bluuebunny/crossref_metadata_2025_split huggingface dataset:
Checkpoint Inhibitor-Associated Autoimmune Diabetes Mellitus: A Case Report
Authors: Gnanapragasam Helen Prathiba , Sharma Rajeev 
Published: May 2021

Abstract
Introduction: Checkpoint Inhibitors have revolutionized the management in oncology by stimulating the immunological response to cancer. On the contrary, there is an increase in immune-related adverse effects affecting various systems including the endocrine. We report a unique case of new-onset diabetes with diabetic ketoacidosis (DKA) within 18 days of receiving checkpoint inhibitors for Merkel Cell Carcinoma.
Clinical Case: An 86-year-old man diagnosed with locally advanced Merkel cell carcinoma underwent surgery and radiotherapy to his right face and neck. Four months later, the positron emission tomography (PET) scan was consistent with liver metastasis. Pembrolizumab, a programmed death receptor-1 (PD-1) inhibitor was initiated as next line treatment. Prior to starting pembrolizumab, his blood glucose was 92 mg/dL (60–120) with no previous history of diabetes mellitus. He presented 18 days later to the emergency room with altered mental status, polyuria, and polydipsia with a blood glucose of 980 mg/dL, anion gap of 26 mmol/L (5–15), and was managed for DKA with new-onset Diabetes Mellitus. HbA1C was 7.0% (4–5.6). He was discharged on subcutaneous insulin glargine once daily, pre-meals insulin aspart, and was referred to the endocrinology clinic. Further investigations obtained during the clinic visit demonstrated low C-peptide of &lt;0.7 ng/mL (0.8–6), glucose 76 mg/dL, positive glutamic acid decarboxylase (GAD-65) antibodies of &gt;25,000 nmol/mL (&lt;0.02), negative islet antigen-2 antibody, islet cell antibody and zinc transporter 8 antibodies. Other endocrine tests showed normal thyroid function, cortisol, and adrenocorticotrophic hormone (ACTH) levels. The patient was educated on checkpoint inhibitor-associated autoimmune diabetes and the need for a lifelong insulin regimen.
Clinical Lesson: Our case highlights the immune-related adverse effect involving the endocrine system from checkpoint inhibitor therapy. In comparison to the other common endocrinopathies associated with checkpoint inhibitors, autoimmune diabetes is rare (~ 1–2% incidence) and only less than half demonstrate antibodies with a median time of 8 weeks since exposure. GAD-65 antibodies are the commonest antibody noted and our patient had a robust GAD-65 antibody of &gt;25,000 depleting C-peptide within 18 days of receiving the Pembrolizumab resulting in DKA with a new onset of diabetes.
We conclude that diabetes mellitus is a rare but serious adverse effect of immune checkpoint inhibitor therapy. Society for Immunotherapy of Cancer Toxicity Management Working Group consensus recommendations from 2017 recommends routine screening to include baseline HbA1c, basic metabolic panel, thyroid function test, AM cortisol, and ACTH prior to treatment. It also recommends repeating the thyroid function test and basic metabolic panel to allow the monitoring of glycemic trends before each cycle.
Combined Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State Associated With COVID 19
Authors: Naranjo José Martín Alanís , Larrondo Eduardo Federico Hammeken , Arroyo María Guadalupe Silva 
Published: May 2021

Abstract
Background: Cases of patients with combined DKA and HHS associated to COVID-19 are scarce but showed Hispanics patients tended to be associated with higher mortality. Clinical Case: A 51-year-old Mexican man with past medical history of T2DM presented to our hospital with 1-week history of fever, dyspnea, polydipsia, and nausea. Initial vital signs were notable for fever (axillary temperature 39°C) and low oxygen saturation (90% on room air). His examination was notable for a BMI of 31.2 kg/m2. Blood tests showed hyperglycemia (663 mg/dl, n 70–100 mg/dL), hypernatremia (146 mEq/L, n 135–145 mEq/L), hyperchloremia (113 mEq/L, n 95–110 mEq/L), elevated C-Reactive Protein [CRP] (18.7 mg/dl, n &lt; 0.7 mg/dl), elevated lactate dehydrogenase [LDH] (672 U/L, n 100–170 U/L), high D-dimer (3420 ng/ml, n &lt;400 ng/ml), elevated WBC count (13,200 cell/mm3, n 4600–10200 cells/mm3), high neutrophil count (11300 cells/mm3, n 2000–6900 cells/mm3) and low lymphocyte count (200 cells/mm3, n 600–3400 cells/mm3). Arterial blood gas analysis showed metabolic acidosis (pH 7.2 [n 7.35–7.45], bicarbonate 8mmol/L [22–28 mmol/L], anion gap 23.5 [8–16]) with ketones (100 mg/dl, n &lt;5 mg/dl) in the urine analysis. Calculated serum osmolarity resulted of 328 mOsm/kg (n 278–305 mOsm/kg). Electrocardiogram showed no alterations. Chest X-ray revealed bilateral ground-glass opacities with bilateral infiltrates. Blood and urine cultures were negative. The patient tested positive for SARS-CoV-2. Intravenous fluids, insulin infusion with ceftriaxone i.v. (2 g daily) and clarithromycin p.o. (1 g daily) were initiated but did not result in clinical improvement, continuing with fever, hyperglycemia, metabolic acidosis and worsening of respiratory status. At first day of hospitalization, he presented acute respiratory distress syndrome and was intubated and sedated. He developed multi-organ failure and expired after 3 days of mechanical ventilation. Conclusion: DM is a predisposing factor leading to severe COVID-19 disease. Patient showed similar features reported in cases who died of combined DKA and HHS associated with COVID-19: male, Hispanic, poor blood glucose control, mechanical ventilation, elevated CRP with high LDH and D-dimer. In this patient, obesity was an additional feature that led to severe COVID- 19. Reference: Hoe Chan K, Thimmareddygari D, Ramahi A, Atallah L, Baranetsky NG, Slim J (2020) Clinical characteristics and outcome in patients with combined diabetic ketoacidosis and hyperosmolar hyperglycemic state associated with COVID-19: a retrospective, hospital-based observational case series. Diabetes Res Clin Pract 166:108279
Euglycemic Diabetic Ketoacidosis With SGLT-2 Inhibitor
Authors: Manas F N U , Mols-Kowalczewski Barbara L , Mandal Shobha 
Published: May 2021

Abstract
Introduction: The SGLT-2 inhibitors (SGLT-2i) are a newer anti-diabetic drugs. Their use has tremendously increased due to their favorable profile but they are also the focus of attention because of their side effect of euglycemic diabetic ketoacidosis (euDKA), which is challenging to diagnose because of its rarity and normal or mildly elevated blood glucose levels. SGLT2i decrease blood glucose independently of insulin secretion, by reversibly inhibiting SGLT2 protein which is responsible for reabsorbing glucose from the proximal renal tubule. Beside glycemic control with reduced glycated hemoglobin, they also decrease all-cause mortality, cardiovascular mortality, and hospitalization for heart failure. The major side effect is genitourinary infections, euDKA and volume depletion. EuDKA is characterized by blood glucose &lt;200mg/dl, anion gap metabolic acidosis and positive serum ketones. It can, therefore, present without hyperglycemia and the symptoms of dehydration, making it challenging to identify. DKA is rarely seen in DM-2 and the normal glucose levels can cause misinterpretation of the patient’s condition, causing a delay in treatment. The beta-hydroxybutyrate and arterial pH should be checked in suspected SGLT2i associated euDKA. The mainstay of treatment of euDKA is immediately stopping SGLT2i and traditional DKA treatment protocol. Patient should be educated regarding adequate hydration and adequate calorie intake while using SGLT2i and physician should avoid using SGLT2i in patients with poor oral intake, alcohol dependence or pregnancy. Case Presentation: A 52-year-old male with uncontrolled type 2 diabetes, on Metformin and Sitagliptin, presented to clinic. Canagliflozin (SGLT-2i) was added to his oral hypoglycemic regimen. Six days later he presented with blurred vision, lightheadedness, nausea, vomiting, and abdominal pain. On examination, he had tachycardia and tachypnea. Labs were significant for glucose levels of 131mg/dL, bicarbonate 12meq/l, anion gap 20, creatinine 0.7mg/dl, normal lactic acid. Serum ketones were positive with elevated beta-hydroxybutyrate of 5.9mmol/l. Blood gas analysis showed a pH of 7.14. The patient was admitted to ICU and managed according to the guidelines for DKA. The symptoms resolved within 24 hours, with a reduction of anion gap to 12. Canagliflozin was discontinued indefinitely and the patient was discharged with the diagnosis of SGLT2i-induced euDKA. Conclusion: SGLT2i-induced euDKA can present without the classical laboratory findings of DKA. The patients, with a history of SGLT2i use and, signs and symptoms of DKA, even in the absence of hyperglycemia, should be suspected of euDKA. The complete lab work with blood gas analysis, blood and urine ketones including beta-hydroxybutyrate level must be done to ensure that the diagnosis is not missed and timely interventions are made to manage this serious condition.
Extreme High Insulin Requirements in Two Non-Diabetic Patients Following Cardiac Transplantation
Authors: Balasubramanian Priyadarshini , Moreau Christi , Ahmad Tariq , Inzucchi Silvio E 
Published: May 2021

Abstract
Introduction: Blood glucose (BG) management is challenging following cardiac transplantation (CT) due to insulin resistance (IR) induced by post-operative stress and inflammation, intravenous pressors, and high-dose steroids. Severe IR manifested by extreme insulin requirements is rare. We report 2 such patients without prior history of diabetes (DM) requiring massive doses of IV insulin in the immediate post-op period. Patient 1: A 59 y/o male with hypertrophic cardiomyopathy (CM) presented with symptoms of acute decompensated heart failure and ultimately underwent orthotopic CT. At baseline, HbA1c was 5.8% and BMI 23 kg/m2. Exam was significant for acanthosis nigricans. He received 1g IV methylprednisolone (MP) during surgery and 125 mg IV Q 8 hours subsequently. His blood glucose (BG) immediately post-op was 312 mg/dL and was started on IV insulin. Despite doses up to 93 U/hr, BG remained &gt;300mg/dl. With steroid taper, insulin requirements declined rapidly. He was transitioned to small dose of insulin glargine and was discharged on metformin monotherapy with near-normal BGs. Patient 2: 49 y/o male with a genetic CM was admitted for elective orthotopic CT. At baseline, HbA1c was 5.8% and BMI 32 kg/m2. Exam was significant for central obesity. He received similar doses of IV MP as patient 1 but also required inotropes (dobutamine, epinephrine, milrinone mixed in 5% dextrose containing fluids.) His BG immediately post-op was 284 mg/dL and was started on IV insulin. Despite doses up to 85 U/hr, BG remained &gt;250 mg/dl. With steroid taper, insulin requirements resolved rapidly and he was discharged with normal BGs off all DM agents. Pseudo insulin resistance (i.e. line occlusion or erroneous IV insulin solution concentration) was excluded in both cases. Conclusion: Although many patients require high insulin doses after CT, rarely are infusion rates as high as in our patients achieved, particularly in non-diabetic individuals. We propose that it was the combination of underlying IR/prediabetes, counter-regulatory hormones, proinflammatory cytokines, increased lipolysis, with exogenous steroids and catecholamine-based inotropic agents that resulted in extreme inhibition of insulin action. However, because this combination of factors is not necessarily rare in post-CT patients, other factors must have been at play and will remain to be elucidated. From a pragmatic standpoint, because of rapid decrease in BG levels as steroids were tapered, we recommend very close follow-up of such patients with rapid decreases in insulin infusion rates as necessitated by trends in prevailing glycemia to prevent hypoglycemia. It would also be helpful to target a slightly higher glucose goal in such patients to prevent subsequent hypoglycemia.
Immune Checkpoint Inhibitor Associated Type 1 Diabetes
Authors: Duenas Jose Andres , Rendon Maria Daniela , Zaidi Syeda Sumbul Zahra , Singh Jassimran , Mirza Lubna 
Published: May 2021

Abstract
Background: Immune-checkpoint inhibitors are increasingly being used in cancer therapy. Nivolumab is a monoclonal antibody that has been used in a variety of conditions such as metastatic melanoma. Treatment with immune checkpoint inhibitors enhances immune response but is also known to diminish immune tolerance and increase autoimmune toxicity. Nivolumab works by binding and inhibiting the programmed death cell 1 receptor (PDC1). This is a negative regulator of the activity of the T lymphocytes. Normally the biding of PDC1 with PDL1 and PDL2 ligand will leads to inhibition of protein kinase signaling pathways that would lead to inhibition of T cells proliferation and production of cytokines.
So Nivolumab will increase the response of T cells by blocking PDC1 increasing selectivity with tumoral cells.
On the other hand, the use of nivolumab inhibiting the PD1 pathway could result in the loss of self-tolerance that can be related to an increase of autoimmune events. Such as autoimmune DM1. Case description: A 67-year-old woman was referred to the Endocrinology service for hypothyroidism in 2016. She had been diagnosed 5 years earlier with malignant melanoma on left forearm that was surgically removed, along with her lymph nodes. No chemo or radiation was required. There was no personal or family history of DM. Blood glucose levels were normal. About one month later, she found out her melanoma came back on her face, (edge of her mouth) and got treated with Nivolumab. A couple of months later she reported to the consult with fatigue, dry mouth, polydipsia, and polyuria. Symptoms were progressive and was hospitalized at initial dx of DM w/glucose &gt;800. She got diagnosed with New onset diabetes. The Diagnosis confirmed with + GAD antibodies and low C-Peptide. Her hemoglobin A1C today (4 years later) is 6% with a fingerstick blood sugar of 147 mg/dl. Average glucose is 131 mg/dl with a standard deviation of 38.87. 87.1% of her blood sugars are staying in target range, low blood sugars less than 70 are 4.3%, high blood sugars are 8.6%. Conclusion: The diagnosis of insulin dependent DM is confirmed because of the clinical presentation, persistent hyperglycemia, and low C-peptide. The normal pre-nivolumab fasting blood glucose levels suggest the absence of diabetes prior to nivolumab. 4 years later, the patient has not shown any signs of remission, so, if develops, DM1 should be considered as a permanent complication of using Nivolumab.
Ketogenic Diet Induced Severe Diabetic Ketoacidosis in an Elderly With Undiagnosed Diabetes
Authors: Lertdetkajorn Khemaporn , Techawantochandej Athittaya , Thavaraputta Subhanudh 
Published: May 2021

Abstract
Introduction: A ketogenic diet is a high-fat, low carbohydrate with adequate amounts of protein diet that is well known and extensively utilized as a nonpharmacological intervention for weight loss and glycemic control. However, a very low level of carbohydrates and high amounts of lipid and protein can lead to ketosis and may trigger ketoacidosis in a high-risk population. Clinical Case: A 74-year-old Caucasian male with hypertension and hyperlipidemia, who presented with shortness of breath, nausea, vomiting, generalized abdominal pain, polydipsia, and polyuria for few days. The patient denied a prior history of diabetes. His family history is significant for rheumatoid arthritis in his mother with no history of diabetes in the family. He reported that he had been on a ketogenic diet for a month and had lost 22 pounds. His BMI is 29.3 kg/m2 on admission. His physical examination was notable for tachycardia with extremely dry mucous membrane. He had fast and deep respirations that were suspicious for diabetic ketoacidosis. His bedside VBG showed pH6.8, pCO2 27 mmHg, and HCO3 5 mmol/L. Other laboratory findings revealed glucose 800 mg/dL, anion gap 39, lactic acid 9 mmol/L, bicarbonate 4 mmol/L, which indicated severe diabetic ketoacidosis. He received a 3 liters of NSS bolus and an insulin drip was started. With a worsening mental status, and increasing in his respiratory drive, endotracheal intubation was performed. DKA protocol was initiated and the patient was then admitted to the ICU for close monitoring. The patient was later stabilized and improved and was extubated. Diabetes ketoacidosis resolved after 2 days. Hemoglobin A1c found to be at 12% which revealed that the patient might be undiagnosed for diabetes after all. Later on, troponin was found to be trending up respectively. A small non-ST elevation microinfarction was suspected. Cardiology was consulted. He was subsequently taken to the cardiac catheterization lab. One DES stent was placed in the mid circumflex successfully. The patient was discharged with Lantus 40 units at nighttime and Lispro 5 units TID premeal on the day seventh of admission. The patient was discharged to home with home health care for diabetic education and teaching insulin administration. Conclusion: Even though the ketogenic diet is considered a safe nutrition option and there is multiple clinical evidence support the use of the ketogenic diet in diabetes, obesity, and endocrine disorders, it may cause serious side effects, including ketoacidosis. An accumulation and elevation of ketone levels have known to be associated with increased oxidative stress and inflammatory process which rising the risk of vascular inflammation and other comorbidities. Therefore, physicians should be cognizant of the complications and risks, and benefits of the ketogenic diet. Risks and benefits of the ketogenic diet should be discussed with patients before initiation of this diet.
Ketosis Prone Diabetes in an Obese Male Adolescent: A Case Report
Authors: Alhammad Zahrah , Aljaman Abdulaziz , Douba Najah Younes , Alhamdan Ali Saleh , Alghamdi Abdulrahman Aidh 
Published: May 2021

Abstract
Introduction: Ketone-prone diabetes (KPD) is an atypical type of diabetes with features from both Type 1 and 2 diabetes, which may lead to its misdiagnosis. Patients usually present with an attack of DKA, but after its resolution, Insulin can be discontinued gradually in most patients with the maintenance of sufficient glycemic control with oral hypoglycemic medications. Clinical Case: A 14 -year-old Saudi male student, presented to the emergency department of our tertiary hospital in November 2017 complaining of nausea and vomiting of two days duration proceeded by a one-week history of generalized fatigue, polydipsia, and polyuria. The patient suffered from long-standing obesity since childhood; otherwise, past medical history was unremarkable. Family history was positive for Type II diabetes in his mother at the age of 48. On examination, the patient was dehydrated, tachypneic, and obese with a BMI of 34 kg/m2 and has patches of acanthosis nigricans over the neck and both axillae. Laboratory investigations showed blood glucose of 455 mg/dL, metabolic acidosis with a pH of 7.22, HCO3 of 11, and a high anion gap of 17, with urine being strongly positive for ketones (++++), HbA1c was 11.6%, and lipid profile showed dyslipidemia. The patient was diagnosed with diabetes ketoacidosis (DKA) and managed with Fluid, Insulin, and potassium infusions according to the Hospital’s DKA protocol. DKA resolved, and the patient was discharged with the impression of ketone prone diabetes based on the presentation of DKA along with features of insulin resistance. Discharge medications were Insulin Glargine 30 units SC once daily, Metformin 500 mg twice daily, and Gliclazide 60 mg Once daily. He was educated on usage and titration of insulin dosage according to glucose readings and monitoring. In subsequent follow-ups as an outpatient, it was noticed that the insulin requirements were gradually declining until it was possible to stop it completely after around six months of follow-up. The patient was transitioned from insulin to GLP-1 agonist (Liraglutide), which helped to achieve significant weight loss. After about one year, Liraglutide (Victoza) was not available in the hospital. However, the patient was controlled on Metformin and Gliclazide. Consequently, the patient has been in remission with adequate glycemic control and had not developed another attack of DKA. Latest review in the clinic in April 2020 showed his BMI of 27.4 kg/m2 and HbA1C of 7.5%. Conclusion: Although it is a rare and atypical type of diabetes, Ketosis Prone diabetes should be kept in mind when a patient presents with DKA but has features of insulin resistance to avoid misdiagnosis and inappropriate management, with proper education to patients and their families on the importance to titrate insulin requirements.
Losartan Induced Hypoglycemia in the Absence of Diabetes Mellitus - a Concealed Diagnosis
Authors: Syed Shumail , Taylon Alain Joseph 
Published: May 2021

Abstract
Background: Losartan has been shown to attenuate symptomatic and hormonal responses to hypoglycemia in prior studies. This results predominantly from blocking AT-II receptors blunting the hypoglycemia-induced rise in plasma epinephrine predisposing them to hypoglycemia unawareness. To our knowledge, however there are no case reports describing losartan induced hypoglycemia in a nondiabetic patient. This abstract is the first description of a patient without diabetes mellitus experiencing severe hypoglycemia induced by the ARB, Losartan. Clinical Case: A 51- year old nondiabetic female was found to be somnolent and in acute respiratory failure. Blood sugar was 34 mg/dL. She received D10 by EMS while coming to the hospital. She was intubated and treated for atypical pneumonia based on bilateral interstitial infiltrates. She remained persistently hypoglycemic around 62 mg/dL. Her most recent A1c was 4.4%. Thyroid function was within normal limits. AM cortisol was 16.8 mcg/dL so there was no concern of adrenal insufficiency. She had no history of gastric bypass surgery. She underwent a 72-hour fast and developed symptomatic hypoglycemia. Her venous blood glucose at this time was 49 mg/dL. Her hypoglycemia panel obtained at this time showed C-peptide 0.7 ng/mL, total insulin 2.9 microU/mL, proinsulin 3.1 pmol/L, IGF 45 ng/mL and BHOB 13.5 mmol/L. Her oral hypoglycemic agent screen was negative. Based on levels that were obtained during the hypoglycemic episode, this correlated to a non-diagnostic study for conventionally described causes of hypoglycemia including exogenous insulin, insulinoma, NIPHS, PGBH, oral hypoglycemic agent, insulin autoimmune or IGF-mediated. Her medication list was analyzed again. We learnt that she had recently been started on losartan about a month prior to this admission for her heart failure management. On further review, the patient mentioned that she was noticing these hypoglycemic events in the last month and that seemed to coincide with when she was started on losartan. We subsequently held losartan which resulted in profound improvement in her glycemic control and her blood sugars improved to a range of 110–140 mg/dL consistently. She was discharged from hospital off losartan. Blood sugar was stable on repeat testing outpatient after discharge.
Conclusion: This is the first case that demonstrates the role of losartan in causing severe hypoglycemia in patients without a history of diabetes mellitus. Discontinuation of losartan resulted in prompt improvement of hypoglycemia.
Reference: (1) Deininger E, Oltmanns KM, Wellhoener P, Fruehwald-Schultes B, Kern W, Heuer B, Dominiak P, Born J, Fehm HL, Peters A. Losartan attenuates symptomatic and hormonal responses to hypoglycemia in humans. Clin Pharmacol Ther. 2001 Oct;70(4):362–9. PMID: 11673752.