (-.73, -.24), p < .01], high-frequency sensor monitoring, early use of insulin pumps, prospective follow-up male, white race, large body mass index-standardised scoring, conscientiousness, agreeableness of mothers, eicosapentaenoic acid, leucine and protein (p < .05) were beneficial for reducing HbA1c levels in children and adolescents with diabetes. Ketoacidosis [WMD = .39, 95% CI (.28, .50), p < .01], selective admission, higher HbA1c level at one time (p < .01), higher glutamate decarboxylase antibody at 1 month after diagnosis, lower socio-economic status, non-living with biological parents, non-two-parent family, family disorder, family history of diabetes and high carbohydrate intake (p < .05) increased HbA1c levels in children and adolescents with diabetes. For children and adolescents with type 1 diabetes mellitus, the use of insulin pump, high-frequency sensor monitoring, prospective follow-up, good family support and reasonable diet are conducive to blood glucose control, while selective admission and DKA are not. Disease characteristics and demographic characteristics of children are closely related to subsequent blood glucose control, and the relationship between diagnosis age and blood glucose control needs to be further explored.

Study of an Ultrasensitive Label-Free Electrochemiluminescent Immunosensor Fabricated with a Composite Electrode for Detecting the Glutamate Decarboxylase Antibody.

Antibody testing for the glutamic acid decarboxylase 65 antibody (GADA) is widely used as a golden standard for autoimmune diabetes diagnosis, while current methods for antibody testing are not sensitive enough for clinical usage. Here, a label-free electrochemiluminescent (ECL) immunosensor for detecting GADA in autoimmune diabetes is fabricated and investigated. In the designed immunosensor, a composite film including the multiwalled carbon nanotubes (MWCNTs), zinc oxide (ZnO), and Au nanoparticles (AuNPs) was prepared through nanofabrication processes to improve the performance of sensor. The MWCNTs, which can provide a larger specific surface area, ZnO as a good photocatalytic material, and AuNPs that can enhance the ECL signal of luminol and immobilize the GAD65 antigen were applied to prefunctionalize indium tin oxide (ITO) glass based on a nanofabrication process. The GADA concentration was detected using the ECL immunosensor after incubating with GAD65 antigen-coated prefunctionalized ITO glass. After a direct immunoreaction, it is found that the degree of decreased ECL intensity has a good linear regression toward the logarithm of the GADA concentration in the range of 0.01 to 50 ng mL-1 with a detection limit down to 10 pg mL-1. Human serum samples positive or negative for GADA all nicely fell in the expected area. The fabricated immunosensor with excellent sensitivity, specificity, and stability has potential capability for clinical usage in GADA detection.

SERS-based detection of early Type 1 diabetes mellitus biomarkers: Glutamate decarboxylase antibody and insulin autoantibody

Glutamate decarboxylase antibody (GADA) and insulin autoantibody (IAA) are essential biomarkers for type 1 diabetes mellitus (T1DM). These islet autoantibodies are present in the serum of patients and are useful for the early diagnosis of T1DM. In this study, we developed a surface-enhanced Raman scattering (SERS)-based immunoassay for the detection of two T1DM-related autoantibodies, GADA and IAA. GADA and IAA are specifically captured by their antigens immobilized on the mercaptobenzoic acid (MBA)-functionalized silver substrates. They can be quantitatively detected based on the Raman frequency shifts of the cross-linker MBA. Combined with a 96-well plate, the immunoassay enabled a high-throughput analysis of the two biomarkers. The results suggest that the proposed method has significant potential for clinical application in rapid, sensitive, and high-throughput screening of T1DM.

Combined Detection of Islet Autoantibodies for Clinical Diagnosis of Type 1 Diabetes in the Low-Prevalence Population.

Single positive islet autoantibodies (IAbs), sometimes detected in healthy individuals and patients with low-risk of developing type 1 diabetes (T1D), are considered to be irrelevant to the development of diabetes, making it difficult to diagnose and classify adult-onset diabetes. To determine the significance and clinical value of IAbs in T1D diagnosis in the low-prevalence population, and to explore whether an electrochemiluminescence IAb detection assay can improve the clinical utility of IAbs in the immunodiagnosis of T1D in the low-prevalence population. A total of 633 newly diagnosed patients with adult-onset diabetes (≥18 years old) were divided into 2 groups according to their clinical phenotypes: 575 patients with age at diagnosis ≥35 years and body mass index (BMI) ≥ 24 kg/m2 were considered a low-prevalence population (population with a low prevalence of T1D) and the other 58 patients were considered a high-prevalence population. All the samples from 633 participants were tested with IAbs using standard radiobinding assays (RBAs) and electrochemiluminescence (ECL) assays in parallel. Compared with the high-prevalence population, fewer positive IAbs (94/575, 16.3% vs 28/58, 48.3%) were detected in the low-prevalence population, and more of whom (69/94, 73.4% vs 9/28, 32.2%) were positive for a single IAb, with glutamate decarboxylase antibodies being the most prevalent single IAb. Single-IAb detection in the low-prevalence population did not always suggest the T1D phenotype. Combined detection of IAbs by RBA and ECL assay had a significant clinical utility to distinguish autoimmune diabetes in the low-prevalence population with low BMI, poor β-cell function at the diagnosis, and an accelerated decline in β-cell function during the follow-up. Combined autoantibody detection by RBA and ECL assays improved differentiating autoimmune from nonautoimmune diabetes in the low-prevalence population.

Diabetes duration and types of diabetes treatment in data-driven clusters of patients with diabetes

This study aimed to cluster patients with diabetes and explore the association between duration of diabetes and diabetes treatment choices in each cluster. A Two-Step cluster analysis was performed on 1332 Chinese patients with diabetes based on six parameters (glutamate decarboxylase antibodies, age at disease onset, body mass index, glycosylated hemoglobin, homeostatic model assessment 2 to estimate β-cell function and insulin resistance). Associations between the duration of diabetes and diabetes treatment choices in each cluster of patients were analyzed using Kaplan-Meier survival curves and logistic regression models. The following five replicable clusters were identified: severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). There were significant differences in blood pressure, blood lipids, and diabetes-related complications among the clusters (all P < 0.05). Early in the course of disease (≤5 years), compared with the other subgroups, the SIRD, MOD, and MARD populations were more likely to receive non-insulin hypoglycemic agents for glycemic control. Among the non-insulin hypoglycemic drug options, SIRD had higher rates of receiving metformin, alpha-glucosidase inhibitor (AGI), and glucagon-like peptide-1 drug; the MOD and MARD groups both received metformin, AGI and sodium-glucose cotransporter 2 inhibitor (SGLT-2i) drug ratio was higher. While the SAID and SIDD groups were more inclined to receive insulin therapy than the other subgroups, with SAID being more pronounced. With prolonged disease course (>5 years), only the MOD group was able to accept non-insulin hypoglycemic drugs to control the blood sugar levels, and most of them are still treated with metformin, AGI, and SGLT-2i drugs. While the other four groups required insulin therapy, with SIDD being the most pronounced. Clustering of patients with diabetes with a data-driven approach yields consistent results. Each diabetes cluster has significantly different disease characteristics and risk of diabetes complications. With the development of the disease course, each cluster receives different hypoglycemic treatments.

PD-1 inhibitor-associated type 1 diabetes: A case report and systematic review

ObjectiveThis study aimed to summarize the clinical characteristics of programmed death receptor 1 (PD-1) inhibitor-associated type 1 diabetes so as to improve the ability of clinicians to correctly diagnose and treat it.MethodsWe reported a case of a 70-year-old woman with gastric cancer who developed hyperosmolar hyperglycemic coma during camrelizumab (a PD-1 inhibitor) treatment and was diagnosed with PD-1 inhibitor-associated type 1 diabetes. We conducted a systematic review of 74 case reports of type 1 diabetes associated with PD-1 inhibitor therapy published before June 2022.ResultsThe patient developed type 1 diabetes with hyperosmolar hyperglycemic coma after receiving camrelizumab chemotherapy for 6 months (9 cycles). We searched 69 English articles comprising 75 patients, all of whom had been treated with a PD-1 inhibitor (nivolumab or pembrolizumab) and progressed to diabetes after an average of 6.11 (1–28) cycles. Nivolumab combined with ipilimumab (a cytotoxic T lymphocyte-associated protein 4 inhibitor) had the shortest onset (4.47 cycles on average). A total of 76% (57/75) of patients developed diabetic ketoacidosis (DKA) at onset, and 50.67% (38/75) of patients had C-peptide <0.1 ng/mL. Most of the patients were tested for insulin autoantibodies, with a positive rate of 33.33% (23/69); of these, 86.96% (20/23) were tested for glutamate decarboxylase antibody and 46.67% (35/75) were tested for human leukocyte antigen (HLA). HLA-DR4 was the most common type.ConclusionsThe progression of type 1 diabetes induced by PD-1 inhibitors is relatively rapid. Islet failure often occurs when detected, seriously endangering patients' lives. Patients treated with PD-1 inhibitors should closely monitor their plasma glucose level during treatment to detect, diagnose, and treat diabetes on time.

Validation of the classification for type 2 diabetes into five subgroups: a report from the ORIGIN trial.

Data analyses from Swedish individuals with newly diagnosed diabetes have suggested that diabetes could be classified into five subtypes that differ with respect to the progression of dysglycaemia and the incidence of diabetes consequences. We assessed this classification in a multiethnic cohort of participants with established and newly diagnosed diabetes, randomly allocated to insulin glargine vs standard care. In total, 7017 participants from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were assigned to the five predefined diabetes subtypes (namely, severe auto-immune diabetes, severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes, mild age-related diabetes) based on the age at diabetes diagnosis, BMI, HbA1c, fasting C-peptide levels and the presence of glutamate decarboxylase antibodies at baseline. Differences between diabetes subtypes in cardiovascular and renal outcomes were investigated using Cox regression models for a median follow-up of 6.2years. We also compared the effect of glargine vs standard care on hyperglycaemia, defined by having a mean post-randomisation HbA1c ≥6.5%, between subtypes. The five diabetes subtypes were replicated in the ORIGIN trial and exhibited similar baseline characteristics in Europeans and Latin Americans, compared with the initially described clusters in the Swedish cohort. We confirmed differences in renal outcomes, with a higher incidence of events in the severe insulin-resistant diabetes subtype compared with the mild age-related diabetes subtype (i.e., chronic kidney disease stage 3A: HR 1.49 [95% CI 1.31, 1.71]; stage 3B: HR 2.25 [1.82, 2.78]; macroalbuminuria: HR 1.56 [1.22, 1.99]). No differences were observed in the incidence of retinopathy and cardiovascular diseases after adjusting for multiple hypothesis testing. Diabetes subtypes also differed in glycaemic response to glargine, with a particular benefit of receiving glargine (vs standard care) in the severe insulin-deficient diabetes subtype compared with the mild age-related diabetes subtype, with a decreased occurrence of hyperglycaemia by 13% (OR 1.36 [1.30, 1.41] on glargine; OR 1.49 [1.43, 1.57] on standard care; p for interaction subtype × intervention = 0.001). Cluster analysis enabled the characterisation of five subtypes of diabetes in a multiethnic cohort. Both the incidence of renal outcomes and the response to insulin varied between diabetes subtypes. These findings reinforce the clinical utility of applying precision medicine to predict comorbidities and treatment responses in individuals with diabetes. ORIGIN trial, ClinicalTrials.gov NCT00069784.

Black oesophagus in an adolescent with type 2 diabetes

A 13-year-old boy with a past medical history of poorly controlled type 2 diabetes and obesity was admitted with massive haematemesis, melaena, and severe epigastric pain. He had developed non-autoimmune diabetes (glutamate decarboxylase antibodies, islet tyrosine phosphatase 2 antibodies, insulin autoantibodies, and Zinc Transporter 8 antibodies were absent); HbA1c 14·5% at the age of 10 years, having multiple paternal inheritance. Although known to have a bulimic behaviour, his medical history was negative for gastrointestinal disorders and for gastrointestinal toxic drugs or caustic consumption.

Serum glutamate decarboxylase antibodies and neurological disorders: when to suspect their association?

To explore different neurological manifestations with suspicion of being associated to serum glutamate decarboxylase antibodies (GAD-Abs) in order to better characterize anti-GAD neurological syndromes. Observational retrospective study including all patients for whom GAD65-Abs titers in serum were requested by the Neurology Department at La Paz University Hospital between 2015 and 2019. GAD-Abs were measured by ELISA. Demographic data, neurological symptoms, comorbidity with diabetes mellitus (DM) or with another autoimmune disease, and GAD-Abs titers were studied. Stiff-person syndrome, ataxia, encephalitis, and epilepsy were considered typical anti-GAD neurological syndromes and were compared to other atypical manifestations. A total of 173 patients (51.7% men, mean age 51.62) were included. A progressive increase in requests of serum GAD-Abs has occurred over the last 5 years, especially in patients with atypical neurological manifestations. GAD-Abs were found in the serum of 22 patients (12.7%); of those, 15 (68.18%) suffered a typical anti-GAD syndrome. Presence of DM or another organ-specific autoimmune disease was predictive of GAD-AB seropositivity (p < 0.001). 6.6% of requested patients with an atypical syndrome had GAD-Abs, but serum levels were significantly lower than those found in patients with a typical syndrome (706.67 vs 1430.23 UI/mL; Mann-Whitney U, p = 0.034), and were finally diagnosed with another neurological disease. Serum GAD-Abs were infrequently found in patients with clinical phenotypes other than those classically described as anti-GAD disorders, and with very low titers. In typical anti-GAD syndromes, there is a high comorbidity with DM and with other autoimmune diseases, and high serum GAD-Abs levels are usually present.

Identification of two novel subgroups in patients with diabetes mellitus and their association with clinical outcomes: A two‐step cluster analysis

Aims/IntroductionThe aim of this study was to determine whether distinct subphenotypes of patients with type 2 diabetes in the European classification exist in Chinese populations, and to further establish novel subphenotypes more suitable for Chinese populations.Material and MethodsThe research retrospectively analyzed 5414 patients with type 2 diabetes from the National Clinical Research Center for Metabolic Diseases Diabetes Center in China, and a two‐step cluster analysis was carried out. First, we confirmed the European classification in Chinese populations by six parameters, including age at disease onset, body mass index, glycosylated hemoglobin, homeostatic model assessment 2 to estimate β‐cell function and insulin resistance, and glutamate decarboxylase antibodies. Furthermore, triglycerides and uric acid were added to refine the cluster analysis, and Cox regression was used to evaluate the risk of diabetic complications.ResultsJust three clusters were replicated in our cohort according to Emma Ahlqvist's European classification. When other variables were added to the cluster analysis, seven subgroups were identified, including five clusters of the European classification and two novel subgroups, namely, uric acid‐related diabetes and inheritance‐related diabetes. Compared with patients with inheritance‐related diabetes, patients with severe insulin‐resistant diabetes showed a higher risk of diabetic peripheral neuropathy, hypertension and chronic kidney disease, and the uric acid‐related diabetes subgroup showed a higher risk of coronary heart disease, cerebral vascular disease and end‐stage renal disease. Patients with severe insulin‐deficient diabetes showed a higher risk of diabetic retinopathy and diabetic foot than those with inheritance‐related diabetes. Furthermore, there were sex‐specific associations between subgroups and clinical outcomes. No significant difference was observed in the prevalence of cancer in each subgroup.ConclusionsSeven subgroups of type 2 diabetes were identified in Chinese populations, with distinct characteristics and disparate clinical outcomes. This etiology‐based stratification might contribute to the diagnosis and management of type 2 diabetes.

Dynamics of Islet Autoantibodies During Prospective Follow-Up From Birth to Age 15 Years.

ContextWe set out to characterize the dynamics of islet autoantibodies over the first 15 years of life in children carrying genetic susceptibility to type 1 diabetes (T1D). We also assessed systematically the role of zinc transporter 8 autoantibodies (ZnT8A) in this context.DesignHLA-predisposed children (N = 1006, 53.0% boys) recruited from the general population during 1994 to 1997 were observed from birth over a median time of 14.9 years (range, 1.9-15.5 years) for ZnT8A, islet cell (ICA), insulin (IAA), glutamate decarboxylase (GADA), and islet antigen-2 (IA-2A) antibodies, and for T1D. ResultsBy age 15.5 years, 35 (3.5%) children had progressed to T1D. Islet autoimmunity developed in 275 (27.3%) children at a median age of 7.4 years (range, 0.3-15.1 years). The ICA seroconversion rate increased toward puberty, but the biochemically defined autoantibodies peaked at a young age. Before age 2 years, ZnT8A and IAA appeared commonly as the first autoantibody, but in the preschool years IA-2A– and especially GADA-initiated autoimmunity increased. Thereafter, GADA-positive seroconversions continued to appear steadily until ages 10 to 15 years. Inverse IAA seroconversions occurred frequently (49.3% turned negative) and marked a prolonged delay from seroconversion to diagnosis compared to persistent IAA (8.2 vs 3.4 years; P = .01).ConclusionsIn HLA-predisposed children, the primary autoantibody is characteristic of age and might reflect the events driving the disease process toward clinical T1D. Autoantibody persistence affects the risk of T1D. These findings provide a framework for identifying disease subpopulations and for personalizing the efforts to predict and prevent T1D.

Validation of the Swedish Diabetes Re-Grouping Scheme in Adult-Onset Diabetes in China

This study applied the Swedish novel data-driven classification in Chinese newly diagnosed diabetic patients and validated its adoptability. This study aimed to validate the practicality of the Swedish diabetes regrouping scheme in Chinese adults with newly diagnosed diabetes. Patients were classified into 5 subgroups by K-means and Two-Step methods according to 6 clinical parameters. Ambulatory care. A cross-sectional survey of 15 772 patients with adult-onset newly diagnosed diabetes was conducted in China from April 2015 to October 2017. None. Six parameters including glutamate decarboxylase antibodies (GADA), age of onset, body mass index (BMI), glycated hemoglobin A1c (HbA1c), homoeostatic model assessment 2 estimates of β-cell function (HOMA2-B) and insulin resistance (HOMA2-IR) were measured to calculate the patient subgroups. Our patients clustered into 5 subgroups: 6.2% were in the severe autoimmune diabetes (SAID) subgroup, 24.8% were in the severe insulin-deficient diabetes (SIDD) subgroup, 16.6% were in the severe insulin-resistance diabetes (SIRD) subgroup, 21.6% were in the mild obesity-related diabetes (MOD) subgroup and 30.9% were in the mild age-related diabetes (MARD) subgroup. When compared with the Swedish population, the proportion of SIDD subgroup was higher. In general, Chinese patients had younger age, lower BMI, higher HbA1c, lower HOMA2-B and HOMA2-IR, and higher insulin use but lower metformin usage than the Swedish patients. The Swedish diabetes regrouping scheme is applicable to adult-onset diabetes in China, with a high proportion of patients with the severe insulin deficient diabetes. Further validations of long-term diabetes complications remain warranted in future studies.

Relationships between Islet-Specific Autoantibody Titers and the Clinical Characteristics of Patients with Diabetes Mellitus.

BackgroundDysimmunity plays a key role in diabetes, especially type 1 diabetes mellitus. Islet-specific autoantibodies (ISAs) have been used as diagnostic markers for different phenotypic classifications of diabetes. This study was aimed to explore the relationships between ISA titers and the clinical characteristics of diabetic patients.MethodsA total of 509 diabetic patients admitted to Department of Endocrinology and Metabolism at the Affiliated Hospital of Nantong University were recruited. Anthropometric parameters, serum biochemical index, glycosylated hemoglobin, urinary microalbumin/creatinine ratio, ISAs, fat mass, and islet β-cell function were measured. Multiple linear regression analysis was performed to identify relationships between ISA titers and clinical characteristics.ResultsCompared with autoantibody negative group, blood pressure, weight, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), visceral fat mass, fasting C-peptide (FCP), 120 minutes C-peptide (120minCP) and area under C-peptide curve (AUCCP) of patients in either autoantibody positive or glutamate decarboxylase antibody (GADA) positive group were lower. Body mass index (BMI), waist circumference, triglycerides (TGs), body fat mass of patients in either autoantibody positive group were lower than autoantibody negative group. GADA titer negatively correlated with TC, LDL-C, FCP, 120minCP, and AUCCP. The islet cell antibody and insulin autoantibody titers both negatively correlated with body weight, BMI, TC, TG, and LDL-C. After adjusting confounders, multiple linear regression analysis showed that LDL-C and FCP negatively correlated with GADA titer.ConclusionDiabetic patients with a high ISA titer, especially GADA titer, have worse islet β-cell function, but less abdominal obesity and fewer features of the metabolic syndrome.

Long-term outcomes in temporal lobe epilepsy with glutamate decarboxylase antibodies.

To assess the long-term outcomes of patients with temporal lobe epilepsy and CSF anti-glutamate decarboxylase antibodies (GAD65-Abs). We retrospectively analyzed the clinical records of 35 patients with temporal lobe epilepsy and CSF GAD65-Abs, collected from January 1993 to December 2016 and assessed cognitive impairment and seizure activity at last visit. Cognitive impairment was considered significant if impacting on daily life activities. Immunohistochemistry on rat brain slices and ELISA were used for antibody detection and titration. Median age was 30years (range 2-63), 32/35 (91%) patients were female, and median follow-up was 68months (range 7-232). At presentation, 20 patients had isolated temporal lobe epilepsy and 15 patients had other limbic symptoms, including anterograde amnesia (n = 10) and behavioral disturbances (n = 5). Progressive clinical deterioration over follow-up was reported in 28/35 patients (80%), including gradual increase of memory impairment (n = 25), and apparition of behavioral disturbances (n = 4) or mood disorders (n = 18). At last follow-up, 24/35 (69%) patients had cognitive disturbances with an impact on patient's daily life activities, and 28/35 (80%) still had active seizures. Most patients with temporal lobe epilepsy and CSF GAD65-Abs develop a chronic disease with progressive cognitive impairment and refractory epilepsy regardless of the presence of additional limbic symptoms at onset.

Clinical Heterogeneity in Patients with Glutamate Decarboxylase Antibody

Objective: To explore the diversity and clinical features of anti-glutamate decarboxylase (GAD) antibody-associated neurological diseases. Methods: Clinical data of a series of 5 patients positive for anti-GAD antibodies were retrospectively analyzed. Results: All 5 patients were female, with a median age of 41.5 years (range 19–60 years). Their neurological symptoms included stiff-person syndrome (SPS), encephalitis, myelitis, cramp, visual loss, and paresthesia. Three patients (60%) were diagnosed with tumors, 2 cases of thymic tumor and 1 of breast cancer. On immunohistochemistry for tumor pathology, expression of GAD65 was found only in 1 patient. Four patients (80%) had abnormal brain MRI findings. All patients received immunotherapy and improved significantly after treatment, but 4 (80%) then experienced a relapse. Conclusions: Neurological manifestations in anti-GAD-positive patients are diverse and include SPS, encephalitis, myelitis, cramp, visual loss, and paresthesia.

Diabetes mellitus associated with the mutation of the ABCC8 gene (MODY 12): features of clinical course and therapy

Maturity-Onset Diabetes of the Young (MODY) is a heterogeneous group of diseases associated with genes mutations leading to dysfunction of pancreatic β-cells. Among the 14 identified MODY variants, MODY 1–5 are the most studied. The article reports a MODY 12 clinical case, with mutation in ABCC8, encoding the sulphonylurea receptor. Diabetes mellitus manifested in a 27-year-old man with hyperglycaemia up to 24 mmol/L, without ketosis. Non-proliferative diabetic retinopathy, microalbuminuria, dyslipidaemia and carotid atherosclerosis were revealed upon initial examination. The levels of pancreatic islet cell antibodies and glutamate decarboxylase antibodies were negative, while the level of C-peptide was within the normal range. Insulin therapy in the basal-bolus regimen was provided with a gradual dose reduction due to frequent hypoglycaemia. The preproliferative retinopathy with macular oedema was revealed after 4 months of therapy, and panretinal photocoagulation of both eyes was performed. A molecular genetics study revealed a mutation in the gene ABCC8, the same mutation was found in patient’s mother and uncle. Insulin therapy was cancelled, and the treatment of gliclazide MR 60 mg/day was initiated, which resulted in extreme glycaemic excursions. Thereby, sodium–glucose cotranporter-2 (SGLT2) inhibitor dapagliflozin 10 mg/day was added. A reduction in glucose variability parameters were observed on combination therapy. After 6 months till 1.5 years of treatment, glycaemic control was optimal, no hypoglycaemic episodes were observed. This case study demonstrates clinical features of MODY 12, and the potential of combination of sulfonylurea and SGLT2 inhibitor in the treatment of this disease.

Diabetes mellitus associated with the mutation of the ABCC8 gene (MODY 12): features of clinical course and therapy

Maturity-Onset Diabetes of the Young (MODY) is a heterogeneous group of diseases associated with genes mutations leading to dysfunction of pancreatic -cells. Among the 14 identified MODY variants, MODY 15 are the most studied. The article reports a MODY 12 clinical case, with mutation in ABCC8, encoding the sulphonylurea receptor. Diabetes mellitus manifested in a 27-year-old man with hyperglycaemia up to 24 mmol/L, without ketosis. Non-proliferative diabetic retinopathy, microalbuminuria, dyslipidaemia and carotid atherosclerosis were revealed upon initial examination. The levels of pancreatic islet cell antibodies and glutamate decarboxylase antibodies were negative, while the level of C-peptide was within the normal range. Insulin therapy in the basal-bolus regimen was provided with a gradual dose reduction due to frequent hypoglycaemia. The preproliferative retinopathy with macular oedema was revealed after 4 months of therapy, and panretinal photocoagulation of both eyes was performed. A molecular genetics study revealed a mutation in the gene ABCC8, the same mutation was found in patients mother and uncle. Insulin therapy was cancelled, and the treatment of gliclazide MR 60 mg/day was initiated, which resulted in extreme glycaemic excursions. Thereby, sodiumglucose cotranporter-2 (SGLT2) inhibitor dapagliflozin 10 mg/day was added. A reduction in glucose variability parameters were observed on combination therapy. After 6 months till 1.5 years of treatment, glycaemic control was optimal, no hypoglycaemic episodes were observed. This case study demonstrates clinical features of MODY 12, and the potential of combination of sulfonylurea and SGLT2 inhibitor in the treatment of this disease.

Hyperglycemic hyperosmolar state in an adolescent with type 1 diabetes mellitus.

SummaryHyperglycemic hyperosmolar state (HHS) and diabetic ketoacidosis (DKA) are the most severe acute complications of diabetes mellitus (DM). HHS is characterized by severe hyperglycemia and hyperosmolality without significant ketosis and acidosis. A 14-year-old Japanese boy presented at the emergency room with lethargy, polyuria and polydipsia. He belonged to a baseball club team and habitually drank sugar-rich beverages daily. Three weeks earlier, he suffered from lassitude and developed polyuria and polydipsia 1 week later. He had been drinking more sugar-rich isotonic sports drinks (approximately 1000–1500 mL/day) than usual (approximately 500 mL/day). He presented with HHS (hyperglycemia (1010 mg/dL, HbA1c 12.3%) and mild hyperosmolality (313 mOsm/kg)) without acidosis (pH 7.360), severe ketosis (589 μmol/L) and ketonuria. He presented HHS in type 1 diabetes mellitus (T1DM) with elevated glutamate decarboxylase antibody and islet antigen 2 antibody. Consuming beverages with high sugar concentrations caused hyperglycemia and further exacerbates thirst, resulting in further beverage consumption. Although he recovered from HHS following intensive transfusion and insulin treatment, he was significantly sensitive to insulin therapy. Even the appropriate amount of insulin may result in dramatically decreasing blood sugar levels in patients with T1DM. We should therefore suspect T1DM in patients with HHS but not those with obesity. Moreover, age, clinical history and body type are helpful for identifying T1DM and HHS. Specifically, drinking an excess of beverages rich in sugars represents a risk of HHS in juvenile/adolescent T1DM patients.Learning points:Hyperglycemic hyperosmolar state (HHS) is characterized by severe hyperglycemia and hyperosmolality without significant ketosis and acidosis.The discrimination between HHS of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in initial presentation is difficult.Pediatrician should suspect T1DM in patients with HHS but not obesity.Age, clinical history and body type are helpful for identifying T1DM and HHS.Children with T1DM are very sensitive to insulin treatment, and even appropriate amount of insulin may result in dramatically decreasing blood sugar levels.