Autoantibodies to N-Terminally Truncated GAD65(96–585): HLA Associations and Predictive Value for Type 1 Diabetes

Objective To evaluate the role of autoantibodies to N-terminally truncated glutamic acid decarboxylase GAD65(96–585) (t-GADA) as a marker for type 1 diabetes (T1D) and to assess the potential HLA-associations with such autoantibodies. Design In this cross-sectional study combining data from the Finnish Pediatric Diabetes Register, the Type 1 Diabetes Prediction and Prevention (DIPP) Study, the DIABIMMUNE Study, and the Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity (EDIA) Study, venous blood samples from 760 individuals (53.7% males) were analyzed for t-GADA, autoantibodies to full-length GAD65 (f-GADA), and islet cell antibodies. Epitope-specific GAD autoantibodies were analyzed from 189 study participants. Results T1D had been diagnosed in 174 (23%) participants. Altogether 631 (83%) individuals tested positive for f-GADA and 451 (59%) for t-GADA at a median age of 9.0 years (range 0.2–61.5). t-GADA demonstrated higher specificity (46%) and positive predictive value (30%) for T1D than positivity for f-GADA alone (15% and 21%, respectively). Among participants positive for f-GADA, those who tested positive for t-GADA carried more frequently HLA genotypes conferring increased risk for T1D than those who tested negative for t-GADA (77 vs. 53%; P<0.001). Conclusions Autoantibodies to N-terminally truncated GAD improve the screening for T1D compared to f-GADA and may facilitate the selection of participants for clinical trials. HLA class II-mediated antigen presentation of GAD(96–585)-derived or structurally similar peptides might comprise an important pathomechanism in T1D.

Changes in the presentation of newly diagnosed type 1 diabetes in children during the COVID-19 pandemic in a tertiary center in Southern Turkey

Objectives The COVID-19 pandemic is a global health problem with high morbidity and mortality. This study aimed to investigate patients who were diagnosed with type 1 diabetes during the pandemic and evaluate the effect of the pandemic on the clinical findings of these patients by comparing them with findings from a year prior. Methods Patients diagnosed with type 1 diabetes mellitus between 2019 and 2021 were separated into two groups: Patients diagnosed prepandemic and those diagnosed during the pandemic. Results The number of newly diagnosed diabetes cases increased from 46 in the prepandemic period to 74 in the pandemic period. The number of cases diagnosed with diabetic ketoacidosis (DKA) in the clinic increased from 58.7 to 91.9%. We found that moderate and severe DKA rates from 18.5 and 14.8% to 23.5 and 22.1%, respectively. Besides, the average HbA1c was higher, while the average bicarbonate was lower in cases diagnosed during the pandemic period compared to the prepandemic period (p=0.048 and p<0.001, respectively). We found that celiac autoantibody positivity antibodies to glutamic acid decarboxylase (anti GAD) positivity, and islet cell antibodies (ICA), ICA and anti GAD positivity coexistence were higher (p=0.045, p=0.008, and p=0.007, respectively) among the patients diagnosed during the pandemic. Conclusions We observed an increase in the number of patients newly diagnosed with type 1 diabetes mellitus, an increase in autoantibody positivity, and higher rates and severity of DKA during the COVID-19 pandemic period compared to the prepandemic period.

Crohn's disease and peptic ulcer disease: A personal comparative analysis

Until the Hruska Postulate and its intellectual fulfillment [1-7], Crohn's disease was a disease entity without either cure or validation. The explanation put forward for its pathogenesis is that the body's immune system selectively turned against something within the gastrointestinal tract. That disruption of the immune system's pro-inflammatory Th1 response could produce evidence of mucosal healing and temporary abatement of disease was aggressively pushed as documentation of the concepts validity. Crohn's disease became the linchpin for 193 journals, 86 conferences and 15,631 articles about or related to autoimmunity. When sought for antibodies to a specific target organ could be demonstrated in a number of diseases. In congenital rubella, the presence of anti-islet cell antibodies introduced the hypothesis that autoimmunity was responsible for the higher incidence of abnormal glucose tolerance tests observed [9]. An equally plausible explanation was that the documented viral replication within islet cells of the pancreas sufficiently altered cellular structure so as to create cross-reacting antibodies. Most claims of autoimmunity have been based upon the demonstration of an antibody that cross-reacts with a cell or subunit within the target organ.

Covid-19 and New Onset Diabetes: A Case Series

Background: During the SARS CoV1 pandemic in 2003, there was much literature published about newly diagnosed diabetes mellitus (DM) in the patient population infected. This phenomenon has not been well established during this SARS CoV2 pandemic. In this case series, we aim to evaluate patients admitted to our facility with new onset DM who had a history of COVID-19 infection. Method: This was a single center case series that included adult patients who presented to our facility with new onset DM during June-October 2020 who had a history of SARS CoV2 positive PCR and/or positive IgG antibody to SARS CoV2. Pregnant patients were excluded. Data was collected from the hospital electronic medical records. Diagnosis of diabetes was determined in these patients via hemoglobin A1C (HbA1C) level greater than 6.5%. Results: Six patients fulfilled our diagnostic criteria. All patients were male with a median age of 54 years. The median BMI is 33.9, with 5 patients considered to be obese and 1 overweight. Other than the increased BMI, 2 patients with pre-DM and 3 patients who had a family history of DM, no other identifiable risk factors for DM were noted in this cohort. Five patients required hospitalization for HHS or DKA and 1 patient was managed as an outpatient. Median random serum glucose on presentation was 761.5 mg/dl and median HbA1C on presentation was 11.5%. Significant dosages of parenteral insulin (0.45 U/Kg) was required for hospitalized patients during their inpatient stay along with immediately after discharge to control their hyperglycemia. Glutamic Acid Decarboxylase and Islet Cell antibodies were done for 2 of the patients and were negative. Three of the patients who had follow up in 2 months showed improvement in their HbA1C (median of 7.1% [5.4–10.7]) and considerably diminished subcutaneous insulin requirement (0.2U/Kg). Two of these patients continued to follow up, and at 4 months from onset of DM, median HbA1C was 5.85% with insulin ceased. Of note, the patient who was lost to follow up was found to have an HbA1C improvement from 11.4% to 5.4% at the 2 month mark. Discussion: Both SARS CoV1 and SARS CoV2 activates the RAAS, causing insulin resistance by altering insulin signaling and increasing oxidative stress leading to dysfunction of pancreatic beta calls. The inflammatory cytokine storm response seen in COVID-19 can also decrease skeletal muscle sensitivity to insulin and decrease peripheral glucose uptake. These mechanisms may be leading to the new-onset DM noticed in our COVID-19 patients. In addition, there may be a possible immune-mediated mechanism given the matched time line between the COVID-19 antibody life span and the duration of DM. It is unknown whether this effect is permanent or temporary, although our results do support the latter. More studies that utilize a larger cohort and longer follow up are needed in order to get a better understanding of the mechanism of DM in COVID-19 infection.

A case of newly diagnosed autoimmune diabetes in pregnancy presenting after acute onset of diabetic ketoacidosis

Objectives We present a case of immune-mediated diabetes mellitus, diagnosed in pregnancy upon presentation with diabetic ketoacidosis, found to have normal glucose control postpartum. Case presentation A 28-year-old medically uncomplicated G1P0 presented in diabetic ketoacidosis at 28.2 weeks gestation. Workup for pancreatic autoantibodies revealed indeterminate anti-islet cell antibodies and positive anti-glutamic acid antibodies. She was stabilized with intravenous fluids and insulin, and transitioned to long and short acting subcutaneous insulin. Her insulin requirements decreased over the course of her pregnancy. Spontaneous vaginal delivery occurred at 37 weeks. Her postpartum glucose control was normal without re-initiation of insulin. Conclusions The diagnosis of diabetic ketoacidosis during pregnancy should prompt further investigation into an underlying diagnosis of immune mediated diabetes. These patients should be followed closely in the postpartum period.

SUN-501 Grave’s Disease Concealing the Diagnosis of Pancreatic Carcinoma

Background: Hyperthyroidism is a disease that presents with various nonspecific symptoms. Unintentional weight loss can often be the presenting complaint. We present a patient with unexplained weight loss that was attributed to Grave’s hyperthyroidism, but was later discovered to be secondary to pancreatic carcinoma. Case Description: A 58-year-old man with no significant medical history, was referred to the endocrine clinic for weight loss, low energy, and abnormal TFT’s. He reported 45 lb. weight loss over the past one year. Past Medical history was notable for opioid use, and is enrolled in the Methadone program for the past 10 years. Family history is significant for type 2 diabetes. He smokes ½ a pack of cigarettes, denies alcohol or drug use. On exam, heart rate was 84 bpm with fine tremors on outstretched upper extremities, no proptosis, lid lag, thyromegaly, or pretibial edema, normal reflexes. His labs were TSH=0.01; (n=0.270 - 4.20 uIU/mL), FT4=2.1; (n= 0.55 - 1.60 ng/dL), FT3=283;(n=2.52 - 4.34 pg/mL) Thyroglobulin Ab 4 IU/ml, Thyroid peroxidase Ab &gt; 900 IU/ml, TSI 358(n=&lt;140%). He was diagnosed with Grave’s disease and was started with Methimazole and Propranolol, which were titrated to an optimal range over the next few months. However, the patient was lost to follow up, and presented one year later to the ED with complaints of abdominal pain, jaundice for one-week, greasy diarrhea for 6 months, also reporting noncompliance with thyroid medications during this time. On examination, he was icteric and jaundiced with hepatomegaly, trace pedal edema. Although LFT’s were previously normal, the labs now showed alkaline phosphatase=533, (n=40-129 IU/L); AST=107 units (n= 0-32 IU/L), ALT=213units (n= 0-40 IU/L), total bilirubin 11.4 (n= 0-1.0 mg/dl), TSH=0.01, FT4=0.6, FT3=3.2. Ultrasound showed gallbladder sludge, CT abdomen-dilatation of the pancreatic duct in neck and body of pancreas, MRCP- marked pancreatic ductal dilatation and soft tissue fullness within the pancreatic head. CA 19-9= 64.8, he underwent ERCP, and was later diagnosed with adenocarcinoma of the Pancreatic head. He was discharged with referrals to GI and Oncology for further treatment. Discussion:Although weight loss and diarrhea are nonspecific, and can often result from hyperthyroidism, this case highlights the importance of further investigation for other causes and avoiding attribution to a single diagnosis. Other diagnoses were only looked into when the patient presented with painless jaundice and hepatomegaly several months later. The effects of autoimmune hyperthyroidism on the pancreas function remain unclear. However, patients with Grave’s hyperthyroidism have a higher number of islet cell antibodies, as compared to controls. Further studies are required in this regard. We also emphasize the importance of patient education and compliance which can lead to earlier diagnosis, and overall better outcomes.

SAT-LB116 Extreme Insulin Resistance: The Diagnostic Challenges When Cost Is a Limitation

Introduction: Insulin resistance occurs most commonly in association with obesity but may result from multiple causes, e.g. medications, lipodystrophy, or antibodies to insulin or insulin receptors. We review a case of an unusual presentation of insulin resistance. We highlight challenges of diagnostic testing and treatment when there are cost limitations. Clinical Case:A 41 year old Hispanic male with T2DM and a history of well-controlled BPD on quetiapine only presents for management of diabetes. His current treatment is metformin and a TDD of 170 U human insulin; A1C is 12.2%. He was diagnosed at age 32 via routine lab tests. At diagnosis BW was 96.4 kg, BMI 29, BP 100/70, CHOL 152, TG 247, HDL 35, LDL 68. Physical exam was unremarkable without acanthosis or lipodystrophy. Anti-GAD, anti-islet cell antibodies, insulin and C-peptide levels were ordered, but not obtained due to cost. He was managed with lifestyle modification for 2 years with maintenance of A1C &lt;7%. At age 35 he developed symptomatic hyperglycemia with A1C 9.4% and was started on metformin and glyburide. At age 36 A1C was &gt;11%, with no change in BW. Glargine 5 U was added, and glyburide was changed to glipizide. Glargine was increased to 40 U without changes in glycemia. At age 37 glipizide was stopped, and he could not afford glargine. He was switched to 70/30 human insulin. Insulin dosages were progressively increased to 220 U a day with no change in glycemia. Liraglutide was tried but not continued due to cost, and quetiapine was switched to trazodone without improvement in A1C. LFTs, CBC, HIV, Hepatitis C and B have been negative. The patient has had multiple visits for education with documented adequate disease understanding and performance of injections. Nonadherence was suspected; for its evaluation, the patient was observed in clinic self-injecting 30 U of regular insulin (brought from home); fasting was confirmed for 3hrs post-injection. BG was 327mg/dL pre-injection and 326mg/dL 3hrs post-injection. Insulin antibodies were requested but not obtained due to cost. Insulin receptor antibodies are not commercially available in the US. Potential empiric strategies, e.g. the NIH protocol for insulin type B resistance (rituximab + dexamethasone + cyclophosphamide) was considered but cost is a limitation. We discussed steroids or methotrexate for possible antibody mediated insulin resistance versus a trial of thiazolidinedione, which has been reported to decrease severe insulin resistance in patients with lipodystrophy. The patient opted to initially try a thiazolidinedione. Conclusion:Although poor adherence has not been excluded, the patient appears to have no response to high doses of injected human insulin, suggesting extreme insulin resistance. Cost limitations preclude optimal diagnostic evaluation. Empiric treatment with low cost options potentially may provide diagnostic information as well as efficacious treatment.