key: cord-0945272-2a1k4prn authors: Suwanwongse, Kulachanya; Shabarek, Nehad title: Newly diagnosed diabetes mellitus, DKA and COVID‐19: causality or coincidence? ‐ A report of 3 cases date: 2020-07-24 journal: J Med Virol DOI: 10.1002/jmv.26339 sha: c0ac0ab74931b95c9135817268fe9b88519f73a7 doc_id: 945272 cord_uid: 2a1k4prn Novel coronavirus disease 2019 (COVID‐19), a 2020 pandemic, has resulted in an unexpected loss of lives, quality of life, and economy. The COVID‐19 clinical spectrum varies from asymptomatic to death, and its complications may involve various organs. Notwithstanding, the impact of COVID‐19 on endocrine systems is understudied. Previous coronavirus outbreak such as SARS‐CoV can cause new‐onset diabetes mellitus (DM). However, there were only two previous case reports on newly diagnosed DM in COVID‐19 patients. Here, we described three patients who had newly diagnosed DM associated with COVID‐19. COVID‐19 likely unmasked existing DM by aggravating its metabolic complications rather than causing the new‐onset DM in these patients. However, more research is needed to evaluate if there is a casualty relationship between the development of DM, DKA, and COVID‐19. This article is protected by copyright. All rights reserved. In 2020, novel coronavirus disease 2019 (COVID-19), has become a catastrophic pandemic affecting people almost entire world and severely shaking the public health security. Its pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a third identified human beta-coronavirus, which reported to target pulmonary systems [1] . Clinical spectrums of COVID-19 are varying from asymptomatic to lethal pneumonia. Besides, COVID-19 has unpredictable effects on many organs. However, the data regarding the endocrine impact of COVID-19 is limited. Herein, we present the three cases of newly diagnosed diabetes mellitus (DM) associated with COIVD-19, raising the question of whether COVID-19 can cause endocrine abnormalities. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jmv.26339. Case presentation An 18-year-old obese man came to our hospital due to abnormally high blood sugar. He reported fatigue, polydipsia, and polyuria for ten days. His mother measured his blood sugar, which ranged between 400 and 500 mg/dl. He had no fever nor respiratory symptoms. Family history was remarkable for DM type 2 in many family members, including his mother and father. He denied previous medical problems. Last HbA1C measured one year prior was normal (4.8%). Vital signs were normal. He had a BMI of 32. Systemic examination was unremarkable except for mild generalized tenderness around the periumbilical area. Blood test results were demonstrated in table 1. Briefly, he had hyperglycemia, high anion gap metabolic acidosis, and ketonemia. Urine analysis showed a large amount of sugar and ketone. Screening SARS-CoV-2 RT-PCR returned positive. Insulin antibodies, islet cells antibodies, anti-cyclic citrullinated peptide (anti-CCP) antibody glutamic acid decarboxylase were all negative. He was diagnosed as diabetic ketoacidosis (DKA) in newly diagnosed DM and asymptomatic COVID-19 and received treatment with insulin drip, intravenous hydration, replacement of electrolytes, and supportive measures. No specific COVID-19 treatment was given. His DKA resolved the following day, and he was discharged home with a subcutaneous insulin regimen and metformin on hospital day 3. He did not have worsening pulmonary symptoms nor hypoxemia throughout hospitalization. A 51-year-old man came to our hospital due to worsening fatigue. He reported having tested positive for COVID-19 two month prior, in which he had fever and cough, but the symptoms were mild and he did not require hospital treatment. However, since then, he had been feeling fatigued, lack of energy, and anorexia. Two weeks prior, he started having polyuria and polydipsia. Later he developed nausea and vomiting for the past two days. He also reported some weight loss during this period but denied any other symptoms. None of the family members had DM nor cardiovascular diseases. He denied previous medical problems, did not drink alcohol nor used any drugs. Vital signs were normal. BMI was 34. Systemic physical examination was unremarkable. Chest X-ray (CXR) was normal. Repeat SARS-CoV-2 RT-PCR was negative. Blood test results revealed hyperglycemia, high anion-gap metabolic acidosis, and ketonemia (Table 1) . He was admitted to the COVID-19 floor diagnosed due to newly diagnosed DM and starvation ketoacidosis, and received treatment with subcutaneous insulin, aggressive intravenous hydration, electrolytes replacement and supportive measures. The patient was discharged with a subcutaneous insulin regimen on day 3. A 64-year-old woman came to our hospital due to polyuria and polydipsia for ten days. She was tested positive for COVID-19 ten weeks prior, in which she had a fever and cough. Her symptoms were completely resolved in a few days, without hospital admission nor specific treatment. She had a positive family history of DM in her Accepted Article siblings. Her past medical history included breast cancer in remission, and she is currently taking tamoxifen. Vital signs were normal. Systemic physical examination was unremarkable. Blood test results showed hyperglycemia (Table 1) . Urine analysis showed a large amount of sugar and a small amount of ketone. She was newly diagnosed with DM, received intravenous fluid, and discharged home on oral metformin. DM negatively impacts COVID-19 outcomes and worsens mortality [2] . However, the effect of COVID-19 on DM has not yet been elucidated. In our institution experience, we encountered many cases of DKA precipitated by COVID-19 in patients with type 2 diabetes, which is uncommon. Approximately 15% of our hospitalized COVID-19 patients with DM had developed DKA. Besides, the mortality of COVID-19 patients with DKA in our institution is almost 50%. There were two previously reported cases of newly diagnosed DM in COVID-19 patients. Chee (2020) described a 37-year-old previously healthy man who presented with DKA from newly diagnoses DM and COVID-19 [3] . The patient had HbA1C of 14.2%, which indicated that he might have pre-existing DM aggravated by COVID-19, causing metabolic complications and DKA. Later, Heaney (2020) published a 54year-old male case with multiple co-morbidities presented with dyspnea and was found to have DKA, newly diagnosed DM, and COVID-19 [4] . HbA1C result was not available, but assuming his multiple co-morbidities, including morbid obesity and hypertension, he might have undiagnosed DM. Both patients had favorable COVID-19 courses, did not require oxygen supplement, and were discharged home in a few days without complications. We report three cases of newly diagnosed DM associated with COVID-19. The first case developed concurrent COVID-19 and DKA, while the second and third cases had the diagnosis of DM following COVID-19 illnesses. Although the causal relationship between COVID-19 and DM cannot be confirmed, it raises the concern of whether COVID-19 can precipitate the development of new-onset DM. Rubino (2020) proposed that SARS-CoV-2 leads to ketosis-prone diabetes via binding to its cellular entry -ACE-2 receptors, which are abundant in pancreatic beta cells and adipose tissue, leading to glucose metabolism abnormalities, and pancreatic beta cells destruction [5] (Figure 1 ). This mechanism underlies the development of DM in SARS-CoV patients [6] . Besides, the aberrant immunity caused by SARS-CoV-2 may induce an auto-immune attack to the pancreatic islet cells mimicking the pathogenesis of insulin-dependent DM. Notwithstanding, the elevated HbA1C and the presence of DM risk factors in several patients may indicate that the newly diagnosed DM is a result of metabolic disturbances from COVID-19 illnesses unmasking the existing DM rather than causing the new-onset of disease. However, the unusual high incidences of DKA in type 2 DM raise the issue of whether COVID-19 can further damage pancreatic islet cells leading to insulin deficiency states. More research is needed to investigate the causal relationship between DM, DKA, and COVID-19. A new coronavirus associated with human respiratory disease in China Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus Newly diagnosed diabetes and diabetic ketoacidosis precipitated by COVID-19 infection New-Onset Diabetes in Covid-19 Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes Impaired glucose metabolism in patients with diabetes, prediabetes, and obesity is associated with severe COVID-19 Why obesity, hypertension, diabetes, and ethnicities are common risk factors for COVID-19 and H1N1 influenza infections This article is protected by copyright. All rights reserved Interestingly, all reported patients had a very favorable course of COVID-19; none had developed hypoxemia, despite the presence of the other negative prognostic factors such as advanced age, obesity, male sex, and multiple-co-morbidities. This result contradicts the verified theory that DM patients have poor COVID-19 outcomes [7, 8] . Several reasons may underlie this unexpected finding. First, the duration of DM may be more important than the presence of DM itself. Second, the worsen COVID-19 prognoses may be a result of other confounding factors in the patients who had DM, such as obesity, kidney disease, cardiovascular disease, and the use of certain medication. Third, it may be just sampling bias, as there were only 5 patients reported so far.In conclusion, we reported three cases of new diagnoses DM associated with COIVD-19 illnesses. More research is needed to evaluate the association between DM, DKA, and COVID-19. This article is protected by copyright. All rights reserved.