Sex: M
Vaccine: COVID19
Symptoms: Anti-GAD antibody, Anti-insulin antibody, Anti-zinc transporter 8 antibody, Antibody test, Autoantibody test
Clinical narrative: Type 1 Diabetes Mellitus Caused by COVID-19 mRNA Vaccination; This is a literature report for the following literature source(s).  A 38-year-old man presented with a sudden onset of polyuria, polydipsia, and blurry vision for the past month. He had also unintentionally lost 10lbs in the same time frame. There was no family history of autoimmune disorders or diabetes. The patient received 2 doses of the mRNACOVID-19 vaccine (Pfizer-BioNTech), 3 weeks apart, with the second dose being about 4 weeks prior to symptom onset. The patient had a healthy lifestyle including daily exercise and a body mass index of 24.6kg/m2. He was not taking any medications or supplements at the time of diagnosis. Initial work up revealed hyperglycemia (randomserumglucose285mg/ dL) and hemoglobin A1c(HbA1c) of 9.4%, higher than the most recent HbA1c of 5.4% 6 months ago. Urinalysis was remarkable for glucosuria without ketonuria. Given the acute onset of DM, there was high concern for latent autoimmune diabetes in adult and the patient was started on insulin. Auto antibody testing revealed elevated titers of antibodies against zinc transporter Zn T8 (>500U/ mL, ref <15U/mL), insulinoma-associated protein 2 (1.13nmol/L, ref 0.02 nmol/L), and glutamic acid decarboxylase (GAD-65) (0.07 nmol/L, ref 0.02 nmol/L), but not to insulin (undetectable). No structural pancreatic pathology was noted on a computed tomography scan of the abdomen. The patient used insulin for a few weeks (glargine 12 U daily and aspart 2 U 3 times daily). However, at the same time, he made further lifestyle modifications with increased intense daily exercise and a very strict low carbohydrate diet, and noted his home glucose readings were within normal range even off insulin. Thereafter, he self-discontinued insulin. Repeat HbA1c 3 months later was 5.2%. He was stable off insulin for 2 months but had to be placed back on it for persistent hyperglycemia. Additional testing for a concomitant celiac disease or thyroid disorder was negative. Fasting C- peptide was low (0.6ng/mL[0.2nmol/L]). Repeat auto antibody testing showed persistently positive GAD-65, insulinoma-associated protein 2 and Zn T8 antibodies with additional anti-insulin antibodies. He continues to be on insulin degludec 14 U daily and insulin aspart 2 to 4 U with meals. Discussion Here, the authors reported a case of a male patient presenting with new onset type 1 DM after a recent mRNA COVID-19 vaccination with evidence of autoantibodies against pancreatic beta cell antigens, who was thereafter treated with insulin. Although the development of type 1 DM was noted after vaccination, it is hard to establish whether the vaccine is causative or merely coincidental. As part of the author's review, a comprehensive search of literature was conducted on Med using the keywords "COVID-19vaccin*," "SARS-CoV-2vaccin*," and "type 1diabetes." Initial search yielded 20 results. After manual review of the results, 14 full-text reports were retrieved, and the 6 were excluded based on article type, study design, study population, or use of non-mRNA COVID-19 vaccine. These 14 reports include a total of 17 patients from 6 countries. The age at presentation ranged from 27 to 73 years (median 51 years [IQR41-60]) and most patients were of x ethnicity (82.3%, n 1/4 14/17). Most patients (76.5%, n 1/4 13/17) received 2 doses of a mRNA COVID-19 vaccine before onset of symptoms. The timeline of symptom onset ranged from 1 day to 15 weeks after the most recent dose of mRNA vaccine. While most patients presented with polyuria, polydipsia, and weight loss (58.8%, n 1/4 10/17), a significant number of patients also had diabetic ketoacidosis as part of their initial presentation (58.8%, n 1/4 10/17). Twelve of these patients (70.6%) had detectable antibodies against pancreatic beta cell antigens, whereas 5 (29.4%) did not. Interestingly, 5 (29.4%) of the patients underwent human leukocyte antigens typing and were noted to have a type 1 DM susceptible genotype. Similar to the patient, all of these patients were managed with insulin and most of them continued to be on insulin on outpatient follow-up. The pathogenesis of type 1A DM has been attributed to genetic susceptibility triggered by environmental agents such as viral infections, childhood immunization, and treatment with immune checkpoint inhibitor therapy. Several hypotheses have been proposed for development of type 1 DM after COVID-19 mRNA vaccination. First, molecular mimicry between SARS-CoV-2 peptide antigens and the human proteins maybe responsible for cross-reactive interactions. In a recent study, the author reported significant cross reactivity between human anti-SARS-CoV-2 spike protein and nucleoprotein antibodies and multiple human target proteins, including GAD-65 antigen. Second, adjuvants included in the vaccine have been implicated in the pathogenesis of type 1 DM, as part of autoimmune/inflammatory syndrome induced by adjuvants. In addition to the COVID-19 mRNA vaccine, autoimmune type 1 DM has been reported after Vaxzevria (AstraZeneca), hepatitis B virus (11cases), and human papilloma virus vaccine (2 cases). Third, the angiotensin-I converting enzyme-2 receptor that is involved in the SARS-CoV-2 interaction with the host cells may also play an important role. Given the angiotensin-I converting enzyme-2 expression on the pancreatic beta cells, SARS-CoV-2 infection can induce beta cell apoptosis. This mechanism that has been postulated to be responsible for the higher risk of diabetes noted after a COVID-19 infection, which itself is poorly understood. Similar mechanisms may be triggered by the COVID-19 mRNA vaccination. In addition to diabetes, COVID-19 vaccine-induced endocrine disturbances such as thyroiditis, Graves' disease, hypophysitis and adrenal insufficiency have been reported. There is growing literature about non endocrine auto immune conditions such as immune thrombocytopenia, vasculitis, Guillain-Barre syndrome, celiac disease and inflammatory arthritis, being triggered by the COVID-19vaccination, including both mRNA vaccines as well as adeno virus vector vaccines. The observations from the author's case and review of literature have certain important implications for the management of individuals who receiveaCOVID-19 mRNA vaccine. First, universal guidelines for screening for prediabetes and diabetes must be followed to establish baseline glycemic control prior to COVID-19 vaccination. The Diabetes Association, the Association of Clinical Endocrinology, and the Preventive Services Task Force recommend screening for diabetes every 3 years in individuals with normal blood glucose levels. Second, clinicians must maintain a high index of suspicion for patients presenting with signs and symptoms concerning for hyperglycemia or diabetic ketoacidosis, especially in the 4 months from recent COVID-19 vaccination. This should be accompanied by early testing for type 1 diabetes, including auto antibody evaluation and initiation of insulin if indicated. Additionally, the lack of literature on this topic must be addressed. There is a need for a centralized repository for collection of data related to autoimmune manifestations of COVID-19 vaccination, including but not limited to type 1 DM, so that well-designed studies can be conducted and mechanisms underlying the disease process can be elucidated. Conclusion: New-onset type 1 DM has been reported after COVID-19 mRNA vaccination. Clinicians should maintain a high index of suspicion and pursue early testing for the same to reduce adverse outcomes and improve long-term prognosis. It must be noted that these adverse events are exceedingly rare, and majority of individuals can be vaccinated without the risk of development of type 1 DM.; Sender's Comments: Although it is difficult to establish temporal association between the reported event Type 1 diabetes mellitus  and suspect drug based on the limited information provided in the case, the causal association between the Reported event and the suspect drug cannot be excluded  as there is no concrete evidence available to eliminate the causal association The impact of this report on the benefit/risk profile of the Pfizer drug is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to Regulatory Authorities, Ethics Committees, and Investigators, as appropriate.