Glutamic Acid Decarboxylase Research Articles

Effects of Acute Haloperidol Treatment on Dopaminergic Markers, GAD67, and A2A Receptors in Rats with High and Low VCMs.

Vacuous chewing movements (VCM) have been utilized as an experimental model of orofacial dyskinesia (OD) in rodents to study the underlying molecular mechanisms related to tardive dyskinesia (TD). This study aimed to investigate if the acute treatment with haloperidol can alter components of the dopaminergic synapse or its modulators such as glutamic acid decarboxylase (GAD67) and adenosine 2A (A2A) receptor. Furthermore, to evaluate if changes in molecular markers are associated with the number of VCMs induced by haloperidol in rats it is proposing a method to classify the animals into High and Low VCM groups. Here, we treated rats with haloperidol decanoate (single injection, intramuscularly, 28mg/Kg of unconjugated haloperidol) and evaluated the number of VCMs after 4 weeks. Haloperidol-treated rats were divided into three groups (Low, High, and Spontaneous VCM) according to the evaluation of the VCM profile proposed here. After, dopamine (DA) levels, monoamine oxidase (MAO) activity, and the immunoreactivity of tyrosine hydroxylase (TH), dopamine transporter (DAT), D2 receptor, GAD67, and A2A were determined in brain structures. No significant differences were found in DA levels, MAO activity, and immunoreactivity of the TH, DAT, D2 receptor, GAD67, and A2A receptor in brain structures. VCM intensity was correlated with TH immunoreactivity in Sn in the High VCM group while it was inversely correlated with the immunoreactivity of the A2A receptor in the striatum of the Spontaneous VCM group. Other significant correlations were found considering the VCM profile suggesting that High VCM after acute haloperidol treatment seems to be associated with the lack of ability to reorganize the neurotransmission in the nigrostriatal pathway. Further studies could clarify the main targets involved in the motor side effects of antipsychotics. The present study demonstrated an easy way to separate the animals into High and Low VCMs.

GABA Prevents Sarcopenia by Regulation of Muscle Protein Degradation and Inflammaging in 23- to 25-Month-Old Female Mice.

Sarcopenia is the gradual decrease in skeletal muscle mass, strength and function in elderly individuals. Gamma-aminobutyric acid (GABA) is a neurotransmitter naturally produced from glutamate by the enzyme glutamic acid decarboxylase. Age-related decline in GABA is linked to age-related motor and sensory decline and seems to affect sarcopenia, yet no detailed study has been conducted. In this study, we aimed to investigate the effect of GABA on improving sarcopenia by suppressing muscle protein degradation through supplementing decreased GABA in old mice. GABA (10 or 30 mg/kg/day) was orally administered daily to young (3 months) and old (21-23 months) C57BL/6 mice for 7 weeks. The body weight and grip strength of the mice were measured weekly at the same time. After sacrificing the mice, the quadriceps and gastrocnemius muscles were excised from their hind limbs, and the spleen and serum were collected. Histological, biochemical and molecular analyses were conducted in various experiments. The administration of GABA increased muscle strength (+41%, +70% compared to the aged mouse control group, GABA at doses of 10 or 30 mg/kg/day respectively, p < 0.05) and muscle mass (quadriceps: +28%, +46%; gastrocnemius: +12%, +19%, p < 0.05) in old mice. This increase was accompanied by a cross-sectional area (CSA) increase in the quadriceps and gastrocnemius muscle (p < 0.05). The administration of GABA increased IGF-1 levels in serum (p < 0.05), leading to the activation of muscle protein synthesis. We found that GABA inhibits sarcopenia by regulating muscle protein degradation through the activation of Akt/mTOR/FoxO3a signalling pathways. GABA also regulates inflammaging, which is a hallmark of age-related muscle atrophy. There was a significant increase in the F4/80 + CD11b + total macrophage ratio in gastrocnemius and spleen, especially the M1 macrophage ratio increased in old mice. However, GABA administration was effective in suppressing M1 macrophages (gastrocnemius: -40%, - 53%; spleen: -22%, -26%, p < 0.05). Pro-inflammatory cytokines such as TNF-α and IL-6, primarily secreted by M1 macrophages, are also decreased by treatment with GABA (TNF-α: -24%, -27%; IL-6: -45%, -59%, p < 0.05). Together, this study demonstrates the importance of GABA in maintaining muscle and low-chronic inflammation during ageing. We suggest that GABA shows potential as a substance that can effectively address sarcopenia and enhance the overall lifespan and well-being of older individuals.

A comprehensive review of immune checkpoint inhibitor-related diabetes mellitus: incidence, clinical features, management, and prognosis

Immune checkpoint inhibitor-related diabetes mellitus (ICI-DM) is a rare complication that medical oncologists seldom encounter in routine practice. The sporadic nature and intrinsic complexity of ICI-DM make it challenging to analyze comprehensively in experimental settings. In this review, we examine phase 3 clinical trials on ICIs and published case reports of ICI-DM, aiming to summarize its incidence, clinical features, management, and prognosis. Phase 3 clinical trials reveal that the incidence of ICI-DM is higher with combination therapies, such as anti-PD-1 and anti-CTLA-4 or anti-PD-L1, compared to anti-PD-1 monotherapy. ICI-DM typically presents as severe hyperglycemia with a fulminant onset and is often associated with diabetic ketoacidosis, accompanied by unexpectedly low HbA1c and C-peptide levels. ICI-DM shares similarities with classic type 1 diabetes, particularly in terms of autoimmunity and genetic predisposition. This includes a high prevalence of islet autoantibodies and susceptibility to certain HLA haplotypes, often with concurrent endocrine gland dysfunction. This suggests that genetic susceptibility and exposure to ICIs may both be necessary for triggering islet autoimmunity and inducing ICI-DM. Notably, patients with positive islet autoantibodies, such as glutamic acid decarboxylase antibody and islet-associated antigen 2 antibody, tend to experience rapid onset of ICI-DM after ICI exposure. Although patients with ICI-DM generally show a high objective response rate to immunotherapy, a significant proportion also face the need to permanently discontinued treatment. Further research is urgently needed to determine whether permanent discontinuation of immunotherapy is necessary and whether this discontinuation negatively impacts overall survival.

IGF-1 impacts neocortical interneuron connectivity in epileptic spasm generation and resolution

Little is known about the mechanisms that generate epileptic spasms following perinatal brain injury. Recent studies have implicated reduced levels of Insulin-like Growth Factor 1 (IGF-1) in these patients’ brains. Other studies have reported low levels of the inhibitory neurotransmitter, GABA. In the TTX brain injury model of epileptic spasms, we undertook experiments to evaluate the impact of IGF-1 deficiencies on neocortical interneurons and their role in spasms. Quantitative immunohistochemical analyses revealed that neocortical interneurons that express glutamic acid decarboxylase, parvalbumin, or synaptotagmin 2 co-express IGF-1. In epileptic rats, expression of these three interneuron markers were reduced in the neocortex. IGF-1 expression was also reduced, but surprisingly this loss was confined to interneurons. Interneuron connectivity was reduced in tandem with IGF-1 deficiencies. Similar changes were observed in surgically resected neocortex from infantile epileptic spasms syndrome (IESS) patients. To evaluate the impact of IGF-1 deficiencies on interneuron development, IGF-1R levels were reduced in the neocortex of neonatal conditional IGF-1R knock out mice by viral injections. Four weeks later, this experimental maneuver resulted in similar reductions in interneuron connectivity. Treatment with the IGF-1 derived tripeptide, (1–3)IGF-1, abolished epileptic spasms in most animals, rescued interneuron connectivity, and restored neocortical levels of IGF-1. Our results implicate interneuron IGF-1 deficiencies, possibly impaired autocrine IGF-1 signaling and a resultant interneuron dysmaturation in epileptic spasm generation. By restoring IGF-1 levels, (1–3)IGF-1 likely suppresses spasms by rescuing interneuron connectivity. Results point to (1–3)IGF-1 and its analogues as potential novel disease-modifying therapies for this neurodevelopmental disorder.

Simultaneous Pancreas-Kidney Transplant Outcomes Stratified by Autoantibodies Status and Pretransplant Fasting C-peptide.

Pancreatic beta cell function and islet autoantibodies classically distinguish types of diabetes (type 1 diabetes mellitus [DM] or type 2 DM). Here, we sought to evaluate simultaneous pancreas-kidney (SPK) transplant outcomes stratified by the presence or absence of beta cell function and autoantibodies. SPK recipients were eligible if pretransplant autoantibodies were measured against insulin, islet cell, or glutamic acid decarboxylase 65-kD isoform. Recipients were categorized as A+ or A- based on the detection of ≥1 autoantibodies. Recipients were similarly categorized on the basis of detectable pretransplant fasting C-peptide of ≥2 ng/mL (β+) or <2 ng/mL (β-). Thus, recipients were categorized into 4 groups: A+β-, A-β-, A-β+, and A+β+. Outcomes of interest were overall pancreas graft failure (non-death-censored), death-censored pancreas, or kidney graft failure (death-censored pancreas graft failure [DCGF]; kidney DCGF), composite outcomes with any of the 3 outcomes as pancreas DCGF, use of an antidiabetic agent, or hemoglobin A1c >6.5. One hundred eighty-three SPK recipients were included: A+β- (n = 72), A-β- (n = 42), A-β+ (n = 49), and A+β+ (n = 20). We did not detect a statistical difference in non-death-censored pancreas graft failure for A+β- recipients compared with other groups: A-β- (adjusted hazard ratio [aHR]: 0.44; 95% confidence interval [CI], 0.14-1.42), A-β+ (aHR: 1.02; 95% CI, 0.37-2.85), and A+β+ (aHR: 0.67; 95% CI, 0.13-3.33) in adjusted analyses. Similar outcomes were observed for other outcomes. In SPK recipients, outcomes were similar among recipients with classic features of type 1 DM and various other types of DM.

Physiological and pathogenic T cell autoreactivity converge in type 1 diabetes

Autoimmune diseases result from autoantigen-mediated activation of adaptive immunity; intriguingly, autoantigen-specific T cells are also present in healthy donors. An assessment of dynamic changes of this autoreactive repertoire in both health and disease is thus warranted. Here we investigate the physiological versus pathogenic autoreactive processes in the context of Type 1 diabetes (T1D) and one of its landmark autoantigens, glutamic acid decarboxylase 65 (GAD65). Using single cell gene expression profiling and tandem T cell receptor (TCR) sequencing, we find that GAD65-specific true naïve cells are present in both health and disease, with GAD65-specific effector and memory responses showing similar ratios in healthy donors and patients. Deeper assessment of phenotype and TCR repertoire uncover differential features in GAD65-specific TCRs, including lower clonal sizes of healthy donor-derived clonotypes in patients. We thus propose a model whereby physiological autoimmunity against GAD65 is needed during early life, and that alterations of these physiological autoimmune processes in predisposed individuals trigger overt Type 1 diabetes.

MiR-375: it could be a general biomarker of metabolic changes and inflammation in type 1 diabetes patients and their siblings.

Type 1 diabetes (T1D) is a chronic autoimmune illness that results in loss of pancreatic beta cells and insulin insufficiency. MicroRNAs (miRNAs) are linked to immune system functions contributing to the pathophysiology of T1D, miRNA-375 is significantly expressed in the human pancreas and its circulatory levels might correspond to beta cell alterations. Pancreatic islet cell antibodies (ICA) and Glutamic acid decarboxylase antibodies (GADA) have roles in autoimmune pathogenesis and are predictive markers of T1D. The aim of this work was to detect serum level changes of miRNA-375, ICA, and GADA in T1D patients, and their siblings compared to healthy controls and correlate them with T1D biochemical parameters. The study included 66 T1D patients (32 males and 34 females; age range 3-18 years), 22 patients' siblings (13 males and 9 females; age range 4-17 years), and 23 healthy controls (7 males and 16 females; age range 4-17 years). MiRNA-375 levels were measured using quantitative reverse transcription polymerase chain reaction (RT-qPCR), while ICA and GADA levels were measured using enzyme-linked immunosorbent assay (ELISA). Data analysis was done utilizing SPSS-17 software. MiR-375 levels were downregulated in T1D patients and further decreased in their siblings when compared to healthy controls. Furthermore, miR-375 exhibited inverse correlations with HbA1c levels but no correlations with Total Insulin Dose, disease duration, or autoantibodies (GADA & ICA). Our study indicates that miR-375 is significantly downregulated in children with T1D and their siblings, suggesting its potential role as a biomarker for beta-cell function and glycemic control.

The epidemiology of type 1 diabetes mellitus in older adults.

Although type 1 diabetes mellitus (T1DM) is traditionally viewed as a youth-onset disorder, the number of older adults being diagnosed with this disease is growing. Improvements in the average life expectancy of people with T1DM have also contributed to the growing number of older people living with this disease. We summarize the evidence regarding the epidemiology (incidence, prevalence and excess mortality) of T1DM in older adults (ages ≥60 years) as well as the genetics, immunology and diagnostic challenges. Several studies report an incidence peak of T1DM in older adults of a similar size to or exceeding that in children, and population prevalence generally increases with increasing age. Glutamic acid decarboxylase antibody positivity is frequently observed in adult-onset T1DM. Guidelines for differentiating T1DM from type 2 diabetes mellitus in older adults recommend measuring levels of C-peptide and autoantibodies, including glutamic acid decarboxylase antibodies. However, there is no gold standard for differentiating T1DM from type 2 diabetes mellitus in people aged 60 years and over. As such, the global variation observed in T1DM epidemiology might be in part explained by misclassification, which increases with increasing age of diabetes mellitus onset. With a growing global population of older adults with T1DM, improved genetic and immunological evidence is needed to differentiate diabetes mellitus type at older ages so that a clear epidemiological picture can emerge.

Treatment switch from multiple daily insulin injections to sulphonylureas in an African young adult diagnosed with HNF1A MODY: a case report

BackgroundMaturity onset diabetes of the young is one of the commonest causes of monogenic diabetes and can easily be mistaken for type 1 diabetes. A diagnosis of maturity onset diabetes of the young can have direct implications for genetic counseling, family screening, and precision diabetes treatment. However, the cost of genetic testing and identifying individuals to test are the main challenges for diagnosis and management in sub-Saharan Africa. We report the very first documented case of HNF1A maturity onset diabetes of the young in the sub-Saharan African region.Case presentationA 20-year-old female Black African young adult diagnosed with type 1 diabetes aged 14 presented for routine out-patient diabetes consultation. She was on multiple daily insulin injections; total combined dose 0.79 IU/kg/day with an HbA1c of 7.7%. The rest of her laboratory examinations were normal. On extended laboratory analysis, she had good residual insulin secretion with post-meal plasma C-peptide levels at 1150 pmol/L. She tested negative for glutamic acid decarboxylase (GAD65), islet antigen-2 (IA-2), and zinc transporter 8 (ZnT8) islet autoantibodies. Targeted next-generation sequencing (t-NGS) for monogenic diabetes was performed using DNA extracted from a buccal sample. She was diagnosed with HNF1A maturity onset diabetes of the young, with the c.607C > T; p.(Arg203Cys) pathogenic variant, which has never been reported in sub-Saharan Africa. Her clinical practitioners provided genetic and therapeutic counseling. Within 10 months following the diagnosis of maturity onset diabetes of the young, she was successfully switched from multiple daily insulin injections to oral antidiabetic tablets (sulphonylurea) while maintaining stable glycemic control (HBA1c of 7.0%) and reducing hypoglycemia. She expressed a huge relief from the daily finger pricks for blood glucose monitoring.ConclusionThis case reveals that HNF1A maturity onset diabetes of the young (and probably other causes of monogenic diabetes) can present in sub-Saharan Africa. A diagnosis of maturity onset diabetes of the young can have significant life-changing therapeutic implications.

Uncommon Pediatric Immune-Mediated Epilepsy: Disease Course, Diagnosis, and Outcome - A Series of Three Cases.

Immune-mediated epilepsy (IME) constitutes a substantial proportion of drug-refractory epilepsies. Rapid diagnosis and prompt immunosuppression are required along with antiseizure medications (ASMs). Here we report three unrelated children who presented with fever, encephalopathy, and refractory epilepsy and subsequently tested positive for rare intraneuronal and surface receptor antibodies, namely, contactin-associated protein like 2 (CASPR2), glutamic acid decarboxylase (GAD65), and paraneoplastic antigen Ma2 (PNMA2). In all of them, brain magnetic resonance imaging (MRI) was noncontributory. Electroencephalography showed nonspecific interictal epileptic discharges. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) brain scan revealed abnormality in metabolic pattern with hypermetabolism in basal ganglia, thalami, frontotemporal cortices, and cerebellar hemispheres, consistent with autoimmune encephalitis. Immunosuppression was initiated along with ASMs. Complete seizure freedom was achieved in GAD65 antibody IME and >50% seizure reduction in CASPR2 and PNMA2 antibody IME. A variable degree of behavioral problems persisted in all. Early immunosuppression is warranted in IME, but does not universally guarantee a complete response.

8070 Atypical New Onset Diabetes Mellitus in a Young Male: Is this LADA vs Type 1 or Type 2?

Abstract Disclosure: S.K. Devineni: None. S. Shaik: None. J.L. Gilden: None. Background: Recent literature suggests that autoantibody seropositivity is common in new onset autoimmune Diabetes Mellitus (DM), especially in younger patients. Latent autoimmune diabetes of adults (LADA), a form of adult-onset autoimmune DM. is considered a mix of type 1 and type 2 DM, sharing similar immune cell characteristics to both subtypes. Unlike type 1, LADA patients do not require insulin for glycemic control for the first six months after diagnosis. Unlike type 2, LADA patients are positive for single islet autoantibody, glutamic acid decarboxylase (GAD), and anti-gliadin antibodies. Patients with LADA often present with symptoms (polyuria, polydipsia, nocturia, fatigue, and visual changes). We present a case of new onset Diabetes Mellitus in a young male, autoantibody seronegative, at the time of diagnosis. Case report: A 19-year-old Caucasian male was sent to the Emergency Department with a serum blood glucose (BG) level of 579 mg% after routine blood tests. He denied any clinical symptoms and serum levels showed no elevation in ketones, nor bicarbonate levels, ruling out ketoacidosis. His hemoglobin A1c at that time was 14.7%. He denied prior knowledge of personal or family history of DM. or other autoimmune disorders. However, it was discovered that routine labs done 1 ½ months earlier on a Health Screen revealed BG=295 mg% with urine positive for ketones (80 mg/dl) and glucose (&amp;gt;1000 mg/dL). Physical Exam: (HT=178 cm; WT=79 Kg) was unremarkable. Autoantibodies for GAD 65, islet-cell, Zinc transporter 8, and Islet Antigen 2 were all negative. He was hospitalized for 9 days. BG levels were difficult to control and required increasing doses of both long acting and short acting insulin. He was discharged with insulin therapy (30 units of glargine at nighttime and 12 units of premeal aspart). One week later, the patient ate several gummy bears as a nighttime snack and subsequently woke up in the middle of the night feeling shaky and having blurry vision. BG was greater than 300 mg%. In the emergency room, he. received intravenous fluids. No insulin was given as his BG normalized and he was discharged. Later, a continuous glucose monitor revealed multiple hypoglycemic episodes. The patient was living in a situation where he only had limited access to certain foods, and thus his insulin regimen was decreased (28 units glargine and 10 units aspart for meals) Conclusion: We present the case of new onset atypical DM in a young patient whose insulin sensitivity and risk factors seem to resemble a pattern of type 1 DM; despite seronegative autoantibodies We predict that he may eventually seroconvert to type 1 DM. It is also possible that he may have an unusual presentation of LADA or type 2 DM, although he had no hyperglycemic symptoms. Presentation: 6/3/2024

9390 Does Znt8a Have An Association With The Duration Of Diabetes? Case Series And Literature Review

Abstract Disclosure: N.M. Rivera Vargas: None. C.S. Botero Suarez: None. S.K. Suryanarayanan: None. S. Saad-Omer: None. Context: Latent autoimmune Diabetes of adults (LADA) is a form of autoimmune diabetes with features of Type 2 Diabetes but positive autoantibodies resembling Type 1 Diabetes. Latent autoimmune diabetes in adults (LADA), has a mixed phenotype with positive islet-cell antibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), protein tyrosine phosphatase autoantibodies (IA2A), insulin autoantibodies (IAA), or zinc transporter-8 autoantibodies (ZnT8A). Since the discovery of ZnT8A, the relevance and clinical utility of this marker has sparked interest. Although ZnT8A is used as a complementary diagnostic aid in children, its utility in adults seems to be unclear. Objective: We report a case series of 26 subjects referred to the Orlando VA Endocrine clinic with measured ZnT8A. We hypothesize that higher ZnT8A will be found in adult autoimmune diabetes with newly diagnosed diabetes rather than those with a longer duration of diabetes. We also explore the association between ZnT8A and family history, duration of diabetes, diabetes complications, and C-peptide levels. Method: A case series of 26 adult patients with diabetes mellitus with a positive ZnT8A (≥15 U/mL). We reviewed medical records of these cases to include ZnT8A levels, years of diabetes diagnosis, C-peptide levels, and diabetes complications. Patients were classified into subgroups based on ZnT8A levels into &amp;lt; 350 U/mL or ≥ 350 U/mL. Results: The 26 patients reviewed had a mean (SD) age of 46 (13) years. The mean (SD) duration of diabetes was 16 (12) years, and HbA1C was 8.4 (1.1) %. Poisson regression analysis showed a statistically significant inverse relationship between ZnT8A and years of diabetes (regression coefficient: -0.028; 95% confidence interval: -0.03 to -0.25; p-value &amp;lt;0.001). Diabetic ketoacidosis was present in 35% of subjects, while diabetic neuropathy was noted in 58% of subjects with positive ZnT8A. Patients with a high ZnT8Ab above 350 U/mL displayed a weak trend towards a lower C-peptide mean (p-value 0.42), and lower prevalence of DKA (p-value 0.42) which was not statistically significant. Conclusion: In this case series of patients with adult-onset diabetes, there seems to be a statistically significant inverse relationship between ZnT8A levels and duration of diabetes suggesting a reduction of ZnT8A levels over time. Although limited by a small number of subjects, this may suggest the need for screening with autoantibodies in the setting of diabetes earlier in the disease process. Presentation: 6/2/2024

12392 Decoding LADA: A Closer Look At A Suspected Case Influenced By Prior IVIG Therapy

Abstract Disclosure: A. Gondhi: None. S. Antharam: None. S.S. Bantu: None. B. Abdulhadi: None. Introduction: LADA(Latent Autoimmune Diabetes of Adults) is defined as a new diagnosis of diabetes after the age of 35, presenting with features of T2DM but with the presence of T1DM associated autoantibodies. Correct diagnosis of LADA is important since prognosis and therapy differs from T2DM. We report an interesting case of transient elevation of Glutamic Acid decarboxylase (GAD-65) antibodies due to IVIG therapy leading to a misdiagnosis of LADA. Case presentation:A 46-year-old women with hypothyroidism was referred for management of LADA. A few months prior to the referral, she was hospitalized for acute bacterial meningitis and developed flaccid quadriparesis concerning for Guillain Barre syndrome (GBS). She received multiple IVIG infusions, steroids with resultant hyperglycemia requiring insulin and was transferred to a rehabilitation facility. During her stay in rehab, her initial dose of glargine 20 units twice daily was titrated down rapidly once steroids are tapered. Blood work revealed HbA1C 6.1%, blood glucose 116 mg/dL, C-peptide levels 4.1 ng/ml (0.9 -7 ng/ml), and GAD-65 antibodies &amp;gt;250 (N&amp;lt;5 IU/ml). She was diagnosed with LADA and discharged on 2 units of glargine. Her primary care physician advised to stay on the 2 units of glargine since her GAD-65 antibodies were significantly elevated and then referred to the endocrine clinic. Repeat bloodwork in our clinic revealed HbA1c of 5.8%, GAD-65 antibodies were repeated twice and were found to be undetectable &amp;lt;5. She was taken off insulin and has been doing well since. Discussion:IVIG is derived from plasma pooled from donors, used to treat a variety of diseases. Autoantibodies contained in IVIG may result in false positive serum tests if levels are checked soon after the infusion. This phenomenon has been documented in previous cases involving treponemal, H. pylori, hepatitis C as well as ANA antibodies. Increases in anti-GAD levels post-IVIG therapy have been previously reported. We saw a similar scenario in our patient, who was initially diagnosed with LADA and started on insulin due to an observed elevation in GAD 65 levels. However, this elevation was transient with negative repeat levels a few months later. Conclusion: Our case highlights the importance of recognizing that IVIG infusions can lead to the transfer of and to transient elevations in autoantibodies including GAD-65, which may lead to misdiagnosis and unnecessary therapies.

6938 An Unusual Case of New-onset autoimmune insulin dependent Diabetes Mellitus Complicating Gestational Diabetes Mellitus in A Pregnant Female Diagnosed Early Postpartum - The Enigma of Autoimmunity and Diabetes During Pregnancy

Abstract Disclosure: R. Abdelmasih: None. W. Pan: None. Introduction: Gestation diabetes is the most common metabolic disorder in pregnancy affecting 25% of pregnancies. T1DM accounts for 0.2-0.5% of all pregnancies in the United States yearly. New-onset autoimmune insulin-dependent diabetes mellitus during pregnancy is very uncommon and it might be overlooked. Diabetes-related autoantibodies have been studied in women with GDM with prevalence of 0-10%. There is controversial data regarding the clinical significance of checking diabetes antibodies in pregnancy. Case Presentation: A 22-year-old G1P1 female with history of Hashimoto hypothyroidism presented during early second trimester for evaluation of GDM with serum glucose of 300s mg/dl in a random blood sample with multiple subsequent high values, hemoglobin A1C of 9.4% (prepartum value was 5.3%). Patient was started on insulin during pregnancy. Pregnancy was complicated with cesarian section and macrosomia. 1 week postpartum, A1c was 5.4%, Insulin was discontinued, and patient was continued on Metformin. 2 months Postpartum, patient presented with persistent high blood glucose values of 300-400 mg/dl with no signs of DKA. Glipizide and Glargine 15 units daily were added though patient continued to have hyperglycemia. Laboratory workup were remarkable for high blood glucose of 342 mg/dl, low C peptide of 0.6 ng/dl, and positive glutamic acid decarboxylase antibodies (GAD Ab) 38.8 U/ml. oral antidiabetics were discontinued and prandial insulin was added. Discussion: GDM is a risk factor for DMII after pregnancy given high insulin resistance postpartum, Data regarding new-onset DMI and diabetes autoimmunity during pregnancy is lacking. About 0-10% of women with gestational diabetes develop DM autoantibodies. GAD Ab exhibits the highest sensitivity of 63% for type 1 diabetes prediction compared to Islet cell antibodies (48%), and tyrosine phosphatase-related islet antigen 2 (34%). Pathophysiology of autoimmune DM during pregnancy is not quite understood; It is thought that when autoimmune tendency is present, GDM causes β-cells to deteriorate due to excessive insulin production in setting of insulin resistance, and the burden of third-trimester gestation may cause the insulin deficiency to be expressed sooner than non-pregnant female. So far, Literature about the predictive value or specific clinical features of checking diabetes autoantibodies is discordant and inconclusive. It is suggested to screen for autoantibodies only when array of clinical hallmarks suggestive of an autoimmune DM form of GDM present as young age, low BMI, need for insulin therapy early in pregnancy, presence of ketones, concurrent other autoimmune conditions (e.g., thyroiditis). This case is to shed light on autoimmunity in pregnancy. More data is needed with longer follow-up to better identify women at risk, their characteristics, indications for autoantibodies testing, follow and prognosis. Presentation: 6/2/2024

8114 The Need For Autoantibody Screening And Diagnostic Criteria For Immune-Checkpoint Inhibitor-Induced Type 1 Diabetes

Abstract Disclosure: A. Gupta: None. H. Sanekommu: None. A.B. Ravin: None. M. Akula: None. J. Cheng: None. Background: Immune-checkpoint inhibitors (ICIs) such as Nivolumab have been extensively studied, especially in relation to their side-effect profiles. Patients on Nivolumab are prone to immune-related adverse events (irAEs) including type 1 diabetes mellitus, thyroiditis, and hypopituitarism. Prior studies have indicated that ICIs can unmask existing diabetic autoimmunities, but currently no specific guidelines exist for autoantibody screening prior to initiating treatment. We report a unique case of a young patient with newly diagnosed immune-checkpoint inhibitor-induced type 1 diabetes (ICI-T1DM) who was found to have mixed autoantibody results. Clinical Case: This is a 31-year-old male who was diagnosed with fibrolamellar hepatocellular carcinoma (pT23N0) and underwent partial hepatic resection later that year. Repeat imaging showed new hepatic lesions, thus Nivolumab was initiated. He received a total of three cycles, after which he presented to the hospital with symptoms of fever and nausea; labs were consistent with diabetic ketoacidosis (DKA) for which he was treated with IV insulin and aggressive hydration with successful resolution. Nivolumab was stopped and the patient was discharged on a basal-bolus insulin regimen. Further outpatient workup was significant for A1c 5.9% (n&amp;lt;5.7%), C-peptide (with glucose 220mg/dL) 0.7 (n=0.8-3.9ng/mL), glutamic acid decarboxylase autoantibody (GAD Ab) 11 (n&amp;lt;5.0U/mL). Insulin antibody and islet cell antibody IgG were negative. Due to the acute onset in the presentation and the recent use of Nivolumab, the patient was diagnosed with ICI-T1DM. He remained insulin-dependent after discharge. Unfortunately, soon after, he began showing signs of liver failure and ultimately underwent liver transplantation. Conclusion: This case highlights two crucial aspects - the importance of screening for autoantibodies prior to initiating an ICI and the necessity for guidelines in diagnosing ICI-T1DM. Given the evidence linking positive GAD Ab to a higher risk of developing DKA and earlier onset ICI-T1DM, it is beneficial to screen patients for these autoantibodies prior to ICI initiation to identify those more susceptible to developing ICIDM1. It may also be beneficial to obtain a C-peptide level prior to initiation to evaluate for endogenous insulin production. Additionally, while several factors support the diagnosis of ICI-T1DM such as recent ICI use, acute DKA presentation, low C-peptide levels, and the need for exogenous insulin, there is currently no specific criteria for the formal diagnosis of ICI-T1DM. Consequently, the decision to continue an ICI remains uncertain until specific diagnostic criteria are established for healthcare providers. Presentation: 6/2/2024

Enhancement of γ-aminobutyric acid content in Huangjiu through rice bran fermentation and its impact on the volatile organic compounds

Rice bran has high glutamic acid decarboxylase (GAD) activity and can be used to enrich and produce γ-aminobutyric acid (GABA). Glutinous rice was used as raw material to brew Huangjiu by liquefaction fermentation. Rice bran extract was added at different fermentation stages, then the content of GABA and basic physicochemical properties were tested, the changes of flavor substances and volatile organic compounds (VOCs) were observed in Huangjiu. The results showed the addition of concentrated GABA-enriched rice bran extract during the post-fermentation stage significantly increases the GABA content in Huangjiu. When the amount of rice bran used is 50 g, the GABA content in the Huangjiu can reach 592.44 mg/L after fermentation. The total sugar and pH of Huangjiu fermented with rice bran extract were higher than the control group, and the total acid and non-sugar solids were lower than the control group. Electronic tongue analysis showed that the addition of rice bran extract would affect the sourness, umami and saltiness taste of Huangjiu. Gas Chromatography-Ion Mobility Spectrometry (GC-IMS) analysis of Huangjiu made by adding rice bran extract at the post-fermentation stage showed increased isoamyl acetate, 2-heptanol, and other substances in comparison with the control group. The results of the study provide a cost-effective and rapid method for increasing the GABA content in Huangjiu. It also offers a theoretical basis and scientific guidance for the production of health-oriented Huangjiu.

Glutamic acid decarboxylase immunoreactivity in the olfactory bulb of a reptile.

The objective is to determine the distribution of glutamic acid decarboxylase (GAD) in the olfactory bulb of a crocodilian, Caiman crocodilus . Avidin-biotin immunohistochemical methodology using a polyclonal antibody to GAD raised in sheep was employed. The following controls were used: substitution of the primary antibody with preimmune sheep serum at concentrations equal to that of the primary antibody; omission of the primary antibody; and omission of the primary antibody and biotinylated rabbit antisheep immunoglobulin. No GAD (+) cells were observed in the control sections. Based on cell and fiber staining, the layering and neuronal organization of the olfactory bulb in Caiman were similar to other vertebrates, including other reptiles. The following elements were GAD (+): granule cells, certain neurons in the outer plexiform layer, periglomerular neurons, and the glomeruli themselves. GAD (+) puncta were present throughout the olfactory bulb. In conclusion, these results in Caiman were similar, in part, to comparable studies in mammals and birds. Taken together, these data indicate that crocodiles not only have a similar pattern of layers that other amniotes possess but also that the immunocytochemical signatures of certain elements of the olfactory bulb are likewise shared.

Sex differences in behavior and glutamic acid decarboxylase in Long Evans rats after prolonged social isolation beginning in adolescence.

Social isolation can have long-term effects on brain development and behavior and increases the risk of developing clinical conditions, including anxiety disorders. One modulator of the stress response is gamma-aminobutyric acid, an inhibitory neurotransmitter synthesized by glutamic acid decarboxylase (GAD). This study examined sex differences in behavior and GAD expression following prolonged social isolation beginning in adolescence in Long Evans rats. Males and females were equally divided into group-housed (GH) and socially isolated conditions on Postnatal Day 28 (n = 8 per group). Beginning 5 weeks later, tests were conducted for anxietylike behaviors (open-field test and elevated plus maze), social interactions (sociability test), and spatial memory (novel object location). Sex differences in behavior were observed, with GH females showing fewer anxietylike behaviors in the open-field test and elevated plus maze and spending more time with objects (sociability task) compared to GH males. Isolation had no effect on males but increased anxiety and reduced neophilic measures in females, removing sex differences. On the sociability task, all groups spent more time with novel rats compared to objects, suggesting social interest was retained after isolation. In the hippocampus, isolation reduced GAD in both sexes, and sex differences were seen (F > M). However, no group differences in behavior were observed in the hippocampal-dependent novel object location task. Our findings suggest that prolonged social isolation beginning in adolescence is anxiogenic for female Long Evans rats. Furthermore, sex and housing impact hippocampal GABA-ergic activity, which may have important implications in the treatment of anxiety disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Comparative Ability of Various Immunosuppressants as Adjuvants on the Activity of T1D Vaccine

Background: Type 1 diabetes (T1D) is an autoimmune disorder characterised by the destruction of insulin-producing beta cells in the pancreatic islets, resulting from a breakdown in immunological tolerance. Currently, T1D treatment primarily relies on insulin replacement or immunosuppressive therapies. However, these approaches often have significant drawbacks, including adverse effects, high costs, and limited long-term efficacy. Consequently, there is a pressing need for innovative immunotherapeutic strategies capable of inducing antigen-specific tolerance and protecting beta cells from autoimmune destruction. Among the various antigens, β-cell antigens like 65 kDa glutamic acid decarboxylase (GAD65) have been explored as vaccine candidates for T1D. Despite their potential, their effectiveness in humans remains modest, necessitating the use of appropriate adjuvants to enhance the vaccine’s protective effects. Methods: In this study, we evaluated the therapeutic potential of kynurenine (KYN), dexamethasone (DXMS), tacrolimus (FK506), and aluminium hydroxide (Alum) in combination with the GAD65 phage vaccine as adjuvants. Results: Our findings demonstrate that KYN, when used in conjunction with the GAD65 vaccine, significantly enhances the vaccine’s immunosuppressive effects. Compared to dexamethasone, FK506, and Alum adjuvants, KYN more effectively reduced the incidence and delayed the onset of T1D, preserved β-cell function, and promoted the induction of regulatory T cells and antigen-specific tolerance. These results suggest that KYN combined with vaccines could offer superior preventive and therapeutic benefits for T1D compared to existing treatments. Additionally, we investigated the dose-dependent effects of the GAD65 vaccine by including a low-dose group in our study. The results indicated that reducing the vaccine dose below 1010 plaque-forming units (pfu) did not confer any protective advantage or therapeutic benefit in combination with KYN. This finding underscores that 1010 pfu is the minimum effective dose for the GAD65 vaccine in achieving a protective response. In conclusion, KYN shows considerable promise as an adjuvant for the GAD65 vaccine in T1D therapy, potentially offering a more effective and durable treatment option than current immunosuppressive strategies.

General population screening for type 1 diabetes using islet autoantibodies at the preschool vaccination visit: a proof-of-concept study (the T1Early study)

ObjectiveType 1 diabetes (T1D) screening programmes testing islet autoantibodies (IAbs) in childhood can reduce life-threatening diabetic ketoacidosis. General population screening is required to detect the majority of children with T1D,...