Positive Glutamic Acid Decarboxylase Research Articles

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

Link Between Autoimmunity and Epilepsy: Neuronal Autoantibodies

Introduction: Autoimmune epilepsy remains under-recognized, and its true incidence remains uncertain. Objective: This study aimed to determine the prevalence of neuronal autoantibodies in patients with epilepsy of unknown etiology. Materials and Methods: An observational, longitudinal, prospective, and analytical study was conducted to assess the presence of autoantibodies associated with autoimmune encephalitis, glutamic acid decarboxylase-65 (GAD65), and onconeural antibodies in the serum and cerebrospinal fluid of consecutive patients with epilepsy of unknown etiology. Results: Sixty patients and 80 controls (30 healthy individuals, 30 with multiple sclerosis, 10 with systemic lupus erythematosus, and 10 with Sjögren's syndrome) were included to detect neuronal antibodies. Among epilepsy patients, 28 out of 60 (47%) tested positive for antibodies against N-methyl-D-aspartate receptor (NMDAR), contactin-associated protein 2 (CASPR2), leucine-rich glioma-inactivated 1 (LGI1), and glutamic acid decarboxylase (GAD), which was significantly higher (p < 0.001) than in the combined control cohort. No onconeural antibodies were detected in epilepsy patients except for 6 cases of epilepsy, 1 case of multiple sclerosis, and 3 cases of lupus with positive GAD by immunofluorescence assay and immunoblotting. There was no significant difference in antibody incidence between male and female epilepsy patients. The incidence of positive autoantibodies was significantly higher in patients with focal epilepsy compared to those with generalized epilepsy (p < 0.01). Conclusions: The findings indicate the presence of antibodies against NMDAR, VGKC-associated proteins (LGI1, CASPR2), and intracellular antigens (GAD65) in the serum and cerebrospinal fluid of patients with epilepsy, suggesting an autoimmune etiology. These results underscore the need for further research to elucidate the role of autoantibodies in epilepsy pathogenesis and to explore immunotherapeutic interventions.

THU296 Effect Of Tirzepatide In GADA-positive Individuals With T2D: A Post Hoc Analysis Of The SURPASS 2-5 Trials

Abstract Disclosure: A.L. Peters: Advisory Board Member; Self; Abbott Diabetes Care, Eli Lilly & Company, Medscape, Novo Nordisk, Zealand. Grant Recipient; Self; Dexcom, Insulet Corporation. Stock Owner; Self; Omada Health, Teladoc. Other; Self; Abbott Diabetes Care. R. Buzzetti: Consulting Fee; Self; Sanofi, Novo Nordisk, Eli Lilly & Company. Speaker; Self; AstraZeneca, Abbott Laboratories. C.J. Lee: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. I. Pavo: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. M. Liu: Other; Self; Eli Lilly & Company. J.S. Paik: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. Tirzepatide, a novel once weekly GIP and GLP-1 receptor agonist, is approved for treatment of type 2 diabetes (T2D). People with T2D and positive glutamic acid decarboxylase autoantibodies (GADA), which is also referred to as latent autoimmune diabetes in adults (LADA), may often remain undetected and may be associated with more rapid progression to insulin therapy. The diagnosis is primarily made by the presence of GADA in patients previously diagnosed with T2D. The aim of this post hoc analysis was to evaluate the effect of tirzepatide on hemoglobin A1c (HbA1c) levels in people with T2D who were GADA-positive versus GADA-negative from the Phase 3 SURPASS clinical trial program. Tirzepatide-treated patients from SURPASS 2-5 studies were included in this analysis. Patients who had GADA concentrations ≥5 IU/mL were categorized as GADA-positive (ELISA, RSR Ltd., Cardiff, UK). Change from baseline in HbA1c at 40/42 weeks was assessed in GADA-positive vs GADA-negative patients using mixed model repeated measures from the efficacy analysis set, adjusting for baseline covariates including study, sex, HbA1c, and body mass index (BMI). All randomized patients who took at least one dose of study drug, excluding patients who discontinued study drug due to inadvertent enrollment and excluding data after initiation of rescue medication or premature discontinuation of study drug, were included in this analysis. Of the 3827 tirzepatide-treated patients who were tested for GADA, 3671 (95.9%) were GADA-negative, 120 (3.2%) were GADA-positive, and 36 (0.9%) were “no GADA status”. Baseline parameters were similar between the groups, except for baseline BMI and serum triglyceride concentration which were slightly lower in GADA-positive patients compared to GADA-negative patients (mean baseline BMI [SD] 32.2 [6.1] vs 33.6 [6.3] kg/m2, mean triglycerides 169.2 [101.3] vs 188.1 [131.4] mg/dL). At 40/42 weeks, both groups achieved significant reductions in HbA1c (-2.11% vs -2.32%; p<0.001 for both groups) and body weight (-9.2 kg vs -9.6 kg; p<0.001 for both groups), for GADA-positive vs. GADA-negative patients, respectively. Reductions in HbA1c were slightly greater in GADA-negative patients (estimated treatment differences [95% confidence interval]: 0.21% [0.03, 0.39]; p=0.024), whereas reductions in body weight did not significantly differ between groups (0.38 kg [-0.99, 1.75]; p=0.588). These data demonstrate that tirzepatide was effective in reducing HbA1c and body weight, irrespective of GADA status in adults with T2D, thus suggesting that tirzepatide may be effective to improve glycemic control in GADA-positive individuals. Future studies could help elucidate the long-term impact of GADA positivity on the progression of diabetes. Presentation: Thursday, June 15, 2023

Real-world adherence to toxicity management guidelines for immune checkpoint inhibitor-induced diabetes mellitus.

Immune checkpoint inhibitors(ICIs) have improved survival and are increasingly used for cancer. However, ICIs use may be limited by immune-related adverse events (irAEs), such as ICI-induced diabetes mellitus(ICI-DM). The objective of the present study was to characterize ICI-DM patients and real-world adherence to guidelines. The present study was a retrospective review of electronic records of ICI-DM patients at the First Affiliated Hospital of Nanjing Medical University between July 2018 and October 2022. 34.8% (8/23)patients monitored blood glucose in every treatment cycle. The proportion of patients with severe diabetic ketoacidosis(DKA) was lower in the tight glycemic monitoring group than the non-tight glycemic monitoring group (16.7% vs. 55.6%, p = 0.049). 78.3%(18/23) patients with hyperglycemia visited a non-endocrinologist first, but 95.7% of patients were then referred to an endocrinologist. Twenty patients were tested for distinguishing the etiology of hyperglycemia and 20% patients with positive glutamic acid decarboxylase antibody(GADA), 55% with C-peptide <3.33pmol/L. High screening rates for other ICI-induced endocrinopathies were observed and half of the patients with ICI-DM developed other endocrine gland irAEs, with the most common being thyroiditis. Moreover, five patients developed non-endocrine serious adverse events(SAEs). Twelve (52.2%) patients were withdrawn from ICI due to ICI-DM. The time to progression of tumor in ICI-DM patients in the continue and interruption group was longer than in the withdrawal group (333.5 ± 82.5 days vs. 183.1 ± 62.4 days, p = 0.161). Only 17.4% of ICI-DM patients were completely managed according to guidelines. Thus, the present study proposed a screening, diagnosis, and management algorithm for ICI-DM in real-world practice. The present study reported the largest number of ICI-DM cases described in a single institute, providing insight into real-world ICI-DM management guideline adherence and highlighting the clinical challenges in ICI-DM management.

A PATIENT WITH ADDISON’S AND GRAVES’ DISEASE AS MANIFESTATION OF AUTOIMMUNE POLYGLANDULAR SYNDROME TYPE 2

Addison's disease is a rare disease caused by insufficient production of glucocorticoids, mineralocorticoids, and androgens in the adrenal cortex. It occurs more frequently in women and develops most often between the ages of 30 and 50. About two-thirds of patients with Addison's disease may develop other autoimmune disorders in the context of autoimmune polyglandular syndrome (APS), including autoimmune thyroid disease (ATD), autoimmune gastritis, type 1 diabetes, premature ovarian failure (POF), vitiligo, or celiac disease. We reported a case of 51-year-old woman with complaints of weakness, nausea, vomiting, weight loss, frequent bowel movements, and hyperpigmentation. Laboratory examinations showed decreased level of morning cortisol, increased ACTH, increased FT4, decreased TSH, increased thyrotropin receptor antibody (TRab), and positive glutamic acid decarboxylase (GAD) 65. Patient was diagnosed with Addison's disease accompanied by autoimmune thyroid disease-causing' disease and type 1 diabetes mellitus, leading to autoimmune polyglandular syndrome (APS) type 2. After being given steroid, insulin, and anti-thyroid drugs therapy, the patient's condition improved.

Elevated IL-6 plasma levels are associated with GAD antibodies-associated autoimmune epilepsy.

Antibodies against glutamic acid decarboxylase (GADA) are present in multiple neurological manifestations, such as stiff-person syndrome, cerebellar ataxia, limbic encephalitis, and epilepsy. Increasing data support the clinical significance of GADA as an autoimmune etiology of epilepsy, however, there is not yet definitive evidence to confirm the pathogenic link between GADA and epilepsy. Interleukin-6 (IL-6), a pro-convulsive and neurotoxic cytokine, and interleukin-10 (IL-10), an anti-inflammatory and neuroprotective cytokine, are crucial inflammatory mediators in the brain. Increased production of IL-6 and its association with epileptic disease profiles are well established, suggesting the presence of chronic systemic inflammation in epilepsy. Therefore, in this study, we investigated the association of plasma cytokine concentrations of IL-6 and IL-10 and their ratio with GADA in patients with drug-resistant epilepsy. Interleukin-6 and IL-10 concentrations were measured by ELISA in plasma, and the IL-6/IL-10 ratio was calculated in a cross-sectional cohort of 247 patients with epilepsy who had their GADA titers measured previously for their clinical significance in epilepsy. Based on GADA titers, patients were grouped as GADA negative (n = 238), GADA low positive (antibody titers < 1,000 RU/mL, n = 5), and GADA high positive (antibody titers ≥ 1,000 RU/mL, n = 4). Median IL-6 concentrations were significantly higher in patients with high GADA positivity [2.86 pg/mL, interquartile range (IQR) = 1.90-5.34 pg/mL] than in GADA-negative patients [1.18 pg/mL, interquartile range (IQR) = 0.54-2.32 pg/mL; p = 0.039]. Similarly, IL-10 concentrations were also higher in GADA high-positive patients [1.45 pg/mL, interquartile range (IQR) = 0.53-14.32 pg/mL] than in GADA-negative patients [0.50 pg/mL, interquartile range (IQR) = 0.24-1.00 pg/mL], however, the difference was not statistically significant (p = 0.110). Neither IL-6 nor IL-10 concentrations were different between GADA-negative and GADA low-positive patients (p > 0.05) or between GADA low-positive or GADA high-positive patients (p > 0.05). The IL-6/IL-10 ratio was also similar among all the study groups. Increased circulatory concentrations of IL-6 are associated with high GADA titers in patients with epilepsy. These data provide additional pathophysiological significance of IL-6 and help to further describe the immune mechanisms involved in the pathogenesis of GADA-associated autoimmune epilepsy.

A Sharp Rise in Autoimmune Encephalitis in the COVID-19 Era: A Case Series.

Autoimmune encephalitis was very rare prior to the current pandemic. A sharp rise in cases has been observed from March to August of 2022 in Los Angeles. Such an increase, especially with certain types of antibodies, may point toward the possibility of post-infectious autoimmune encephalitis. While review articles on autoimmune encephalitisduring this pandemic have been published, a sharp rise in one geographic area within a short period of time has not been documentedyet. To report an alarming increase in autoimmune encephalitis with mostly positive glutamic acid decarboxylase (GAD) and/or voltage-gated potassium channel (VGKC) antibodies over six months during 2022 in Downtown Los Angeles. This is an observational case series from one neurocritical care practice in Downtown Los Angeles. Autoimmune encephalitis antibody panels were sent to patients with altered mental status or neurologic deficits of unclear etiology from March to August of 2022. Of the 29 patients tested, 12 reports came back positive. Ten had positive GAD and/or VGKC antibodies, one had a positive myelin oligodendrocyte glycoprotein antibody, and one had a positive leucine-richglioma-inactivated 1 protein antibody; a 41% positive rate. This observation has important implications: (1) We may be entering an era of heightened autoimmune encephalitis. (2) These occurrences may be post-infectious in nature at this point of the pandemic. (3) Mostly GAD and VGKC antibodies have been identified (10 of them), which may point toward a new direction of research from a molecular mimicry standpoint. (4) To benefit patients, clinicians need to be aware of such disease manifestations and increase testing; resources must be increased to improve test availability and shorten turnaround time; and treatment, which is expansive, must be made widely available for these potentially reversible diseases.

New-Onset Type 1 Diabetes Mellitus (T1DM) in a Pediatric Patient with Beckwith-Wiedemann Syndrome

Abstract Introduction Beckwith-Wiedemann Syndrome (BWS) is the most common overgrowth syndrome with up to 50% of infants found to have hypoglycemia which has been believed to be related to hyperinsulinemia. However, our case report highlights a patient with the unusual presentation of concurrent BWS and T1DM along with the discussion of genetic factors that may contribute to the pathogenesis. Clinical Case We present the case of a 4-year-old African American female with a past medical history of BWS, twin gestation, prematurity, omphalocele, and patent ductus arteriosus. Her BWS had been diagnosed at birth via genetic testing which found a loss of methylation on the maternal chromosome at imprinting center 2 (IC2) on chromosome 11. During her newborn period, she did not have hypoglycemia. She presented to her primary care physician with a 2.4-kilogram weight loss, new-onset headaches, polyuria, and polydipsia for three months. She also had a viral upper respiratory tract infection a month prior to presentation. Her twin sister did not have similar complaints. Her physical exam including vital signs was reassuring. With the concern for diabetes, further work-up was done which showed an elevated serum glucose level of 681 mg/dL, and hemoglobin A1C of 12.4%. She was admitted for new-onset diabetes. Further labs on admission also showed elevated transglutaminase IgG and positive glutamic acid decarboxylase 65 (GAD65) antibody (level: 444 nmol/L, normal: ≤0.02 nmol/L). Notably, no acidosis was detected in the initial investigations and, unfortunately, due to laboratory error the diabetes antibody panel was cancelled. She was started on a basal-bolus insulin regimen with the diagnosis of new-onset T1DM without ketoacidosis. BWS does not have T1DM as a known characteristic. Hypoglycemia secondary to hyperinsulinemia rather than the opposite, such as our case, is associated with BWS. Due to this, our case is rare, and we found a case report from Europe describing a similar phenomenon. Our patient had a GAD65 antibody being positive which explains having T1DM although there are no studies showing the association of BWS with a positive GAD65 antibody. Our patient also had a viral infection prior to the diagnosis of T1DM which may have triggered autoimmunity. Further, IC2 loss of methylation present in our patient regulates the expression of CDKN1C which has been previously reported to be associated with diabetes. Conclusion Further studies will be required to identify the possible case of T1DM in a patient with BWS. We plan on obtaining a diabetes antibody panel to further assess the genetics of our patient.

A case of Type 1 Diabetes Mellitus with Klinefelter’s Syndrome

Type 1 diabetes mellitus (T1DM) is a model of chronic autoimmune disease beginning with genetic susceptibility in affected individuals and progressing to autoimmune destruction of β cells, precipitated by environmental insult. Some of the patients with T1DM have associated genetic disorders, such as Klinefelter’s syndrome (KS), Down’s syndrome and Turner’s syndrome. This paper reports a case of T1DM accompanied by KS. The patient was a 14-year-old male who had been confirmed by absolute insulin deficiency and positive glutamic acid decarboxylase antibody (GADA). After chromosome analysis was performed because of the delay in his puberty, he was diagnosed with Klinefelter’s syndrome, 47 XXY karyotype, at his follow-up.

PSUN269 Suboptimal Sulfonylurea Therapeutic Response in a Patient with MODY-3 with a Rare HNF1A Pathogenic Genetic Variant

Abstract Maturity-onset diabetes of the young (MODY) is a rare non-autoimmune type of diabetes, seen in 1-6% of patients with diabetes, caused by a single gene variant defect that ultimately impairs pancreatic b-cell insulin secretion. MODY-3, caused by mutations in HNF1A gene, accounts for most MODY cases. Misdiagnosis of MODY as type 1 diabetes (T1DM) or young-onset type 2 diabetes (T2DM) due to their overlapping features is common, leading to suboptimal pharmacologic management. When pharmacologic therapy is indicated, patients with MODY-3 typically present an excellent response to sulfonylurea monotherapy. We describe a case of a young adult woman diagnosed with MODY-3, previously treated as T1DM, with an atypical suboptimal response to sulfonylurea therapy possibly attributed to a rare HNF1A pathogenic genetic variant. A 24-year-old female with a BMI of 21, diagnosed with diabetes at age 13 managed as T1DM on insulin, underwent genetic analysis at age 23 after her 14-year-old sister was found to have MODY-3. DNA sequencing revealed heterozygous HNF1A gene with pathogenic variant c.365A&amp;gt;G (p.Tyr122Cys). Sulfonylurea therapy was initiated with the goal to lower the insulin regimen. Additional workup revealed a new HbA1C 12%, new-onset microalbuminuria, positive glutamic acid decarboxylase (GAD) antibody (0.22 nmol/L), negative islet cell antibody, and zinc transporter-8 antibody (ZnT8), in addition to normal C-peptide level of 1.5ng/mL. Upon follow-up visit, sulfonylurea dose was doubled, and basal and pre-prandial insulin were lowered and discontinued, respectively. Although the HbA1C improved to 9.8%, the patient admitted to self-resuming previous basal and pre-prandial insulin regimen after consistently having hyperglycemia 300 mg/dL when following last pharmacologic adjustments. MODY usually has autosomal-dominant inheritance although de novo mutations can occur. The molecular diagnosis aims at tailoring the choice of the most appropriate treatment to improve blood glucose control, reduce the risk of hypoglycemia, and prevent long-term micro and macrovascular complications. Typically, patients with MODY-3 are highly sensitive to monotherapy with sulfonylureas especially when shorter diabetes duration, lower BMI, and lower HbA1C are present at the time of genetic diagnosis. Although our patient's HbA1C level improved once sulfonylurea therapy was initiated, HbA1C remains above the goal level and discontinuation of insulin regimen has not been able to be achieved despite increasing sulfonylurea dose. Similar cases of MODY-3 with atypical sulfonylurea therapeutic response have been reported and attributed to the presence of novel HNF1A genetic variants. Moreover, studies have predicted that about 50% of MODY-3 patients require insulin therapy as the disease progresses. Nonetheless, more research is needed to elucidate possible additional contributing factors to a suboptimal sulfonylurea therapeutic response in MODY-3 cases. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

PSUN92 Type 1 Diabetes and Obesity: The Overlooked Epidemic

Abstract Introduction The type 1 diabetes (T1D) cohort in the DCCT study (1983-1989) began with a 1.3% prevalence of obesity that climbed to 18.6% with intensive insulin therapy, and subsequently increased further to a prevalence of 31% in the EDIC observational study (2005).1, 2 The aim of this report was determine the prevalence of overweight and obesity in T1D patients seen at our institution. Methods The electronic health record system was used to create a cross-sectional summary of patients with T1D seen on or before the index date (8/12/2021). Patients were included if they were ≥18 years of age, with at least two outpatient encounters with primary care provider or endocrinologist within the past 18 months, along with an active diagnosis of T1D (ICD-9 or -10 code) on their problem list, or at least 2 encounter diagnosis for T1D in the past 18 months, or documentation of a positive glutamic acid decarboxylase (GAD)-65 antibody titer. Categorical and continuous variables were summarized using N (%) and median (IQR), respectively. Results A total of 2,165 patients were identified. The population was 51% female and 86% Caucasian, with median age of 44 years (33, 55). The median A1C (%) was 7.9% (6.9, 9.4), median income $63,381 ($49,611, $78,367), and insurance coverage was 50% commercial, 11% Medicaid, 23% Medicare, and 16% other. While the median BMI (kg/m2) was 26.7 (23.6, 30.5), the % with a BMI 25-29.9 or ≥30 were 37% and 28%, respectively. Conclusion There is a high prevalence of overweight and obesity in patients with T1D. While the prevalence of these comorbidities is less than what is observed in the general population, 31.1 and 42.4%, respectively (2017–2018)3, it signifies that the T1D population still has a heavy burden of these comorbidities that is contradictive to the stereotype T1D patients are lean. These results stand in stark comparison with the starting 1.3% prevalence of obesity in the DCCT study. Studies directed at the burden of overweight and obesity in T1D patients are necessary to optimize the treatment and prevention of these comorbidities. Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14): 977–986. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005 Dec 22;353(25): 2643-53. doi: 10.1056/NEJMoa052187. PMID: 16371630; PMCID: PMC2637991. Centers for Disease Control and Prevention. Obesity and Overweight. https://www.cdc.gov/nchs/fastats/obesity-overweight.htm. Last visited 1/12/2022. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP260 New Type of Autoimmune Diabetes

Abstract Immune checkpoint inhibitors (ICIs) are an emerging therapy that has revolutionized the management of certain cancers. Data on long-term side effects of these drugs are now showing a risk for development of new endocrinopathies. In this case report, a patient with new Type I diabetes (DMI) is discussed. The patient is a 67 year old male with past medical history of metastatic renal cell carcinoma with multiple recurrences of disease. A brief review of the patient's oncologic history revealed multiple surgeries, including complete nephrectomy, multiple drugs, including ICIs, and radiation therapy. Over the course of his treatment, he received Nivolumab (anti-PD1 agent) for 5 cycles with HbA1c increased from 5.4% to 6.9% from pre-treatment to post-treatment, but the HbA1c improved to 5.8% one year after drug cessation. Later he was started on Pembrolizumab (anti-PD1) and has had 10 cycles of therapy to date. Random blood glucose frequently exceeded 200 after start of pembrolizumab therapy. Ipilimumab (anti CTLA-4) was started in combination with pembrolizumab six months later, but it was held after the second cycle due to development of diabetes with HbA1c of 11.1%. He was also found to have persistent, severe hyperglycemia noted during routine bloodwork. Autoimmune DM was confirmed with a positive glutamic acid decarboxylase antibody (GAD65) of 8 nmol/L. Consequently, the patient had multiple hospital admissions for glucose exceeding 400. His condition was exacerbated by the fact that he had difficulty coming to terms with his diagnosis, and he was noncompliant with medication. At that time, the patient stated that he had not done anything wrong and did not understand why this had happened to him. He was resistant to starting therapy and had difficulty understanding insulin dosing, blood glucose monitoring, and the consequences of hyperglycemia/hypoglycemia. After extensive education during a 2 week hospitalization, the patient was eventually place on an appropriate dose of basal-bolus insulin therapy and is currently doing well. It is important to note some emerging challenges to treating this new population of patients with DM1 due to ICI therapy. Firstly, many patients in this scenario live alone and have poor support systems. They have difficulty learning new technology (glucometer, insulin pen, etc.) and self adjusting medication (sliding scale). Older patients can also be more resistance to change in diet and lifestyle. They may have pre-existing insulin resistance that makes initial insulin dosage difficult. Finally, noncompliance is dangerous due to risk of hypoglycemia, diabetic ketoacidosis, and exacerbation of other comorbidities. Clinicians should also consider the patient's psychosocial ability to understand and manage this condition. Presentation: No date and time listed

Clinical characteristics and outcomes of immune checkpoint inhibitor-induced diabetes mellitus

ObjectiveTo better understand immune checkpoint inhibitor (ICI)-induced diabetes mellitus (DM) in cancer patients. Design and methodWe present a case of ICI-induced diabetic ketoacidosis (DKA) and conduct a systematic review of the PubMed and Web of Science databases up to September 2021 to identify all published cases of ICI-induced diabetes. ResultsIn addition to our case, a total of 171 published cases were identified during the literature search. Summary and statistical analyzes were conducted for all 172 cases. The median onset time from ICI initiation to DM diagnosis was 12 weeks (range: 0–122). DKA was present in 67.4% (116/172) of the cases, and low C-peptide levels were detected in 91.8% (123/134), indicating an acute onset of diabetes. Patients with positive glutamic acid decarboxylase antibodies (GADA) had an earlier onset of ICI-induced diabetes (median time 7 weeks vs. 16 weeks for GADA-negative patients, p < 0.001) and a higher frequency of DKA development (82.8 vs. 62.1%, p = 0.006). All but two patients developed insulin-dependent diabetes permanently. Immunotherapy rechallenge was reported in 53 cases after glycemia was well controlled. ConclusionICI-induced DM is a serious adverse event that often presents with life-threatening ketoacidosis. GADA positivity is related to an earlier onset of ICI-induced diabetes and a higher frequency of DKA development. Close monitoring of glucose levels is needed in patients receiving ICI treatment. ICI-induced DM is usually insulin-dependent since damage to β cells is irreversible. On the premise of well-controlled glycemia, immunotherapy rechallenge is feasible.

The coexistence of autoimmune diabetes and maturity-onset diabetes of the young (MODY): a case series.

SummaryThe coexistence of autoimmune diabetes and maturity-onset diabetes (MODY) is rare. The absence of pancreatic autoantibodies is a key factor prompting MODY genetic testing. In this study, we report three cases of young-onset diabetes with progressive beta-cell dysfunction, strongly positive glutamic acid decarboxylase (GAD) antibodies, and genetic confirmation of pathogenic gene variants of HNF-1A, HNF-4A, and ABCC8-MODY. The first case is a woman diagnosed with HNF-1A-MODY diabetes more than 30 years after her diagnosis of adult-onset diabetes at 25 years. She required insulin after her fourth pregnancy. She became ketotic on oral hypoglycaemic agents (OHAs) and subsequently, her GAD antibodies tested positive. The second case is a woman diagnosed with diabetes at 17 years who was subsequently diagnosed with HNF-4A-MODY after many hypoglycaemic episodes on low-dose insulin. GAD antibodies were strongly positive. The last case is a man diagnosed with diabetes at 26 years who was well controlled on OHAs and required insulin years later due to sudden deterioration in glycaemic control. His ABCC8-MODY was diagnosed upon realisation of strong family history and his GAD antibodies tested positive. All subjects are now treated with insulin. Less than 1% of subjects with MODY have positive autoantibodies. These cases highlight individuals who may have two different types of diabetes simultaneously or consecutively. Deterioration of glycaemic control in subjects with MODY diabetes should highlight the need to look for the emergence of autoantibodies. At each clinic visit, one should update the family history as MODY was diagnosed in each case after the development of diabetes in their offspring.Learning pointsThese cases highlight the rare coexistence of autoimmune diabetes and MODY.Deterioration of glycaemic control in subjects with MODY diabetes should highlight the emergence of autoantibodies.One should revise and update the family history as the diagnosis of MODY was made after the development of diabetes in offspring.Understanding the spectrum of diabetes allows for precision medicine.

Predictors of associated and multiple autoimmunity in children and adolescents with type 1 diabetes mellitus.

PurposeType 1 diabetes mellitus (T1DM) is an autoimmune condition characterised by the presence of antipancreatic antibodies. The autoimmune process is also directed against other organs, most frequently against the thyroid gland, intestinal mucosa, and gastric parietal cells.MethodsOur investigation included 121 children with T1DM with a mean age±standard deviation of 11.99±4.63 years (range, 2.0–20.0 years). We explored the frequency of associated autoimmunity; the presence of predictive factors such as current age, sex, and severity at diabetes diagnosis; T1DM duration; and family history of autoimmunity.ResultsAssociated autoimmunity was present in 28.9% of T1DM patients. Children with associated autoimmunity were older at diabetes diagnosis (P=0.009) and had a longer diabetes duration compared to children without associated autoimmunity (P=0.044). Adolescents aged 12–20 years had a statistically significant higher chance of developing thyroid autoimmunity compared to children aged 1–5 years (P=0.019). Multiple autoimmunity (MA), T1DM, and 2 or more autoimmune diseases were present in 5.8% of the study population. All children with MA presented with ketoacidosis at diabetes diagnosis and had a higher percentage of familial autoimmunity (P=0.042). The familial autoimmunity of these patients most frequently affected ≥3 relatives (P=0.026) and was more frequently diagnosed before 5 years of age (P=not significant).ConclusionsAssociated autoimmunity was present in almost one-third of T1DM patients. Significant associations with associated autoimmunity were longer diabetes duration, female sex, older age at diabetes diagnosis, and glutamic acid decarboxylase positivity. Predictors of MA were age <5 years at T1DM diagnosis, the presence of diabetic ketoacidosis at diagnosis, and a significant family history of autoimmunity.

CONSIDERATIONS FOR SODIUM-GLUCOSE TRANSPORTER 2 INHIBITOR THERAPY RESULTING IN EUGLYCEMIC DIABETIC KETOACIDOSIS

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Sodium-glucose transporter 2 inhibitors (SGLT2i) have recently become an increasingly popular treatment choice for type 2 diabetics. A rare complication of SGLT2i use is euglycemic diabetic ketoacidosis (EDKA), during which life threatening severe metabolic acidosis and ketonemia arises in the setting of glucose levels of <250 mg/dL. CASE PRESENTATION: A 40-year-old male with a history of presumed type 2 diabetes mellitus (DM-2) which was diagnosed six years prior was transferred to our intensive care unit with persistent diabetic ketoacidosis (DKA). Past medical history was positive for prior episodes of DKA. His diabetic medications included glimepiride, dapagliflozin, metformin, and degludec insulin. He presented with a one day history of vomiting and polydipsia. Despite five liters of intravenous (IV) fluids, IV bicarbonate, and IV insulin, he persisted with a high anion gap metabolic acidosis (HAGMA). Lab work revealed an anion gap of 32, an osmolar gap of 26 with a normal lactic acid, and blood glucose of 148 mg/dL [Figure 1]. Arterial blood gas (ABG) revealed a pH of 7.046 and bicarbonate of 3.2. He was treated with an IV bicarbonate drip, IV insulin drip, and high volume IV fluids. He also underwent monitoring with serial ABGs, frequent blood glucose checks, and basic metabolic panels. The HAGMA gradually resolved over the next 48 hours. Additional serology revealed a positive glutamic acid decarboxylase (GAD) antibody; indicative of latent autoimmune DM in adults (LADA). After improvement his glimepiride, dapagliflozin, and metformin were discontinued. He was ultimately transitioned from an IV insulin drip to a basal/bolus insulin regimen at discharge. DISCUSSION: SGLT2i medications enhance excretion and block reabsorption of filtered glucose from the proximal convoluted tubule, resulting in a state of glucose starvation thereby increasing the glucagon/insulin ratio [1]. The HAGMA seen in EDKA is thought to result from increased lipolysis due to the glucagon/insulin imbalance, ultimately leading to ketoacidosis [2]. The mechanism of ketone production in EDKA is similar to DKA; acetoacetic acid reduces to beta-hydroxybutyric acid [2]. EDKA is a rare but known complication in type 2 diabetics who are prescribed SGLT2i therapies. Use of SGLT2i is not recommended in those with autoimmune diabetes by the Food and Drug Administration as ketone-associated complications can be as high as 9% [3]. LADA is an anti-islet cell autoimmune adult-onset DM. In our patient, he was initially misdiagnosed with DM-2; however, his blood work revealed that he had LADA. CONCLUSIONS: As SGLT2i usage becomes increasingly more common, providers should be cognizant of the patient's diabetic history and ensure the correct etiology of their patient's diabetes. Additionally, critical care providers should remain vigilant of the phenomenon of EDKA and its predisposing risk factors. REFERENCE #1: Pfützner A, Klonoff D, Heinemann L, Ejskjaer N, Pickup J. Euglycemic ketosis in patients with type 2 diabetes on SGLT2-inhibitor therapy-an emerging problem and solutions offered by diabetes technology. Endocrine. 2017 Apr;56(1):212-216. doi: 10.1007/s12020-017-1264-y. Epub 2017 Mar 17. PMID: 28303514. REFERENCE #2: Plewa MC, Bryant M, King-Thiele R. Euglycemic Diabetic Ketoacidosis. 2021 Feb 3. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 32119457. REFERENCE #3: Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015 Sep;38(9):1687-93. doi: 10.2337/dc15-0843. Epub 2015 Jun 15. PMID: 26078479; PMCID: PMC4542270. DISCLOSURES: No relevant relationships by Jonathan Ross Ang, source=Web Response No relevant relationships by Parth Patel, source=Web Response No relevant relationships by Tarang Patel, source=Web Response No relevant relationships by Shaili Patel, source=Web Response No relevant relationships by SACHIN PATIL, source=Web Response

194-LB: Case of Pembrolizumab-Induced Type 1 Diabetes Mellitus

Immune checkpoint inhibitors, anti-PD1 and anti-CTLA-4, have become widely utilized and proven effective in treating various forms of cancer. Although the discovery of immunotherapy has been a major advancement in the field of oncology, a series of endocrinopathies have been described and research is still ongoing. We would like to report a case of diabetes mellitus with positive glutamic acid decarboxylase (GAD) antibodies secondary to pembrolizumab therapy for locally advanced Merkle Cell Carcinoma. A 70-year-old male with no history of diabetes presented to the ER with severe hyperglycemia after his fifth cycle of pembrolizumab. His labs revealed a blood glucose of 659 mg/dL, an A1c of 8.5%, creatinine of 1.45 mg/dL, and urine negative for ketones. He demonstrated elevated anti-GAD antibodies (&amp;gt;250 IU/mL), suggesting type 1 diabetes. The patient was started on both long acting insulin glargine and prandial short acting insulin with improved glycemic control. The first case reports of pembrolizumab induced diabetes and diabetic ketoacidosis were published in 2015. During the initial clinical trials, only 0.1% of patients using pembrolizumab developed type 1 DM, but a review of current literature suggests that it has become more prevalent with rates as high as 2%. The rise in cases has also demonstrated that the majority of immunotherapy induced diabetes results primarily in patients receiving anti-PD1 therapy. A study done on mice demonstrated PD-L1 expression in inflamed pancreatic beta cells of mice that had developed diabetes. These results suggest that pembrolizumab causes destruction of insulin producing cells, releasing intracellular proteins such as GAD, and triggering the immune system to create autoantibodies. This emphasizes the need for further studies investigating the relationship between immunotherapy and autoimmune diabetes. In addition, it is essential that clinicians become aware and remain vigilant of this potentially life-threatening complication. Disclosure S. Spyropoulos: None. A. Manessis: Advisory Panel; Self; Medtronic, Research Support; Self; IQVIA, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., MannKind Corporation, Sanofi US.

Checkpoint Inhibitor-Associated Autoimmune Diabetes Mellitus: A Case Report

Introduction: Checkpoint Inhibitors have revolutionized the management in oncology by stimulating the immunological response to cancer. On the contrary, there is an increase in immune-related adverse effects affecting various systems including the endocrine. We report a unique case of new-onset diabetes with diabetic ketoacidosis (DKA) within 18 days of receiving checkpoint inhibitors for Merkel Cell Carcinoma.Clinical Case: An 86-year-old man diagnosed with locally advanced Merkel cell carcinoma underwent surgery and radiotherapy to his right face and neck. Four months later, the positron emission tomography (PET) scan was consistent with liver metastasis. Pembrolizumab, a programmed death receptor-1 (PD-1) inhibitor was initiated as next line treatment. Prior to starting pembrolizumab, his blood glucose was 92 mg/dL (60–120) with no previous history of diabetes mellitus. He presented 18 days later to the emergency room with altered mental status, polyuria, and polydipsia with a blood glucose of 980 mg/dL, anion gap of 26 mmol/L (5–15), and was managed for DKA with new-onset Diabetes Mellitus. HbA1C was 7.0% (4–5.6). He was discharged on subcutaneous insulin glargine once daily, pre-meals insulin aspart, and was referred to the endocrinology clinic. Further investigations obtained during the clinic visit demonstrated low C-peptide of <0.7 ng/mL (0.8–6), glucose 76 mg/dL, positive glutamic acid decarboxylase (GAD-65) antibodies of >25,000 nmol/mL (<0.02), negative islet antigen-2 antibody, islet cell antibody and zinc transporter 8 antibodies. Other endocrine tests showed normal thyroid function, cortisol, and adrenocorticotrophic hormone (ACTH) levels. The patient was educated on checkpoint inhibitor-associated autoimmune diabetes and the need for a lifelong insulin regimen.Clinical Lesson: Our case highlights the immune-related adverse effect involving the endocrine system from checkpoint inhibitor therapy. In comparison to the other common endocrinopathies associated with checkpoint inhibitors, autoimmune diabetes is rare (~ 1–2% incidence) and only less than half demonstrate antibodies with a median time of 8 weeks since exposure. GAD-65 antibodies are the commonest antibody noted and our patient had a robust GAD-65 antibody of >25,000 depleting C-peptide within 18 days of receiving the Pembrolizumab resulting in DKA with a new onset of diabetes.We conclude that diabetes mellitus is a rare but serious adverse effect of immune checkpoint inhibitor therapy. Society for Immunotherapy of Cancer Toxicity Management Working Group consensus recommendations from 2017 recommends routine screening to include baseline HbA1c, basic metabolic panel, thyroid function test, AM cortisol, and ACTH prior to treatment. It also recommends repeating the thyroid function test and basic metabolic panel to allow the monitoring of glycemic trends before each cycle.

Development of autoimmune diabetes with severe diabetic ketoacidosis and immune-related thyroiditis secondary to durvalumab: a case report

Immune-mediated endocrinopathies are among the most frequent immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) targeting programmed death-ligand 1 (PD-L1)/PD-1. However, the development of auto-immune diabetes is an uncommon event during PD(L)-1 blockade, either as monotherapy or in combination therapy. Here we report a case of a 75-year-old male with a mediastinal recurrence from a stage IA squamous cell carcinoma of the lung previously treated with stereotactic body radiotherapy (SBRT) who early developed a severe diabetic ketoacidosis (DKA) caused by new-onset auto-immune diabetes, with positive glutamic acid decarboxylase (GAD65) autoantibodies, during durvalumab consolidation therapy after concurrent chemoradiation. The patient had no personal or family history of diabetes or auto-immune diseases and was admitted after the second cycle of durvalumab to the intensive care unit (ICU) with severe DKA. During his hospitalization, insulin and fluid therapy were started and the patient had a favorable clinical course. Durvalumab treatment was interrupted and thyroiditis was verified during follow-up, without anti-thyroid antibodies, that progressed to subsequent hypothyroidism with need of thyroid hormone replacement therapy. This case highlights the rare irAE of autoimmune type 1 diabetes during anti-PD(L)-1 therapy, which can be life-threatening and requires adequate patient education and prompt medical treatment within a multidisciplinary team, including endocrinology and emergency medicine. Besides its low incidence, this case show how irAE must be taken in account about decision of ICI treatment, especially in curative setting, as they can be potentially fatal and impair overall survival. Furthermore, as reported in the present case, multiple endocrine irAEs can occur in the same patient either simultaneously or sequentially, suggesting that active surveillance is needed in those who develop endocrinopathies as a result of ICI treatment. Immune-mediated endocrinopathies are generally irreversible and cause life-long morbidity, which must be taken into consideration when deciding on further lines of treatment.

Serum brain-derived neurotrophic factor and neurocognitive function in children with type 1 diabetes

This study aimed to clarify whether brain-derived neurotrophic factor (BDNF) is a biomarker for cognitive dysfunction in children with type 1 diabetes. We conducted a cross-sectional case-control study of children aged between 6 and 18 years with type 1 diabetes and healthy volunteers. Serum BDNF level was measured in all of the studied children, and they all underwent intelligence tests with the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV). We further compared the cognitive function and BDNF levels in the diabetic children with positive glutamic acid decarboxylase 65 antibody (GAD65-Ab) and those with negative GAD65-Ab. Forty-five children with type 1 diabetes (mean age 14.0±2.6 years, 42% male) and 50 normal controls (mean age 13.2±2.3 years, 54% male) were recruited. The serum BDNF level was significantly lower in the diabetes group than in the controls (15.92±7.2 vs. 18.5±5.1ng/mL, respectively, t=-2.03, p=0.045) and much lower in the subgroup with GAD65-Ab positive type 1 diabetes. The average Full-Scale IQ, verbal comprehension, perceptual reasoning and working memory scores in the diabetes group were significantly lower than in the controls (all p<0.05). Among the children with type 1 diabetes, poor glycemic control was related to lower general cognitive abilities (r=-0.34, p<0.02), lower verbal comprehension (r=-0.305, p<0.05), and lower perceptual reasoning scores (r=-0.346, p=0.02). The children with type 1 diabetes had a lower serum BDNF level and poorer neurocognitive function than normal healthy children, especially those with GAD65-Ab positive diabetes. Poor glycemic control was correlated with worse cognitive performance.