SARS-CoV-2 Positive Serology and Islet Autoantibodies in Newly Diagnosed Pediatric Cases of Type 1 Diabetes Mellitus: A Single-Center Cohort Study.

Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, although presenting less severe forms of the disease in children, seems to play a role in the development of other conditions, including type 1 diabetes mellitus (T1DM). After the beginning of the pandemic, an increase in the number of T1DM pediatric patients was observed in several countries, thus leading to many questions about the complex relationship between SARS-CoV-2 infection and T1DM. Our study aimed to highlight possible correlations between SARS-CoV-2 serology and T1DM onset. Therefore, we performed an observational retrospective cohort study that included 158 children diagnosed with T1DM in the period April 2021-April 2022. The presence or absence of SARS-CoV-2 and T1DM-specific antibodies and other laboratory findings were assessed. In the group of patients with positive SARS-CoV-2 serology, a higher percentage had detectable IA-2A antibodies, more children were positive for all three islet autoantibodies determined (GADA, ICA, and IA-2A), and a higher mean HbA1c value was found. No difference existed between the two groups regarding DKA presence and severity. A lower C-peptide level was found in the patients presenting diabetic ketoacidosis (DKA) at T1DM onset. When compared to a group of patients diagnosed before the pandemic, an increased incidence of both DKA and severe DKA, as well as a higher age at diagnosis and higher levels of HbA1c were present in our study group. These findings have important implications for the ongoing monitoring and management of children with T1DM after the COVID-19 pandemic and highlight the need for further research to better understand the complex relationship between SARS-CoV-2 infection and T1DM.

Newly-onset Autoimmune Diabetes Mellitus triggered by Covid 19 infection: A case based review.

The devastating global pandemic Coronavirus disease 2019 (Covid 19) which was isolated in China in January 2020 is responsible for outbreak of pneumonia and other multisystemic complications. The clinical picture of the infection has an extreme variability: it goes from asymptomatic patients or mild forms with fever, cough, fatigue and loss of smell and taste, to severe cases ending up in the intensive care unit (ICU). This is due to possible cytokine storm that may lead to multi organ failure, septic shock, or thrombosis. Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV -2) which is the virus that causes Covid 19, binds to angiotensin-converting enzyme 2 (ACE2) receptors, which are expressed in key metabolic organ and tissues including pancreatic beta cells, adipose tissue, the small intestine and the kidneys. Therefore it is possible to state tht newly-onset diabetes is triggered by Covid 19 infection. Although there have been many hypotheses which clarify the potential diabetogenic effect of Covid 19, only few observations were reported during this pandemic. Two male patients who were admitted to us with devastating hyperglycemia symptoms were diagnosed as type 1/autoimmune diabetes mellitus within 3 months following Covid 19 infection. Autoantibodies and decreased C peptide levels were detected in these patients. We speculated that autoimmune insulitis and pancreatic beta-cell destruction might be triggered by Covid 19 infection through several mechanisms. Our purpose is to raise awareness on the possible link between SARS-CoV-2 and newly onset type 1 diabetes mellitus. Further studies are needed to determine a more definitive link between the two clinical entities.

The First Reported Case of Lorlatinib-Associated Diabetic Ketoacidosis

Introduction: Lorlatinib is a third-generation tyrosine kinase inhibitor that inhibits anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1). Although 2-10% of patients with non-small cell lung cancer developed hyperglycemia in phase 2 and 3 studies of lorlatinib, only one case has subsequently reported hyperglycemia >500 mg/dL, and no cases of diabetic ketoacidosis (DKA) have been previously reported. Phase 1 trials in neuroblastoma are ongoing. Case Description: A 34-year-old woman with ALK-mutated paraspinal neuroblastoma presented with DKA 14 months after initiation of lorlatinib. Prior to starting lorlatinib, her hemoglobin A1c had been 5.0% (n: < 5.7%). After 12 months of therapy, her A1c increased to 7.8%, prompting the initiation of metformin 500 mg daily. However, two months later she was admitted for DKA with a blood glucose of 591 mg/dL (n: 65-99 mg/dL), CO2 17 mmol/L (n: 20-30 mmol/L), anion gap 18 (n: 8-12), moderate serum ketones, and 3+ ketonuria. Her A1c was 14.8%, C-peptide was 1.2 ng/mL (n: 1.1-4.3 ng/mL), and her glutamic acid decarboxylase-65 and islet antigen-2 autoantibodies were negative. She was also found to be incidentally positive for COVID-19 but was asymptomatic without any oxygen requirement. The patient's DKA was successfully treated with IV insulin infusion, and she was discharged after 3 days with insulin glargine 27 units twice daily and insulin aspart 16 units with meals. One month later, her hemoglobin A1c had improved to 9.4%, and the patient's oncologist discontinued lorlatinib due to sustained remission of her neuroblastoma and her complication of DKA. After stopping lorlatinib, her blood glucose rapidly improved, and she self-discontinued all her insulin in the following 3 weeks. One month later, she was seen in endocrine clinic only taking metformin 500 mg twice daily with fasting and post-prandial blood glucose ranging 86-107 mg/dL. Discussion(s): This is the first reported case of DKA associated with lorlatinib. This case highlights the importance of close glucose monitoring and the risk of severe hyperglycemia and DKA while on lorlatinib therapy. Discontinuation of lorlatinib results in rapid improvement of glycemic control, and glucose-lowering treatments should be promptly deescalated to avoid hypoglycemia.Copyright © 2023

New Onset of Type 1 Diabetes After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination

Introduction: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses the greatest threat of our times. SARS-CoV-2 vaccines are one of the most effective strategies against this infection. Diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, and new-onset diabetes as adverse effects of SARS-CoV-2 vaccination have been infrequently described in the literature. We hereby report a rare case of new-onset type 1 diabetes after SARS-CoV-2 vaccination. Case Description: An 18-year-old male presented to the outpatient office for evaluation of breast pain. On routine laboratory tests, he was noted to have fasting blood glucose of 200 mg/dL. On further questioning, he reported some polyuria, nocturia, and a 10-pound weight loss over the preceding month. He received the initial dose of Pfizer-BioNTech SARS-CoV-2 vaccine in May 2022 and the second dose in June 2022, approximately one month before the onset of symptoms. He denied any earlier viral infections and had no personal or family history of autoimmune conditions. On evaluation, his body mass index was 20 kg/m2, but otherwise, he had a normal physical exam, including a breast exam. Over the next few days, his blood glucose progressively increased to over 300 mg/dl. HbA1c was noted to be elevated at 8.6%, glutamic acid decarboxylase-65 (GAD-65) antibodies were remarkably high >250 IU/ml (normal 5 IU/ml), C-peptide was 1.51 ng/ml (normal 0.80 - 3.85 ng/ml), blood glucose 156 mg/dl, islet-cell antibody titer was 320 (< 1.25 JDF units) and insulin autoantibodies were negative. He was diagnosed with autoimmune Type 1 diabetes and a basal-bolus insulin regimen was initiated to improve glycemic control. On a one-month follow-up, his insulin requirements remained low but persistent and his glycemic control was acceptable. Discussion(s): Various viruses are known to play a fundamental role in the onset of type 1 diabetes via a variety of effects on pancreatic beta-cells because of either the direct lytic effects of viral replication or the inflammatory response to the virus, which is mediated by autoreactive T cells. The limited release of islet cell antigens induces molecular mimicry and paves the way for long-term autoimmunity and the development of type 1 diabetes mellitus. Our patient did not report any viral illnesses before the onset of his symptoms. He also did not have a family or personal history of autoimmune diseases. His onset of diabetic symptoms coincided temporally with receiving the SARS-CoV-2 vaccine. The detection of a considerable titer of GAD-65 antibodies proved autoimmunity. Clinicians must stay vigilant about this potential side effect of SARS-CoV2 vaccine so that a timely diagnosis can be made.Copyright © 2023

Investigating the efficacy of baricitinib in new onset type 1 diabetes mellitus (BANDIT)-study protocol for a phase 2, randomized, placebo controlled trial.

BACKGROUND: Type 1 diabetes (T1D) places an extraordinary burden on individuals and their families, as well as on the healthcare system. Despite recent advances in glucose sensors and insulin pump technology, only a minority of patients meet their glucose targets and face the risk of both acute and long-term complications, some of which are life-threatening. The JAK-STAT pathway is critical for the immune-mediated pancreatic beta cell destruction in T1D. Our pre-clinical data show that inhibitors of JAK1/JAK2 prevent diabetes and reverse newly diagnosed diabetes in the T1D non-obese diabetic mouse model. The goal of this study is to determine if the JAK1/JAK2 inhibitor baricitinib impairs type 1 diabetes autoimmunity and preserves beta cell function. METHODS: This will be as a multicentre, two-arm, double-blind, placebo-controlled randomized trial in individuals aged 10-30 years with recent-onset T1D. Eighty-three participants will be randomized in a 2:1 ratio within 100 days of diagnosis to receive either baricitinib 4mg/day or placebo for 48 weeks and then monitored for a further 48 weeks after stopping study drug. The primary outcome is the plasma C-peptide 2h area under the curve following ingestion of a mixed meal. Secondary outcomes include HbA1c, insulin dose, continuous glucose profile and adverse events. Mechanistic assessments will characterize general and diabetes-specific immune responses. DISCUSSION: This study will determine if baricitinib slows the progressive, immune-mediated loss of beta cell function that occurs after clinical presentation of T1D. Preservation of beta cell function would be expected to improve glucose control and prevent diabetes complications, and justify additional trials of baricitinib combined with other therapies and of its use in at-risk populations to prevent T1D. TRIAL REGISTRATION: ANZCTR ACTRN12620000239965 . Registered on 26 February 2020. CLINICALTRIALS: gov NCT04774224. Registered on 01 March 2021.

A Clinical Case of Pheochromocytoma Presenting with Decompensated Diabetes Mellitus and Paroxysmal Hypertension

Introduction: Pheochromocytoma is a rare neuroendocrine tumor that originates from the adrenal medulla, less commonly from extraadrenal chromaffin cells (paraganglioma). In about 90% of cases, the tumor produces abnormal amounts of catecholamines. Pheochromocytomas are usually benign, but in rare cases can be malignant. Typical clinical manifestations are the result of the haemodynamic and metabolic effects of catecholamines and usually include paroxysmal hypertension with the classic triad (headache, excessive sweating, palpitations), carbohydrate disorders, etc. Elevated levels of catecholamine metabolites (metanephrine and normetanephrine) tested in plasma or in 24-hour urine confirm the diagnosis. Surgical removal of the tumor is the only radical treatment. Follow-up of patients postoperatively should be lifelong and performed by a multidisciplinary team in a specialized center of expertise. Case report: A 36-year-old female patient referred to the clinic for decompensated diabetes mellitus. Detailed history revealed paroxysmal hypertension and the classic triad of pheochromocytoma. The diagnosis was confirmed by high urinary metanephrine levels and an abdominal CT scan, showing a tumor in the right adrenal gland with features typical of pheochromocytoma. Surgical removal of the pheochromocytoma and normalization of catecholamine levels led to normalization of blood pressure and reversal of diabetes mellitus. Conclusion(s): Pheochromocytoma is a difficult diagnosis in endocrinology practice as it can mimic many other diseases. Early detection and surgical removal of the tumor are crucial to avoid complications caused by elevated serum catecholamine levels.Copyright © 2022 Medical Information Center. All rights reserved.

IDF2022-0635 Can COVID-19 infection provoke new-onset A-beta+ KPD (ketosis-prone diabetes)? - Insights from an Indian prospective study

Background COVID-19 as a trigger for A-beta+ ketosis-prone diabetes (KPD) [1,2] in previously normoglycemic individuals presenting with new-onset DKA, has been sparsely studied. Aim To study prospective changes in insulin secretion and insulin resistance in suspected A-beta+ KPD patients presenting with COVID-associated new-onset DKA. Method 22 previously non-diabetic, antibody-negative patients with new-onset DKA and RT-PCR positive COVID-19 (suspected A-beta + KPD), were followed up for one year. They were compared with 20 Type 1A and 18 Type 2 DM patients, with serial assessments (0,6 and 12 months) of insulin secretion rates (ISR) and multi-tissue insulin resistance (IR). 75-g OGTT with serial glucose, insulin and C-peptide estimation (0,15, 30,45, 60,90,120, 150 and 180 minutes) was used to derive IS, while hepatic and peripheral IR was calculated based on study by Ghani et al. [3]. Results At baseline, ISR in suspected KPD (n = 22) was significantly reduced but similar to Type 1A DM(p = 0.15). Serial ISR demonstrated complete recovery in 17 (77%) patients who became insulin independent at one-year follow-up (remission), while 5(23%) patients continued to require insulin (non-remission). KPD patients showed significant hepatic and peripheral IR at baseline compared to Type 1A DM (p < 0.05). The remission group (n = 17) showed significantly enhanced recovery of hepatic and peripheral insulin sensitivity at 6 and 12 months follow-up (all p < 0.01) compared to the non-remission (n = 5) group, with IR in the latter being comparable to Type 2 DM at follow-up (all p > 0.05). Younger age, lower BMI, initial severity of DKA and inflammation (IL-6 levels), along-with reduced 25-hydroxy-Vitamin-D levels were factors associated with poorer recovery of beta-cell secretion amongst the KPD patients. Conclusion This is the first prospective study to demonstrate progressive recovery of p-cell secretion in new-onset A-beta + KPD provoked by COVID-19 infection in Indian adults, with a distinctly different profile from Type 1A DM.Copyright © 2023 Elsevier B.V.

Diabcovid a New Type of Diabetes Following Sars Cov2 Infection?

Background and Aims: During the SARS COV 2 pandemic, the number of cases of unrecognized diabetes increased in those hospitalized for pneumonia. It has been hypothesized that some forms of diabetes not classified as classic are attributable to SARS COV 2 infection. Method(s): We studied the prevalence of diabetes in those admitted to our Covid Hospital from January 2021 to September 2022. A total of 1200 subjects studied by cross-analysis of hospital discharge forms with diabetes mellitus and final therapy as research item. Result(s): The prevalence of diabetes mellitus was 2.16%. Of the subjects diagnosed with diabetes, 26.9% were not classifiable as type 1 or type 2 and the condition of diabetes mellitus was not previously known. HbA1c values were not statistically (7,86+/-0,95 vs 8,1+/-1,1 p = NS) different among subjects with diabetes and autoimmune markers were not present. Fasting C-peptide levels (ng/ml) were significantly lower (0,8- 0,23 vs 2,36+/-0,8 p < 0.05) in those with not previously known diabetes, 57.2% were discharged on insulin therapy. and continued it after 92- 18 days of follow-up. Conclusion(s): The interrelationship between COVID-19 and diabetes remain uncertain and researchers hope to understand whether Covid-19 causes a new form of diabetes or more simply a stress response that triggers classic diabetes. In our experience those individuals with fasting C-peptide levels lower than usual obeserved in Type 2 diabetic subjects continued insulin theraphy for a limited time. They could be a new entity of diabetes classification but longitudinal data are further required to confirm what we can call DIabCovid.

DIABETIC KETOACIDOSIS IN A NEW ONSET ELDERLY TYPE 1 DIABETES AFTER SARS-CoV-2 VACCINATION: ASSOCIATION OR COINCIDENCE?

Introduction In the era of the COVID-19 pandemic, several cases of new onset diabetes associated with COVID-19 have been reoprted. Additionally, patients with diabetes, a high-risk population, are prioritised for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. The vaccine against the (SARS-CoV-2) could represent a new environmental trigger for autoimmune disorders such as Graves' disease, immune thrombotic thrombocytopenia, autoimmune liver diseases, Guillain-Barré syndrome, systemic lupus erythematosus and type 1 diabetes. case We report a case of diabetic ketoacidosis in a new onset Type 1 diabetes in an elderly female following SARSCoV- 2 vaccination. A 69-year-old female with a history of treated TB abdomen in 2015 with no history of diabetes received her second dose of SARS-CoV-2 vaccination (COMIRNATY) on 21st August 2021. Two weeks following vaccination, she developed osmotic symptoms, reduce appetite and lethargy. Her random blood glucose (RBS) was 41 mmol/L, serum ketone 4.4 mmol/L, pH of 7.29 mmHg, bicarbonate 12.5 mmol/L and serum osmolarity of 298 mOsm/kg. She was treated for DKA with intravenous insulin infusion and hydration with resolution of DKA within 12 hours. Anti-Glutamic Acid Decarboxylase and anti-Islet Cells antibodies were positive with low fasting C-peptide of 102 pmol/L. She was discharged well with basal bolus insulin. Four months later, HbA1c reduced from 15.6% to 7.7% with a random C-peptide of 152 pmol/L. Conclusion The occurrence of hyperglycaemia crisis following SARSCoV- 2 vaccine in patients with pre-existing diabetes is known but the occurrence of new onset autoimmune diabetes following vaccination is rare. Further studies are needed to better understand the underlying pathogenesis of autoimmune diabetes following SARS-CoV-2 vaccine.

An Unusual Case of Autoantibody-Negative KetosisProne Diabetes (KPD) Secondary to Marked Insulin Resistance

KPD is classically regarded as an atypical form of diabetes caused by near-complete beta-cell failure. A 37-year-old Egyptian man (BMI: 27.7 Kg/m2) presented with hyperglycemia (362 mg/dL) and DKA (arterial pH 7.20, ketonemia 5.0 mmol/L, ketonuria 80 mg/dL) . He was afebrile, with recent polyuria, polydipsia and weight loss. HbA1c was 107 mmol/mol (11.9%) and blood tests excluded diabetes secondary to endocrinopathies. SARS-CoV-2 RT-PCR test was negative. IV insulin infusion (0.1 IU/kg/h) and IV fluid therapy were started. He was shortly transitioned to a sc basal-bolus insulin regimen (0.7 IU/kg/day) . Mixed-meal tolerance test (MMTT) revealed a peak 120-min stimulated C-peptide of 12.3 ng/mL, suggesting marked insulin resistance. Islet autoantibodies (ICA, IAA, GADA, IA-2A, ZnT8A) and insulin receptor autoantibodies (IgG/IgM) were negative. HLA genotyping detected the following haplotypes: DRB1∗01, ∗04;DQA1∗01:01P, ∗03:01P;DQB1∗03:02P, ∗05:01P. Insulin dose was gradually reduced and insulin therapy was discontinued after 4 months in favor of metformin (2550 mg/day) plus sc semaglutide (up to 1 mg/week) . After one year, MMTT revealed a peak 60-min stimulated C-peptide of 8.25 ng/mL. During the 18-month follow-up period, fasting capillary beta-hydroxybutyrate values were <0.2 mmol/L and HbA1c remained <48 mmol/mol (<6.5%) , indicating disease remission. This case suggests the existence of an autoantibody-negative KPD subtype driven by marked insulin resistance rather than by insulinopenia.

C-peptide levels and glycemic indices in COVID-19 patients

Type 2 diabetes (T2DM) is a common comorbidity in COVID-19 patients, which could favor disease progression. Our study aimed to evaluate the impact of some glycemic biomarkers on characteristic features of COVID-19. Electronic medical records of patients consecutively admitted to a COVID-19 ward were analyzed. Demographic and anthropometric as well as clinical and laboratory parameters were obtained. T2DM was present in 47% of the patients, with 22.58% of diabetic patients being newly diagnosed at admission. The most important predictors of severe COVID-19 were age (OR 1.214 [1.078-1.366], p = 0.001), creatinine levels (OR 1.018 [1.003-1.034], p = 0.017), glucose above 7.0 mmol/L at admission (OR 7.800 [2.232-27.255], p = 0.001) and HbA1c ≥ 6.5% (OR 4.840 [1.428-16.405], p = 0.011) irrespective of the presence of DM. C-peptide levels correlated positively with age, creatinine level, the severity of hypoxia and ferritin levels of patients (p < 0.05 for all) and appeared to be a significant predictor of leukocytosis. Suboptimal glycemic indices and impaired kidney function might predict COVID-19 disease worsening. Early detection of DM and optimization of glycemic control in diabetic patients should be among the priorities of the public health systems during COVID-19 pandemics. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

BNT162b2 mRNA COVID-19 Vaccine Does Not Impact the Honeymoon Phase in Type 1 Diabetes: A Case Report.

Type 1 diabetes (T1D), which is caused by the autoimmune destruction of insulin-secreting pancreatic beta cells, represents a high-risk category requiring COVID-19 vaccine prioritization. Although COVID-19 vaccination can lead to transient hyperglycemia (vaccination-induced hyperglycemia; ViHG), its influence on the course of the clinical remission phase of T1D (a.k.a. "honeymoon phase") is currently unknown. Recently, there has been an increasing concern that COVID-19 vaccination may trigger autoimmune phenomena. We describe the case of a 24-year-old young Italian man with T1D who received two doses of the BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine during a prolonged honeymoon phase. He experienced a transient impairment in glucose control (as evidenced by continuous glucose monitoring) that was not associated with substantial changes in stimulated C-peptide levels and islet autoantibody titers. Nonetheless, large prospective studies are needed to confirm the safety and the immunometabolic impact of the BNT162b2 vaccine in T1D patients during the honeymoon phase. Thus far, T1D patients who are going to receive COVID-19 vaccination should be warned about the possible occurrence of transient ViHG and should undergo strict postvaccination surveillance.

DIABETES AUTOANTIBODIES STATUS IN NEWLY DIAGNOSED CHILDREN AND YOUTH WITH TYPE 1 DIABETES MELLITUS DURING COVID-19 PANDEMIC AT SINGLE SETTING (2020-2021)

Background and Aims: Four pancreatic islet cell autoantibodies (Abs) mostly associate with Type 1 diabetes (T1D) - glutamic acid decarboxylase antibodies (anti-GAD65), tyrosine phosphatase antibodies (IA 2-Ab), insulin autoantibody (anti- IAA) and zinc transporter 8 antibody. Aim: To evaluate the frequency of positive islet autoantibodies at T1D diabetes onset in youth at Varna's diabetes center during COVID-19 pandemic (2020-2021). Methods: A total of 66 newly-diagnosed patients were tested for anti-GAD65, anti-IA2 and anti-IAA (2020-2021) by ELISA. Results: The mean age of the participants was 9.0±4.3 years (52% boys), 63.6% were prepubertal. At the onset of T1D, 83.3% were with at least one positive diabetes related autoantibody while 16.7 % were with negative Abs (p < 0.0001). At diagnosis, 6.1% of patients were with 3 positive Abs, 39.3% had 2 Abs and 37.9% had 1 positive Ab. of all positive, 89.1% had anti- GAD65, followed by 60% anti-IA2, and 16.4% anti-IAA positive, resp. (p < 0.01). of all participants, 81.8% had low level of C-peptide. Weak significant correlations were found between positivity for Abs, gender (r = -0.325, p = 0.008) and age (r = 0.259, p = 0.036);as well as between C-peptide levels and age (r = 0.483, p < 0.001), anti-GAD65 (r = -0,210, p = 0.018), and anti-IA2 (r = -0.259, p = 0.036). Four patients were positive for COVID-19 at diagnosis. All of them had low C-peptide levels and at least one positive Ab. Conclusions: Most frequent diabetes associated antibody at our setting was anti-GAD65, followed by anti-IA2 and anti- IAA as reported worldwide. No Abs differences were found between those who were COVID-19 positive at diagnosis, compared to the rest, although the numbers were too small to conclude.

Type 1 Diabetes onset and COVID-19 infection in a child with Sanjad Sakati Syndrome: a case from Kuwait

Background: Sanjad Sakati Syndrome (SSS) is an autosomal recessive multisystem disorder characterized by congenital hypoparathyroidism, prenatal and postnatal growth and mental delay, dysmorphic features, and hypocalcemia seizures. It has not been linked with autoimmune disorders such as Type 1 Diabetes (T1D). Viral infections may play a role in triggering the development of T1D. Contracting SARS-CoV-2 virus may induce an autoimmune response by damaging the pancreatic β cells and accelerate the onset of T1D. To the best of our knowledge, no case studies of SSS has been reported to develop T1D were reported. Aim: To present a child with SSS who was newly diagnosed with T1D and SARS-CoV-2 infection (COVID-19). Method: Data on the patient were extracted from the Childhood Onset Diabetes electronic Registry (CODeR) in Kuwait. Results: The child was diagnosed early in life with SSS by tubulin-specific chaperone E (TBCE) gene mutation. The child is under multidisciplinary care and managed by alphacalcidol treatment. In May 2021, she presented with a history of fever, cough, polyuria, polydipsia, and poor appetite which lasted for 6 days. On investigations, random blood sugar level was 22 mmol/l and HbA1c level was 10%. There was no evidence of diabetic ketoacidosis. Autoantibodies to glutamic acid decarboxylase (GAD) and thyroperoxidase antibodies (TPO) were positive, with normal thyroid function results. Serum insulin and c-peptide levels were low (0.93 miu/ml, 28 pmol/l respectively). Thus, T1D diagnosis was made, and insulin therapy was started. No family history of diabetes was reported. On admission, the child tested positive for SARS-CoV-2 PCR and had positive contacts with family members with COVID-19 infection. As per WHO COVID-19 infection severity criteria, the child’s condition was classified as mild. She was discharged home with no short-term sequelae of COVID-19 infection;diabetes and dietary education was provided. Discussion: To the best of our knowledge, this is the first case reported in literature of a patient with SSS who presented with T1D onset along with COVID-19 infection. Viral infections such as SARS-CoV-2 virus may trigger the development of autoimmune diseases such as T1D. Exploring the relationship between COVID-19 infection and T1D onset is needed for better understand the effect of COVID-19 infection and outcome on pediatric patients with comorbidities. Further explorations are also needed to study the relationship of SSS and autoimmune disorders as well;to fully appreciate the impact on such patients.

Severe hypernatremia in soft drink ketoacidosis and hyperglycemic hyperosmolar state at the onset of type 2 diabetes mellitus: a case series of three adolescents

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are diabetic emergencies. Some patients with a hyperglycemic crisis can present with an overlap of DKA and HHS. The coexistence of DKA and HHS is associated with higher mortality than in isolated DKA and HHS. In addition, electrolyte derangements caused by global electrolyte imbalance are associated with potentially life-threatening complications. Here, we describe three cases of mixed DKA and HHS with severe hypernatremia at the onset of type 2 diabetes mellitus. All patients had extreme hyperglycemia and hyperosmolarity with acidosis at the onset of diabetes mellitus. They consumed 2 to 3 L/d of high-carbohydrate drinks prior to admission to relieve thirst. They showed severe hypernatremia with renal impairment. Two patients recovered completely without any complications, while one died. Severe hypernatremia with mixed DKA and HHS is rare. However, it may be associated with excess carbohydrate beverage consumption. Reduced physical activity during the COVID19 pandemic and unhealthy eating behaviors worsened the initial presentation of diabetes mellitus. We highlight the impact of lifestyle factors on mixed DKA and HHS.

Recurrent severe hypoglycaemia: Think about antibiotic choice

A 64 year-old Caucasian woman was admitted profoundly unwell with lethargy and generalised weakness. She had rheumatoid arthritis, with no history of diabetes or long-term steroid-use. Blood tests revealed pancytopaenia secondary to methotrexate (stopped on admission), acute kidney injury and severe metabolic acidosis. CT demonstrated lung base ground-glass changes. The patient had been double-vaccinated for covid-19 and all covid swabs were negative. Despite receiving Tazocin, respiratory symptoms worsened. High-dose co-trimoxazole was commenced to treat potential Pneumocystis infection from being immunocompromised. Subsequently she developed new confusion. Random blood glucose at midday was 1.2mmol/l. After treatment, hypoglycaemia recurred and persisted despite repeated intravenous dextrose boluses and glucagon injection. Blood glucose only improved with continuous 10% dextrose infusion. Causes were explored -a recent CT scan showed no pancreatic or intra-abdominal pathology;morning cortisol was normal. Literature review revealed very rarely Co-trimoxazole causes hypoglycaemia;hence this was stopped. Hypoglycaemia resolved within 48 hours;confusion improved. When serum glucose was 3.3mmol/l, c-peptide measured was inappropriately high (5175pmol/L). Co-trimoxazole is biochemically similar to sulfonylureas, mimicking their action on pancreatic beta-cells. Endogenous insulin hypersecretion raises c-peptide levels during hypoglycaemia. As Co-trimoxazole is renally excreted, when renal function is impaired it accumulates, with exacerbation of side effects such as protracted hypoglycaemia, especially at higher doses, as in our case. Hypoglycaemia will likely resolve after a 24-48h washout period, especially if renal function improves back to baseline. We recommend awareness of hypoglycaemia risk with co-trimoxazole treatment and blood glucose monitoring for inpatients taking high doses, especially in the setting of renal impairment.

INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes.

BACKGROUND: The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. METHODS: In this context, we have developed a Master Protocol, based on the "backbone" of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. DISCUSSION: The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.

New Onset Autoimmune Diabetes Associated with Acute SARS-COV-2 Infection

Introduction: Infection with SARS-CoV-2 has been shown to cause complications affecting nearly all organ systems of the human body. Here, we outline a case of SARS-COV-2 associated with new onset of autoimmune diabetes. Case Description: A 62-year-old female with past medical history of class III obesity, primary hypothyroidism, obstructive sleep apnea, and endometrial cancer established care with a multidisciplinary bariatric team in March 2021. This team included a dietician and psychologist to promote healthful lifestyle intervention with the intent to undergo bariatric surgery in December 2021. At a follow up visit in September 2021 her HbA1c was 6.7% (normal < 5.7 %) and she was diagnosed with type 2 diabetes treated with healthful lifestyle. After lifestyle modification the patient successfully lost 40 pounds. In December 2021, she presented to the ED (Emergency Department) complaining of fatigue and neuropathy. She was found to be hyperglycemic with glucose 369 mg/dL (normal 70-100 mg/dL). β-hydroxybutyrate was 32.1 mg/dL (normal 0.20-2.81 mg/dL) and anion gap was 10 mmol/L (normal 3-13 mmol/L). She was resuscitated with fluid and referred urgently to Endocrinology. One week later, she was seen in the office by her endocrinologist for initial consultation. She was acutely complaining of anosmia and ageusia and found to be positive for acute SARS-COV-2 infection. Bloodwork revealed an increase in HbA1c to 13.9 %, fasting glucose 303 mg/dL (normal 70-100 mg/dL), normal C-peptide 1.6 ng/dL (normal 0.5-3.3 ng/dL), elevated GAD antibody 154.3 IU/mL (normal 0-5 IU/mL), elevated anti-Islet Cell antibody IgG ratio 1:64 (normal < 1: 4), elevated anti-Islet Antigen 2 antibody >120 U/mL (normal 0–7.4U/mL), and elevated anti-Zinc Transporter 8 antibody 500 U/mL (normal 0–15 U/mL). Patient was diagnosed with autoimmune diabetes associated with acute SARS-COV-2 infection and was started on basal-bolus insulin with improvement in her hyperglycemia. She did not require hospital admission or steroid treatment for SARS-COV-2 infection. Discussion: Although viral infections are associated with type I diabetes related autoimmunity in children, this case study is unique regarding its mechanism in association with SARS-CoV-2 infection. Potential mechanisms underlying onset of diabetes in patients with SARS-COV-2 infection are still under investigation. One potential mechanism involves pancreatic beta cell dysfunction with diminished insulin secretion due to a systemic inflammatory cascade. This case is unique in as the patient’s C-peptide was still detectable indicating intact beta cell function. Furthermore, the patient’s diabetes paradoxically worsened after a more healthful lifestyle and 40-pound weight loss. This patient’s case of autoimmune diabetes illustrates the need for further research into the mechanisms underlying the onset of diabetes after SARS-COV-2 infection.

Euglycemic diabetic ketoacidosis in a young adult associated with the use of SGLT2 inhibitors

Introduction: In 2015, the FDA warned the risk of euglycemic diabetic ketoacidosis (eDKA) as an adverse effect of SGLT-2 inhibitors (SGLT2i), with a frequency of < 0.1%. We present the case of a patient with type 2 diabetes mellitus (T2D) who developed eDKA with empagliflozin. Case Description: A 34-year-old man with a history of obesity, hypothyroidism and T2D 5 years ago, with regular medication of metformin 850mg bid and levothyroxine 100ug/d. He was admitted to the emergency room due to dyspnea, abdominal pain, vomiting, and drowsiness. He reported that from 4 days before his admission, he took the combination of empagliflozin/metformin 12.5/1000mg bid due to blood glucose of 385mg/dL. Analytical: leukocytes: 12940 x mm3, hemoglobin: 16,5 g/dL, platelets: 219000 x mm3, sodium: 130 mmol/L, potassium: 4,29 mmol/L, glucose: 179 mg/dl, creatinine: 0,89 mg/dl, urea : 22,1 mg/dl, test for COVID-19 (-);arterial blood gases test: pH 7,13;pC02 13;HCO3 4,2;Gap Anion: 13,8;Lactate: 1,2;Osm: 269. Ketonuria: 4+. With the diagnosis of eDKA he was managed in emergency with EV hydration, EV bicarbonate, and EV infusion of insulin. In the Endocrinology service: A1c: 9.4%, C-peptide: 6.72ng/ml, cGFR (CKD-EPI): 119 mL/min/1.73 m2, LDL: 30 mg/dL, HDL: 33 mg/dL, triglycerides: 148 mg/dl. He was discharged with nutritional medical therapy, NPH-insulin: 40UI/d, metformin 850 tid. In follow-up by teleconsultation, home self-monitoring showed capillary blood glucose between 80-130mg/dL. Discussion: the eDKA due to SGLT2i is uncommon in patients with T2D;factors that were identified in some of the reports as possible triggers for ketoacidosis were certain serious illnesses, a reduced intake of food and fluids, and a reduced insulin dose. The remission time for eDKA is similar to other cases reported in the literature. In view of the increased use of these drugs and the risk of eDKA in patients with T2D, we must consider this adverse effect when prescribing some iSGLT2.

Development of New Onset, Protracted Hyperglycemia Triggered by COVID-19 Vaccination with Ultimate Resolution in an Individual without Prior Dysglycemia

Introduction: Frequently, endocrinologists are asked for advice on COVID-19 vaccination. For patients with diabetes, promoting vaccination against COVID-19 is critical;research has shown a significantly increased risk of severe infection in these patients. Notably, there appears to be a physiological connection between COVID-19 infection and hyperglycemia. There have been multiple cases of patients developing hyperglycemia after contracting COVID-19. In contrast, there are few reported cases of new onset hyperglycemia developing after the COVID-19 vaccination. Case Description: We present the case of a 63-year-old woman with no significant past medical history. She maintained a healthy lifestyle and stable weight for several decades (BMI 24.3). She received her first dose of the Pfizer COVID-19 vaccination in December 2020. Frequent workplace testing (weekly, between 12/4/20 and 2/12/21) documented no evidence of COVID-19 infection, and no symptoms of COVID-19 had occurred at any time before or after immunization. Four days post-vaccination, she developed significant polyuria and polydipsia, but accepted a second dose 3 weeks later. The patient’s symptoms persisted for months and were accompanied by weight loss. Five months later, she finally sought medical attention. Her HbA1c and serum glucose were elevated (12.9% and 295 mg/dL, respectively). At her endocrinology appointment in May 2021, BMI was 22.4, consistent with her reported weight loss of 1 pound per week. Metformin (500 mg twice per day) and sitagliptin (100 mg per day) were prescribed and a low-carbohydrate diet was recommended. One week later, with fasting blood glucose between 114 - 188 mg/dL, sitagliptin was discontinued. The next week, fasting blood glucose between 71 - 95 mg/dL allowed metformin discontinuation. In September 2021, she reported continued weight loss (BMI 20.2), attributed to the low-carbohydrate diet. After 2 months off medication, both fasting and postprandial blood glucose were < 100 mg/dL. HbA1c (5.1%), C-peptide (1.1 ng/mL), and serum glucose (90 mg/dL) were all normal. She remains normoglycemic without medication. Discussion: There have been several reports of new-onset diabetes following COVID-19 vaccination. However, to date, we identified no published case reporting complete resolution of diabetes. We hypothesize that immune changes resulting from her COVID vaccine were associated with increases in inflammatory markers causing temporary beta cell toxicity. It is unclear what the impact of a booster will be on her glycemic control, therefore we recommend she remain vigilant for symptoms of hyperglycemia after getting her third dose.