Diabetes Autoantibodies Research Articles

1143-P: ZnT8 Autoantibody Positivity Does Not Predict Pediatric Diabetes Presentation or Subsequent Clinical Course

Introduction: Type 1 diabetes specific autoantibodies are glutamic acid decarboxylase (GAD65), protein tyrosine phosphatase-like islet antigen 2 (IA2), insulin (IAA), and Zinc transporter 8 protein (ZnT8). The aim of our study was to determine if the presence of ZnT8 antibodies(Ab) was predictive of clinical presentation at diagnosis or subsequent disease course. Methods: Between January 2003 and May 2019, 105 patients aged ≤ 21 years with a clinical diagnosis of T1DM had at least 1 diabetes autoantibody measured. For subjects who had less than 4 autoantibodies analyzed initially, residual serum sample was retrieved, and remaining autoantibodies were analyzed. Retrospective chart review was completed. At diagnosis, we evaluated BMI z-score, HbA1c, and the presence and severity of DKA. Complications recorded post diagnosis included episodes of DKA, diagnosis of autoimmune (AI) disease, and the presence of vascular complications. Results: Of the 105 patients, 71 were ZnT8(+) (68%). When comparing ZnT8Ab(+) to (-) patients at diagnosis, there was no difference in age (p=0.94), BMI z-score (p=0.83) or presence of DKA (p=0.26). There was no difference in duration of follow up between ZnT8 Ab (+) and (-) groups (p=0.54). Over follow-up, (0.05-15.7 years), there was no difference in rates of DKA episodes (p=0.71). There were no macrovascular complications recorded and no difference in microvascular complications between the 2 groups (p=0.14). There were more AI conditions in the ZnT8Ab(+) group, 77% compared to 23% in ZnT8Ab(-), but this did not reach statistical significance (p=0.12). Conclusions: Our study, unlike others, suggests that the presence of ZnT8 Ab does not result in a difference in disease course at presentation. This study adds to the literature as it has follow up on patients. Over up to 15 years of follow-up, there is no difference in complications between those with and without ZnT8 Ab’s. This study should be validated with larger numbers and longer follow up. Disclosure A. R. Dahl: None. S. Jenkins: None. J. Zbacnik: None. J. Foster: None. S. Pittock: None.

Land Cover of Early-Life Environment Modulates the Risk of Type 1 Diabetes.

OBJECTIVEEnvironmental microbial exposures have been implicated to protect against immune-mediated diseases such as type 1 diabetes. Our objective was to study the association of land cover around the early-life dwelling with the development of islet autoimmunity and type 1 diabetes to evaluate the role of environmental microbial biodiversity in the pathogenesis.RESEARCH DESIGN AND METHODSAssociation between land cover types and the future risk of type 1 diabetes was studied by analyzing land cover types classified according to Coordination of Information on the Environment (CORINE) 2012 and 2000 data around the dwelling during the first year of life for 10,681 children genotyped for disease-associated HLA-DQ alleles and monitored from birth in the Type 1 Diabetes Prediction and Prevention (DIPP) study. Land cover was compared between children who developed type 1 diabetes (n = 271) or multiple diabetes-associated islet autoantibodies (n = 384) and children without diabetes who are negative for diabetes autoantibodies.RESULTSAgricultural land cover around the home was inversely associated with diabetes risk (odds ratio 0.37, 95% CI 0.16–0.87, P = 0.02 within a distance of 1,500 m). The association was observed among children with the high-risk HLA genotype and among those living in the southernmost study region. Snow cover on the ground seemed to block the transfer of the microbial community indoors, leading to reduced bacterial richness and diversity indoors, which might explain the regional difference in the association. In survival models, an agricultural environment was associated with a decreased risk of multiple islet autoantibodies (hazard ratio [HR] 1.60, P = 0.008) and a decreased risk of progression from single to multiple autoantibody positivity (HR 2.07, P = 0.001) compared with an urban environment known to have lower environmental microbial diversity.CONCLUSIONSThe study suggests that exposure to an agricultural environment (comprising nonirrigated arable land, fruit trees and berry plantations, pastures, natural pastures, land principally occupied by agriculture with significant areas of natural vegetation, and agroforestry areas) early in life is inversely associated with the risk of type 1 diabetes. This association may be mediated by early exposure to environmental microbial diversity.

Autoimmune Diabetes After Initiation of Nivolumab in a Patient With Hepatocellular Carcinoma

Abstract Background: Immune checkpoint inhibitors have become an integral part of oncologic treatment, and their role is rapidly evolving. Nivolumab is an immune checkpoint inhibitor to anti-programmed cell death protein-1 (PD-1), which blocks PD-L1 from binding to PD-1, allowing the T cell to activate. While nivolumab has been shown to improve outcomes in certain malignancies, anti-PD-1 therapy can cause multiple endocrinopathies, including autoimmune diabetes (AD). Case: Here we present a 60-year-old male with a past medical history of end-stage liver disease secondary to hepatitis C and hepatocellular carcinoma (HCC). After undergoing transarterial chemoembolization for HCC, nivolumab was initiated. The patient initially tolerated the immunotherapy well. However, after three cycles, the patient acutely developed nausea, vomiting, lethargy and confusion. On presentation, he was afebrile, blood pressure of 85/46 mmHg, and a heart rate of 92 bpm. Exam was significant for abnormal mentation, and diffuse guarding of the abdomen. Laboratory workup showed hyperglycemia (1,178 mg/dL), positive serum ketones (beta-hydroxybutyrate 11.4 mmol/L), anion gap metabolic acidosis (AG 31, CO2 7 mmol/L), anemia, thrombocytopenia, acute kidney injury, leukocytosis, and elevated lipase. He was admitted to the intensive care unit, and further workup for acute pancreatitis was unrevealing. C-peptide was low (0.8 ng/mL) with corresponding hyperglycemia (1,055 mg/dL). GAD-65, islet cell, and insulin antibodies were undetectable. Hemoglobin A1c was 8.0%. Blood sugars from the previous one and a half years were in normal range. The patient was ultimately diagnosed with DKA and AD secondary to anti-PD-1 therapy. Discussion: This case is representative of AD secondary to nivolumab. While there have been many cases of AD reported after nivolumab, this is the fifth case that has been reported in a patient being treated for HCC. Our patient presented acutely in DKA with no prior diagnosis of diabetes. His antibody testing was undetectable, C-peptide was low in the context of hyperglycemia, and he continued to require insulin therapy until his passing. Prior case reports have demonstrated that the majority of patients with AD related to anti-PD-1 therapy present in DKA, while less than half have detectable diabetes autoantibodies. Specific haplotypes and diabetes autoantibodies have been postulated as risk factors for AD secondary to anti-PD-1 therapy. However, this does not explain the pathology behind a number of patients who have neither of these risk factors. While AD is a rare complication of nivolumab (<1%), this case identifies the need for patients and clinicians to be aware of and discuss the risk of AD after starting nivolumab. Future research is needed to identify risk factors for patients at highest risk of developing AD related to anti-PD-1 therapy and reporting every case encountered is the first step.

Alpelisib-Induced Diabetic Ketoacidosis

Introduction: Alpelisib is a alpha-specific phosphoinositide 3-kinase inhibitor (PI3K) recently approved for patients with advanced or metastatic breast cancer with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and activating mutations in the PIK3CA gene. PI3K is involved in the insulin receptor signaling pathway that leads to glucose uptake. Hyperglycemia is a frequent adverse effect of Alpisilib but diabetic ketoacidosis (DKA) is considered a rare occurrence.Case ReportA 53 year-old woman with metastatic breast cancer presented with 5 days of worsening polydipsia, fatigue, nausea, vomiting, slurred speech and altered mental status. She was started on Alpelisib 300 mg daily two weeks prior to admission and instructed to check glucose twice weekly but did not follow directions. Family history was significant for type 2 diabetes. On physical exam blood pressure was 150/90, heart rate 120 beats/minute, respiratory rate 120 breaths/minute; BMI was 27 Kg/m2. The neurological exam was significant for a lethargic state with the patient arousable to verbal stimuli. The skin exam was negative for acanthosis nigricans or skin tags. Laboratory tests showed glucose at 1425 mg/dl, bicarbonate 11 mEq/l (19–34), anion gap 39 (6–22), sodium 138 mmol/l (135–146), potassium 5.0 mmol/l (3.5–5.5), serum osmolality 378 mosm/kg (275–295), Cr 3.99 mg/dl (0.4–1.1), lactic acid 3.5 mmol/l (0.5–2.0), ketonuria and glucosuria. No arterial blood gas was performed. HbA1c was 5.9% before starting Alpelisib. Results were consistent with DKA and hyperosmolar hyperglycemic state. Additional tests showed HbA1c 10.5 %, c-peptide 1.2 ng/ml (1.1–4.4) with glucose 183 mg/dl; type 1 diabetes autoantibodies were negative. Alpesilib was held and the patient managed with insulin drip and then insulin basal/bolus regimen. Patient was discharged on basal insulin and metformin with the plan to resume alpelisib at a lower dose and monitor.ConclusionIn the SOLAR-1 trial hyperglycemia was reported in 63% of patients taking alpesilib and two cases of DKA were observed. A case of a patient who developed DKA with Alpesilib was also recently reported. The mechanism underlying DKA in these patients is unclear. PI3K inhibitors may prevent the transcription of the insulin gene in response to high concentrations of glucose and the combination of impaired peripheral glucose uptake with impaired insulin secretion trigger DKA. Further studies are needed to identify which patients on Alpelisib are at increased risk of developing DKA. Clinicians should be aware of this life threatening complication.

Hypocalcemia in a 15 Year Old With New Onset Type 2 Diabetes Mellitus

Abstract Background: Diabetic ketoacidosis and significant hyperglycemia are associated with known electrolyte derangements in sodium, potassium, and phosphorus. Hypocalcemia and hypoparathyroidism occurring in uncontrolled diabetes are rare. We present a case of new-onset diabetes with severe hypocalcemia. Case: A 15-year-old obese Caucasian male with ADHD and autism presented to the Emergency room due to hyperglycemia found on laboratory evaluation for hypertension. Serum glucose was 563 mg/dL, serum bicarbonate 24 meq/L (21 - 31 meq/L), and HgbA1C 11.4% (4.0 - 5.6%). He was admitted to initiate insulin and for diabetes education. On admission, hypocalcemia was noted: serum calcium 6.6 mg/dL (8.5 - 10.5 mg/dL), alkaline phosphatase 352 units/L (48 - 277 units/L), and albumin 4.6 g/dL (3.5 - 5.0 g/dL). Repeat testing revealed serum calcium 5.1 mg/dL, phosphorus 4.3 mg/dL (2.5 - 4.5 mg/dL), and magnesium 1.7 mg/dL (1.6 - 2.9 mg/dL). He endorsed a 2 month history of tetany, paresthesia, and muscle weakness. Due to food aversions, his dietary intake of calcium and vitamin D was minimal. He had limited sun exposure. Subsequent PTH was 40 pg/mL (10 - 65 pg/mL) with concurrent serum calcium of 6.5 mg/dL. QTc was prolonged [529 msec (<440 msec)], prompting transfer to the intensive care unit for telemetry, intravenous calcium gluconate, and regular calcium monitoring. Treatment was commenced with cholecalciferol 2000 international units daily and oral calcium carbonate (50 mg elemental calcium/kg/day) in divided doses for presumed Vitamin D deficiency. After several intravenous calcium gluconate doses over 24 hours, the patient’s QTc and ionized calcium normalized. At discharge, calcium was 8.5 mg/dL. He was discharged on the above regimen of calcium and cholecalciferol, and basal and bolus insulin. After discharge, laboratory results returned indicating negative diabetes autoantibodies (GAD 65, Insulin, IA-2) and 25-OH Vitamin D <10 ng/mL (30 - 100ng/mL). Two days after discharge, calcium was 7.3 mg/dL. Two weeks later, labs were: 25-OH Vitamin D 11.3 ng/mL, PTH 10.4 pg/mL, and calcium 9.6 mg/dL. Conclusion: This teen presented with new-onset type 2 diabetes and symptomatic hypocalcemia, an atypical feature of new-onset diabetes. This patient’s hypocalcemia was likely due to both vitamin D deficiency and hypoparathyroidism. He had a low vitamin D level and poor calcium intake with elevated alkaline phosphatase; however, his high normal serum phosphorus and inappropriately normal PTH (instead of elevated in the setting of severe hypocalcemia) indicated a component of hypoparathyroidism. Calcium normalized with detectable 25-OH Vitamin D levels but PTH remained low. Our case highlights the importance of recognizing both that electrolyte abnormalities at diabetes onset may not be directly attributable to diabetes/hyperglycemia and that vitamin D deficiency and hypoparathyroidism may co-exist.

Painless foot drop: an unusual acute presentation of new onset type 1 diabetes mellitus.

SummaryA 26-year-old Caucasian female with no past medical history or family history of auto-immune disease presented to the emergency department with new onset painless left foot drop. A panel of blood tests revealed blood glucose of 49.9 mmol/L and raised blood ketone levels. The patient was referred to the diabetes team who made a clinical diagnosis of type 1 diabetes (T1DM) and insulin treatment was initiated. Elevated levels of diabetes auto-antibodies were subsequently detected. Nerve conduction studies demonstrated a left common peroneal nerve lesion with conduction block at the fibular head. After 2 weeks of insulin treatment, a significant improvement of her foot drop was observed and after 8 weeks she was walking normally. The most probable cause of her foot drop was acute diabetic mononeuropathy. To our knowledge, there are no similar cases in adult patients reported in the literature. Our case highlights the importance of physicians being aware of atypical presentation of new onset T1DM.Learning points There is an increasing incidence of T1DM with more than half of patients presenting after the age of 20. Diabetic peripheral neuropathy can present both acutely and as a mononeuropathy. Although rare, clinicians should be aware of mononeuropathy as a presenting symptom of T1DM to avoid delay in the treatment initiation. This case highlights an unusual presentation of T1DM and illustrates the importance of the early diagnosis and management of T1DM.

Assessment of immune-alternations and their correlations with therapeutic outcomes of transplantation of autologous Mesenchymal and Allogenic fetal stem cells in patients with type 1 diabetes: a study protocol.

Stem-cell therapy, which has recently emerged as a potentially therapeutic option for diabetes, is demonstrated to significantly alter both cellular and non-cellular elements of the immune system. In addition, it is demonstrated that allogenic stem-cells, once considered immune-privileged, can be rejected by the host immune system almost similar to any other somatic cell. To date, nonetheless, details of these intricate interactions remain obscure. The current study is designed to illuminate both aforementioned favorable and unfavorable stem cell-mediated immune reactions. Findings of this study may shed some light on how stem cells may exert their therapeutic effect in type 1 diabetes through immune system-mediated mechanisms and illuminate the partially-obscure immune-caused rejection of these cells. For the purpose of this study, frozen whole blood samples obtained from patients with type 1 diabetes who received stem cells at the Endocrinology and Metabolism Research Institute of Tehran University of Medical Sciences in two different clinical trials will be thawed and analyzed. These clinical trials were carried out using two different sources of stem cells, namely allogenic fetal and autologous mesenchymal cells. The samples we aim to analyze were obtained from the patients before the procedure and regularly after it, one, three, six, 12, and 24months later. For the purpose of this study, the following parameters will be measured: C-peptide levels, IDAA1c (a surrogate marker of beta cell function which is calculated as HbA1c (%) + [4 × insulin dose (units per kilogram per day)]), frequencies of islet-specific autoreactive CD8+ T cells (CTL), different lymphocyte subsets, thymic function indicators, T cell repertoire diversity (including Treg/Tconv ratios), plasma levels of several pro- and anti-inflammatory cytokines, diabetes autoantibodies, and HLA typing. The stem cell transplantation clinical trials which provided the primary source of our samples were carried out at the Endocrinology and Metabolism Research Institute of Tehran University of Medical Sciences between 2008 and 2012. These series of clinical trials have secured approval of the ethics committee of Tehran University of Medical Sciences (ethical code number: E-0089) and registered on the national clinical trial registry of Islamic Republic of Iran (IRCT) with the identifier codes: IRCT138810271414N8 (for autologous mesenchymal cells) and IRCT201103171414N23 (for allogenic fetal cells). Our findings are to be presented at international scientific events, published in peer-reviewed journals, and disseminated both electronically and in print. Besides, results of the current study will be used for design and implementation of future laboratory investigations and clinical trials at the Endocrinology and Metabolism Research Institute of Tehran University of Medical Sciences.

Peripheral autoreactive CD8 T-cell frequencies are too variable to be a reliable predictor of disease progression of human type 1 diabetes.

ObjectivesThe detection of a peripheral immune cell signature that specifically reflects autoimmunity in type 1 diabetes would enable the prediction and staging of disease on an individual basis. However, defining such a signature is technically challenging. Reliable interpretation of immune cell‐related biomarkers depends on their inherent variability and, to understand this variability, longitudinal analyses are required.MethodsWe performed a longitudinal observational study in which 40 individuals with elevated genetic risk of type 1 diabetes and persistent islet autoantibodies provided a blood sample every 4–6 weeks for > 1 year.ResultsPeripheral immune cell composition (T cells, NK cells and monocytes) was assessed using well‐validated flow cytometry panels and demonstrated that, while non‐antigen‐specific immune cell subsets were stable over time, autoantigen‐reactive T‐cell frequencies were highly variable in and between individuals. Neither the frequency nor phenotype of non‐antigen‐specific subsets or autoreactive CD8+ T cells associated with clinical onset of T1D.ConclusionThe findings from the Type 1 Diabetes Longitudinal BIomarker Trial underscore the inherent challenge of evaluating changes in peripheral immune cell populations as surrogates of organ‐specific disease activity. The variability of peripheral antigen‐specific T cells precludes their use as a prognostic marker and clearly demonstrates that a reliable prognostic cell signature remains elusive.

Incidence and predictors of type 1 diabetes among younger adults aged 20–45 years: The diabetes in young adults (DiYA) study

AimsTo estimate incidence of type 1 diabetes (T1D) and to develop a T1D prediction model among young adults. MethodsAdults 20–45 years newly-diagnosed with diabetes in 2017 were identified within Kaiser Permanente’s healthcare systems in California and invited for diabetes autoantibody (DAA) testing. Multiple imputation was conducted to assign missing DAA status. The primary outcome for incidence rates (IR) and the prediction model was T1D defined by ≥1 positive DAA. ResultsAmong 2,347,989 persons at risk, 7862 developed diabetes, 2063 had DAA measured, and 166 (8.0%) had ≥1 positive DAA. T1D IR (95% CI) per 100,000 person-years was 15.2 (10.2–20.1) for ages 20–29 and 38.2 (28.6–47.8) for ages 30–44 years. The age-standardized IRs were 32.5 (22.2–42.8) for men and 27.2 (21.0–34.5) for women. The age/sex-standardized IRs were 30.1 (23.5–36.8) overall; 41.4 (25.3–57.5) for Hispanics, 37.0 (11.6–62.4) for Blacks, 21.4 (14.3–28.6) for non-Hispanic Whites, and 19.4 (8.5–30.2) for Asians. Predictors of T1D among cases included female sex, younger age, lower BMI, insulin use and having T1D based on diagnostic codes. ConclusionsT1D may account for up to 8% of incident diabetes cases among young adults. Follow-up is needed to establish the clinical course of patients with one DAA at diagnosis.

Adult-onset autoimmune diabetes: comparative analysis of classical and latent presentation

IntroductionAdult-onset autoimmune diabetes (AID) has two different phenotypes: classic type 1 diabetes mellitus (T1DM), with insulin requirement just after diagnosis, and latent autoimmune diabetes in adults (LADA). The purpose of this study is to characterize patients with AID followed on a tertiary centre, comparing classic T1DM and LADA.MethodsWe collected data from patients with diabetes and positive islet autoantibodies, aged 30 years old and over at diagnosis. Patients who started insulin in the first 6 months were classified as T1DM and patients with no insulin requirements in the first 6 months were classified as LADA. Data regarding clinical presentation, autoantibodies, A1C and C-peptide at diagnosis, pharmacologic treatment and complications were analysed.ResultsWe included 92 patients, 46 with classic T1DM and 46 with LADA. The percentage of females was 50% in T1DM group and 52.1% in LADA group. The median age at diagnosis was 38 years (IQR–15) for T1DM and 42 years (IQR–15) for LADA (p = 0.057). The median time between diagnosis of diabetes and diagnosis of autoimmune aetiology was 0 months in T1DM group and 60 months in LADA group (p < 0.001). The mean BMI at diagnosis was 24.1 kg/m2 in T1DM group and 26.1 kg/m2 in LADA group (p = 0.042). In T1DM group, 67.4% of the patients had more than one positive autoantibody, comparing to 41.3% of LADA patients (p = 0.012). There was no statistical difference in what concerns to title of GAD autoantibodies, A1C and C-peptide at diagnosis of autoimmune aetiology. The presence of symptoms at diagnosis was associated with T1DM group (p < 0.001). The median daily insulin dose was 40 IU for T1DM (0.58 IU/kg) and 33.5 IU for LADA (0.57 IU/kg), with no statistical difference. LADA patients were more often under non-insulin antidiabetic drugs (p = 0.001). At 10 years follow up, 21.1% of T1DM patients and 63.3% of LADA patients had microvascular complications (p = 0.004). Diabetic nephropathy was present in 23.5% of T1DM patients and 53.3% of LADA patients (p = 0.047). At the last evaluation, 55.6% of T1DM and 82.6% of LADA patients had metabolic syndrome and this difference was independent of diabetes duration.ConclusionPatients with classic T1DM presented more often with symptoms, lower BMI and higher number of autoantibodies, which may be related to a more aggressive autoimmune process. Patients with LADA developed more frequently microvascular complications for the same disease duration, namely diabetic nephropathy, and had more often metabolic syndrome.

Prevalence of autoantibodies in type 1 diabetes mellitus pediatrics in Mazandaran, North of Iran.

Objectives Type 1 diabetes is an autoimmune disease. Its most important immunologic markers are pancreatic beta-cell autoantibodies. This study aimed to determine diabetes mellitus antibodies frequency among children and adolescents with type 1 diabetes. Methods This descriptive study evaluated the frequency of four diabetes autoantibodies (glutamic acid decarboxylase 65 autoantibodies [GADA], islet cell autoantibodies [ICA], insulin autoantibodies [IAA], tyrosine phosphatase-like insulinoma antigen-2 antibodies [IA-2A]) and their serum level in children and adolescents diagnosed with type 1 diabetes mellitus at the diabetes department of Bou-Ali-Sina Hospital and Baghban Clinic, Sari, Iran, from March 2012 to March 2018. The relationship between the level of different antibodies and age, gender, and diabetes duration were determined. A two-sided p value less than 0.05 indicated statistical significance. Results One hundred forty-two eligible patient records were screened. The average age at diabetes diagnosis was 4.2±4.4 years. The median duration of diabetes was 34.0 (12.7-69.7) months. 53.5% of patients were female, and 81.7% of them had at least one positive autoantibody, and ICA in 66.2%, GADA in 56.3%, IA-2A in 40.1%, and IAA in 21.8% were positive. The type of the autoantibodies and their serum level was similar between females and males but there was a higher rate of positive autoantibodies in females. The level of IA-2A and ICA were in positive and weak correlation with age at diagnosis. Conclusions More than 80% of pediatric and adolescent patients with type 1 diabetes were autoantibody-positive. ICA and GADA were the most frequently detected autoantibodies. The presence of antibodies was significantly higher in females.

Gluten-free diet impact on dynamics of pancreatic islet-specific autoimmunity detected at celiac disease diagnosis.

Almost 6% of celiac disease (CD) patients at diagnosis are positive for at least one of the main pancreatic islet autoantibodies that characterize type 1 diabetes (T1D). Few information, dated back to almost two decades ago, exist as to whether a gluten-free diet (GFD) could reduce the islet-specific autoimmunity detected in patients at CD diagnosis. Aim of the study was to evaluate the impact of GFD on 31 patients who presented islet-specific autoimmunity at CD diagnosis. CD patient sera collected at diagnosis and throughout the GFD were analyzed for the main humoral autoantibodies so far identified in T1D, directed against one or more among insulin, glutamic-acid decarboxylase, tyrosine-phosphatase 2, and zinc cation-efflux transporter autoantigens. GFD (median duration 39 months) was associated to a decrease or disappearance of the islet-specific autoantibodies in 71% of CD patients. Almost 80% of the patients who became autoantibody-negative during the GFD were positive for only one of the islet-specific autoimmune markers at CD diagnosis, with none of them developing diabetes. Conversely, 80% of the CD patients positive at diagnosis for ≥2 islet-specific autoantibodies were still positive after more than two years of GFD, with 25% of them developing T1D. Various factors appear to influence, individually or in combination, the effects of the GFD on pancreatic islet-specific autoimmune response detected at CD diagnosis. These factors include the number of diabetes autoantibodies found at CD diagnosis, the adherence to the GFD, its duration and an asymptomatic clinical presentation of CD.

1482-P: Effect of Age on Diabetes-Specific Autoantibodies in a Large Laboratory-Based Cohort

Type 1 diabetes mellitus (T1DM) can occur at any age, the presence of diabetes related autoantibodies predicts increased risk of disease and supports an autoimmune etiology for T1DM. Since 2017, Mayo Clinic Laboratories has been offering a comprehensive type 1 diabetes autoantibody evaluation (DM1Eval) which includes testing for 4 autoantibodies targeting glutamic acid decarboxylase autoantibodies (GAD), protein tyrosine phosphatase-like islet antigen 2 (IA-2), insulin (IAA), and zinc transporter 8 protein (ZnT8). The aim of this study was to determine the frequency of individual antibodies and antibody clusters (2, 3 or 4) stratified into 4 ages groups (children 0-17, young adult 18-35, middle aged 36-55 and older &amp;gt;55 years). Over a 30 month period (June 2017-Nov 2019) the DM1Eval was performed on 6,446 samples. At least 1 autoantibody was found in 3596 (56%) of all samples: 68% of children, 49% of young adults, 40% of middle aged and 41% of older adults. In patients with at least 1 antibody positive, GAD 65 antibodies were the most common in all age groups followed by ZnT8 in those &amp;lt;36 years or IAA antibody in those 36 and older older (Figure). The frequencies of IA2 and ZnT8 antibodies dropped significantly with increasing age strata. Autoantibody clusters of 3 or 4 antibodies were more frequently encountered in younger patients (41% of pediatric and 27% of young adult patients in contrast to just 12% in middle and older age groups). Disclosure A.R. Dahl: None. S. Pittock: None. A. McKeon: None. J. Foster: None. J. Mills: None.

MON-057 MODY Diagnosis: Missed Opportunity to Avert Insulin Therapy. A Case Series

BACKGROUND Prevalence of MODY is 1.2% in pediatric diabetes population. SEARCH study reported most of these patients were misdiagnosed as T1DM or T2DM up to 36% and 51% respectively (1). GCK (MODY 2) and HNF1A/HNF4A (MODY3) are the most common forms of MODY. Despite improvement in testing strategy (panel testing instead of step-wise approach) and cost, MODY testing remains underutilized. These conditions do not require insulin therapy, and MODY 2 patients may even be discharged from clinic after diagnosis. We present 4 cases and valuable lessons learned. MODY 2 Case 1. 4 yo M referred for hyperglycemia in the 300s during surgery. A1c 6.4%. FBG at home 150s, asymptomatic. MGM and MGM’s siblings have diabetes. Diabetes autoantibodies (DAA) negative. C-peptide 5.4 (NL 0.78 - 5.19 ng/ml). MODY panel (GeneDx) showed heterozygous mutation in GCK gene (c.70 C>T). Patient remains off insulin, family reassured and advised to undergo genetic testing. MODY 2 Case 2. 8 yo M diagnosed at local ED with “T1DM” after presenting with polyuria, polydipsia, and random BG 237. A1c 6.7%, C-peptide 1.9, started on basal-bolus insulin. MODY panel (sent a year later when patient was found to have low insulin requirement, negative DAA) showed pathogenic variant in GCK gene. Weaned from insulin, A1c unchanged (6.3–7%). Mother found to have same mutation. MODY 3 Case 1. 16 yo F referred by PCP who started her on insulin a year prior after an incidental finding of hyperglycemia. A1c was 7.5% at diagnosis. Mom, MGM have diabetes, unknown type (MGM thin by report). DAA neg, C-Peptide 1.74. MODY Panel showed HNF1A heterozygous gene mutation for RI31Q. She was switched to Glyburide, blood glucose 90s. MODY 3 Case 2. 10 yo M referred from the ED for “T1DM” (weight loss, fatigue, A1c 7.6%) started on basal-bolus insulin, but lost to follow up for a year. Brother has MODY 3. DAA neg, C-Peptide 3.1. Targeted gene sequencing showed HNF1A gene mutation. He was switched to Glyburide, A1c improved to 6.7%. However, patient became noncompliant as teenager, A1c now 9.3%. CONCLUSION MODY remains underdiagnosed. A high index of suspicion should be maintained in nonobese, DAA-negative patients diagnosed with DM before 25yo. Although DAA and genetic testing can be costly, diagnosis can dramatically alter diabetes management as illustrated in all 4 cases, and overall cost of management may be lower in the end. Patients with MODY 2 do not develop vascular complications associated with diabetes, nor require pharmacotherapy. MODY 3 patients may be safely switched to sulfonylurea monotherapy, though degree of diabetes control depends on compliance with medication. Testing gives relatives previously misdiagnosed the opportunity to improve their own quality of life. More education for health care providers is warranted for prompt diagnosis and appropriate management of this condition.Reference:1. Pihoker, et al. JCEM 2013; 98:4055–62

SAT-673 Acute Onset Type 1 Diabetes Mellitus Caused by the Checkpoint Inhibitor Nivolumab

Background. Checkpoint inhibitors are monoclonal antibodies that augment immune system antitumor activity. Nivolumab is a checkpoint inhibitor that targets the programmed cell death receptor 1 (PD-1). Approximately 15% of patients treated with checkpoint inhibitors experience endocrine immune-related adverse events (irAEs), with autoimmune thyroid disorders and hypophysitis the most common endocrine irAEs. We present a case of acute onset type 1 diabetes mellitus (T1D) complicating treatment with nivolumab. Case. An 84 year old female received nivolumab (Opdivo) for metastatic small cell lung cancer. She tolerated twelve cycles of treatment well, but after the thirteenth cycle, she developed polydipsia and polyuria that prompted her to seek medical attention. Laboratories in the emergency department were notable for plasma glucose 998 mg/dL, bicarbonate 13 mM, anion gap 24, and strongly positive serum and urine ketones. An insulin infusion and parenteral fluids promptly resolved diabetic ketoacidosis (DKA), and the patient was then managed with subcutaneous basal/bolus insulin. Antibody markers (e.g. anti-GAD65) for T1D were undetectable, and evaluation for other endocrine irAEs was unremarkable. Given the rapid onset of DKA and the patient’s advanced age, she was diagnosed with nivolumab-induced T1D and discharged home on exogenous insulin. Conclusions. In a recent meta-analysis of 38 immune checkpoint inhibitor trials and over 7,500 patients, T1D was the least common endocrine irAE. The incidence of T1D was 0.2% compared to 6.6% for hypothyroidism, 2.9% for hyperthyroidism, 1.3% for hypophysitis, and 0.7% for primary adrenal insufficiency. All but one case (12/13) of T1D occurred in patients treated with a PD-1 inhibitor. Markers of both cellular and humoral diabetes-associated autoimmunity have been demonstrated in patients with T1D during treatment with nivolumab, and autoimmune destruction of beta-cells is the presumed etiology of diabetes. However, diabetes autoantibodies are detected in only about 50% of cases, and the absence of humoral markers does not exclude the diagnosis of nivolumab-induced T1D. There is a slight male predominance among published cases of nivolumab-induced T1D, and though median onset of T1D1 is after 11 weeks of treatment, there is a wide range of recorded times to T1D onset. Approximately 70% of patients present in DKA, and the significant majority of patients have undetectable or low C-peptide levels. Unfortunately, loss of beta-cell function persists after stopping nivolumab, and lifelong exogenous insulin is required for diabetes management. Though nivolumab-induced T1D is rare, the high risk of DKA as in this patient’s case illustrates the importance of recognizing nivolumab as a potential cause of autoimmune diabetes in older patients receiving anti-PD-1 immunotherapy.

Type 1 diabetes, thyroid, gastric and adrenal humoral autoantibodies are present altogether in almost one third of adult celiac patients at diagnosis, with a higher frequency than children and adolescent celiac patients

Background: No data are available on the frequency of organ-specific humoral autoimmunity at diagnosis of adult celiac disease (CD).Aim: To evaluate the humoral immunoreactivities specific of type 1 diabetes (T1D), thyroid (THD), atrophic-gastritis (AG) and Addison’s (AD) diseases in 92 adult CD patients at diagnosis and 237 adult healthy subjects (CTRL).Methods: T1D, THD and AD specific autoantibodies were analyzed by radioimmunoprecipitation assays. AG autoantibodies were detected by enzyme-linked immunosorbent assay.Results: Of 92 CD patients, 31.5% were positive for at least one of the organ-specific autoantibodies investigated (p < .0001 vs CTRL). Thyroid, diabetes, gastric and adrenal-autoantibodies, that increase with age at diagnosis, were detected in 12.0%, 10.9%, 10.9%, 2.2% of CD patients, respectively. Gastric- and diabetes- rather than thyroid- and adrenal-autoimmunity seem to be specifically related to presence of CD.Conclusions: One third of adult CD patients at diagnosis is target of at least one organ-specific autoantibody. A systematic organ-specific autoantibody screening in these patients might be of value to promptly identify, prevent or treat the relative diseases.

PRO103 REASSESSMENT OF A REAL-WORLD POPULATION OF ADULTS WITH TYPE 2 DIABETES (T2D): WHEN LOW LEVELS OF C-PEPTIDE OR PRESENCE OF DIABETES AUTOANTIBODIES MIGHT INDICATE POSSIBLE TYPE 1 DIABETES (T1D)

To identify a cohort of patients from a US EMR database that might meet a definition for T1D based on C-peptide or diabetes autoantibodies laboratory findings despite having been classified by their medical provider as T2D patients. From the IQVIA US Ambulatory EMR database of 75 million patients (2006 forward), adults (18 years of age) were selected if they had any problem record between 1/1/2006-10/31/2019 for T2D (ICD-9/10-CM), and excluding those with evidence of T1D. From available labs, C-peptide <0.80ng/mL was assessed and autoantibody status determined for glutamic acid decarboxylase (GAD), IA-2, islet cell (ICA) and insulin antibody tests. An abnormal indicator for each antibody result (as documented in EMR) was used to determine antibody status. Patients were indexed on date of first qualifying test from patient selection step. Patient demographics and clinical profiles were summarized, including insulin and oral antidiabetic prescriptions and HbA1c levels. 7,410 patients with C-peptide or diabetes autoantibody findings were identified from over 5 million T2D patients: mean database observation period 5.0±3.7 years, with 46.3% women, mean age at index 55.8±14.5 years, and 59.6% Caucasian. Diabetes prescriptions within ±12 months of index were identified for 6,816 patients (92.0%), of which 93.5% were prescribed insulin (either with or without oral) and 6.5% were prescribed oral medications. Among insulin patients, mean (SD) for the max-HbA1c within ±12 months was 9.5%±2.2% pre-index and 8.9%±2.0% post-index. The non-insulin group had max-HbA1c of 9.1%±2.3% pre-index but had improved post-index results of 7.9%±2.0%. A cohort of 7,410 patients with laboratory test profile consistent with T1D was identified from EMR data despite having T2D as the provider-specified diagnosis. These patients were primarily prescribed insulin medications, but a small subset was prescribed oral medications and had no evidence of insulin orders in their history, and another small subset were not prescribed any diabetes medications.

Study of the difficult glycemic control in relation to autoantibodies present among patients of Type 1 Diabetes mellitus (Glutamic acid decarboxylase autoantibodies GADA- Islet cells cytoplasmic autoantibodies ICA- Insulin autoantibodies IAA)

Abstract Background Type 1 DM is sub-divided into type 1A (immune-mediated) and type 1B (other forms of type 1 DM that include virus-triggered autoimmune response, genetic factors and idiopathic). It is widely recognized that the presence of two or more auto-antibodies has a high sensitivity and specificity for rapid progression to insulin dependency within 5 years. It is hypothesized that the difficult glycemic control among some type 1 diabetic patients is attributed to the presence of diabetes-autoantibodies. Aim This study was designed to assess the relationship between the presence of diabetes autoantibodies and the poor glycemic control developed by patients who receive more than 100 insulin units per day and yet they are not controlled i.e. HbA1c &amp;gt; 7%, elevated plasma glucose level on frequent monitoring although they are non-obese and strictly stuck to healthy diet and exercise, and whether the number of positive autoantibodies affect the glycemic control or not. Methods This study was conducted on 60 patients 30 males and 30 females, they were all subjected to full history taking, anthropometric measurements, clinical examination and laboratory assessment in the form of C-peptide, fasting blood glucose, 2 hours post-prandial blood glucose, HbA1c level, serum GADA level, serum ICA level and serum IAA level. The patients were classified according to presence of diabetes autoantibodies into two groups; Group I consisted of 6 patients (10%) with negative auto-antibodies and Group II consisted of 54 patients (90%) with positive auto-antibodies, Group II was further classified according to the number of positive diabetes autoantibodies into 3 sub-groups, Group II a: Formed of 9 patients with 1 positive autoantibody (16.7% of the study population). Group II b: Formed of 12 patients with 2 positive autoantibodies (22.2% of the study population) and Group II c: Formed of 33 patients with 3 positive autoantibodies (61.1% of the study population). Results HbA1c level was significantly higher in group II than group I (11.85 ± 1.61% vs. 8.52 ± 0.41%, p = 0.000). Similarly it was higher in group IIc than group IIb than group IIa (12.25 ± 1.48% vs. 11.57 ± 1.59% vs. 10.78 ± 1.73%, p = 0.038).Moreover HbA1c was significantly higher in patients with positive GADA, patients with positive ICA and those with positive IAA than those with negative GADA, negative ICA and negative IAA (p = 0.000, p = 0.000, p = 0.012 respectively). The total number of insulin units per day was significantly higher in group II than group I (109.83 ± 7.77 U/day vs. 100.83 ± 1.83 U/day, p = 0.007). The duration of diabetes mellitus was significantly higher in group I than group II (10.17 ± 1.94 years vs. 8.11 ± 2.20 years, p = 0.033). By doing the multivariate regression analyses we found that HbA1c level, total number of insulin units per day and the duration of developing diabetes mellitus were significant predictive factors for the presence of diabetes autoantibodies (p = 0.007, p = 0.033 and p = 0.043 respectively). Conclusion The presence of diabetes autoantibodies affect the glycemic control represented by HbA1c level; also it affects the total number of insulin units per day used by the patients; the more the presence of diabetes autoantibodies, the higher the HbA1c level, the more insulin units required by patients to control their glycemic state.

Time-varying risk of microvascular complications in latent autoimmune diabetes of adulthood compared with type 2 diabetes in adults: a post-hoc analysis of the UK Prospective Diabetes Study 30-year follow-up data (UKPDS 86)

Latent autoimmune diabetes of adulthood (LADA) differs in clinical features from type 2 diabetes. Whether this difference translates into different risks of complications remains controversial. We examined the long-term risk of microvascular complications in people enrolled in the UK Prospective Diabetes Study (UKPDS), according to their diabetes autoimmunity status. We did a post-hoc analysis of 30-year follow-up data from UKPDS (UKPDS 86). UKPDS participants with diabetes autoantibody measurements available and without previous microvascular events were included. Participants with at least one detectable autoantibody were identified as having latent autoimmune diabetes, and those who tested negative for all autoantibodies were identified as having type 2 diabetes. The incidence of the primary composite microvascular outcome (first occurrence of renal failure, renal death, blindness, vitreous haemorrhage, or retinal photocoagulation) was compared between adults with latent autoimmune diabetes and those with type 2 diabetes. The follow-up ended on Sept 30, 2007. Baseline and updated 9-year mean values of potential confounders were tested in Cox models to adjust hazard ratios (HRs). UKPDS is registered at the ISRCTN registry, 75451837. Among the 5028 participants included, 564 had latent autoimmune diabetes and 4464 had type 2 diabetes. After median 17·3 years (IQR 12·6-20·7) of follow-up, the composite microvascular outcome occurred in 1041 (21%) participants. The incidence for the composite microvascular outcome was 15·8 (95% CI 13·4-18·7) per 1000 person-years in latent autoimmune diabetes and 14·2 (13·3-15·2) per 1000 person-years in type 2 diabetes. Adults with latent autoimmune diabetes had a lower risk of the composite outcome during the first 9 years of follow-up than those with type 2 diabetes (adjusted HR 0·45 [95% CI 0·30-0·68], p<0·0001), whereas in subsequent years their risk was higher than for those with type 2 diabetes (1·25 [1·01-1·54], p=0·047). Correcting for the higher updated 9-year mean HbA1c seen in adults with latent autoimmune diabetes than in those with type 2 diabetes explained entirely their subsequent increased risk for the composite microvascular outcome (adjusted HR 0·99 [95% CI 0·80-1·23], p=0·93). At diabetes onset, adults with latent autoimmune diabetes have a lower risk of microvascular complications followed by a later higher risk of complications than do adults with type 2 diabetes, secondary to worse glycaemic control. Implementing strict glycaemic control from the time of diagnosis could reduce the later risk of microvascular complications in adults with latent autoimmune diabetes. European Foundation for the Study of Diabetes Mentorship Programme (AstraZeneca).

The expression of Tim-1 and Tim-4 molecules in regulatory T cells in type 1 diabetes

The TIM family comprises of eight genes in the mouse, three of which are conserved in humans (TIM-1, TIM-3, and TIM-4). Previous studies have revealed the relationships between Tim3+ Tregs and autoimmune disease. There was little study about the expression of Tim1 and Tim4 surface molecules on Tregs. We evaluated the frequency of the Tim1+Tregs and Tim4+Tregs in type 1 diabetes (T1D) in the present study. A total of 28 patients with T1D and 14 gender-, age-, and ethnically matched healthy volunteers were recruited. PBMCs from these individuals were isolated and analyzed by flow cytometry. Splenocytes from mice were also analyzed by flow cytometry. There is no difference in the frequency of Treg cells in peripheral blood isolated from T1D patients. Tim1 on CD4+CD25+ T cells decreased significantly in PBMC of patients with T1D(1.19 ± 0.17% vs 2.78 ± 0.38%, 95% CI:0.87-2.31, P < 0.0001), while expression of Tim4 on CD4+CD25+ T cells in PBMC was less frequent in patients with T1D than healthy people(3.0 ± 0.39% vs 6.25 ± 1.08%, 95% CI:1.08-5.43, P = 0.0044). The frequencies of CD4+CD25+Tim1+ T cells and CD4+CD25+Tim4+ T cells also decreased in spleen of hyperglycemic NOD mice. There were no significant correlations between CD4+CD25+Tim1+T-cells, CD4+CD25+Tim4+T-cells and any clinical features such as age, HbA1c, Fasting C-peptide, diabetic autoantibodies, disease duration, total cholesterol, LDL, HDL, and TG. It is the first report of the expression of Tim1 and Tim4 molecules on Treg cells in T1D in the present study. We also presented evidence that the frequencies of Tim1+Tregs and Tim4+Tregs decreased significantly in both type 1 diabetic patients and hyperglycemic NOD mice. However, the specific functions of Tim1+Tregs and Tim4+Tregs are still unclear.