bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the Use of Telemedicine in Endocrinology Clinic
Authors: Nemati Maryam , Reddy Archana , Jung Syung , Nguyen Jessica
Published: May 2021

The COVID-19 pandemic changed patient-physician interaction. As the need to reduce COVID-19 transmission, many clinic providers have converted their in-person visits to video or phone visits. Our endocrinology clinic initiated tele visits early on when the pandemic had just started. Telemedicine may help with patient’s compliance by decreasing various burdens. Some studies show that patients and providers hope telemedicine will continue after the crisis. In this study we evaluated benefits and challenges of telemedicine in our endocrinology clinic. Patients who had a telemedicine endocrinology visit after informed consent were surveyed on 10 questions regarding benefits and limitations of the tele visits compared to the clinic visit. Patient also responded if they want to continue with telehealth after COVID-19 pandemic. Providers also were surveyed about the benefits and limitations of telemedicine and responded if they want to continue with telemedicine after pandemic. We also analyzed no-show rate from January 2020 through May 2020 for 6 weeks before and after the implementation of telemedicine. Among 109 patients who were interviewed 65% declared that they would like to continue with telemedicine after pandemic. Total of 42% of patients prefer video visit and 37% prefer phone calls. Among Interviewers 45% report benefit of spending less time, however 54% stat the time of meeting, itself was about the same. 54% believe they spent less money with telemedicine. 37% of interviewers report no limitation for telehealth while 25% report connection difficulty. 63% of patients state they do not have any difficulty traveling to the hospital. 90% of the patients declare all their question and concerns were responded and 77% stated the quality of care with telemedicine is almost the same via clinic visit. Among providers 75% want to continue telehealth after COVID-19 pandemic. 50% of providers mention patient satisfaction and 25% notice time saving as benefits. 46% of the providers mention lack of physical exam and 40% mention technology connection as the limitation for video visit. 60% of providers believe lack of exam is the limitation of phone visit. 87% of the providers believe the quality of care via phone is not like in clinic visit while 75% of the providers believe the quality of care is similar in video visit compare to in clinic visits. No show rate decreased from 30% to 27% after the implementation of telemedicine in 6 weeks prior and after pandemic. Endocrinology clinic has significant number of patients who need long term close follow up for medication adjustments, symptom checks and counseling. Given patients and providers satisfaction rate, telemedicine can be incorporated as part of regular clinic visits after the Covid crisis ends. Telehealth can be more efficient for both patients and providers but there are challenges which needs to be addressed.
The Impact of Diabetes and African American Race in COVID-19 Severity
Authors: Arosemena Marilyn A , Pyzer Athalia , Yu Jovian , Flood Blake , Rouhani Sherin , Trujillo Jonathan , Gajewski Thomas , Casimiro Isabel
Published: May 2021

Introduction: COVID-19, an illness caused by the novel coronavirus usually presents as a mild to moderate flu like illness, but can lead to pneumonia, acute respiratory distress syndrome and death in some patients. Since the onset of the COVID-19 pandemic there has been special attention towards patients with diabetes. Not only is diabetes highly prevalent in patients with COVID-19, but diabetes has been reported as a significant predictor of morbidity and mortality. Furthermore, race seems to be a predictor of severity with black people dying at 2.3 times the rate of white people. Methods: Here we performed a retrospective study of 524 cases of COVID-19 at an academic center in Chicago between March 2020 until August 2020. Data were obtained from patients that consented to the study to examine the relationship between diabetes, BMI, age, and race with degree of COVID-19 severity. Not all patients had all clinical and demographic data available. COVID-19 severity was determined using a severity index obtained from the measured SpO2 divided by the FiO2/fraction of inspired oxygen times 100. Numbers ≥ 315 mmHg were defined as low severity with patients generally requiring outpatient care, while 235–314 mm Hg were classified as moderate severity generally requiring inpatient care and≤ 234 mm Hg indicated high severity generally requiring intubation/ICU care. The Pearson correlation coefficient was used for linear correlation analyses. Proportion for categorical values were compared using the Chi squared test, the means for continuous variables were compared using two-tailed t tests or one way ANOVA (with Tukey post-test) for comparisons involving more than two conditions. A multiple linear regression model was used to assess the contribution of different variables. Differences were considered statistically significant at p<0.05 Results: Among 120 patients with an A1c, 55 (46%) patients had diabetes and 65 (54%) did not have diabetes. More patients with a high severity index were seen in the cohort with diabetes compared to those without diabetes (72% compared to 28% p=0.004). Univariate analyses revealed statistically significant positive correlations with higher COVID-19 severity and older age, BMI, and African American race. ANOVA analysis revealed a statistically significant difference between increasing BMI and worse severity category with a BMI mean of 29.3 kg/m2 in the low severity category compared to 34.9 kg/m2 in the moderate severity category (p=0.006). A multi-variate analysis adjusting for all variables revealed that A1c, older age and race were positively associated with higher COVID-19 severity. Conclusion: Increased A1c, older age and race are positively and independently associated with a higher COVID-19 severity index. Further research regarding the relationship between COVID-19 and these associations is urgently needed.
A Case of Autoimmune Hypoglycemia (Insulin Autoimmune Syndrome)
Authors: Mon Myint Myat Su , Htun Kyaw Wynn , Mulla Awais , Moe Khaing , Mukherji Rajat , Kazeem Saka
Published: May 2021

Introduction: Insulin Autoimmune Syndrome (IAS) is a condition caused by Insulin Autoantibody (IAA). IAS was initially reported in 1970 by Yukimasa Hirata from Japan. From 1970 to 2009, 380 cases were reported worldwide. We report a case of IAS in an African-American man who had recurrent episodes of syncope secondary to hypoglycemia. Case Report: A 50-year-old African American man with hypertension presented to emergency room after syncope. His initial blood glucose (BG) was 27 mg/dl. After Dextrose and glucagon injection, BG became 270 and he regained consciousness without any deficit. Vital signs and physical examination were unremarkable. He was not on any medication, and had no access to insulin or oral hypoglycemic agents. No family history of endocrine disorders, malignancy or autoimmune diseases were reported. He had been hospitalized two times for syncope secondary to hypoglycemia. During hospitalization, fasting insulin level was >1000 IU/ml with high C-peptide (3.5ng/ml). Hypoglycemic agents assay was negative. During outpatient follow-ups, fasting labs showed C-peptide 1.59 ng/ml, Insulin antibody 37.6 U/ml while venous BG was 65 mg/dl. Random BG at different occasions were 65, 68 and 55 mg/dl. HbA1C was normal. BMI was gradually increased from 32.4 to 34.8 in 6 months. During the third hospitalization, fasting venous BG were 45 and 57 on two different days, Insulin was 2111 IU/ml and C-Peptide was 1.78 ng/ml. Other labs including cortisol and TSH were normal. CT abdomen was unremarkable.

Discussion: In IAS, Insulin secreted after meal is bound by IAA. It causes hyperglycemia unchecked which triggers further insulin secretion. When the bound insulin dissociates from antibodies, it causes significant hyperinsulinemia and subsequent hypoglycemia. IAS can occur regardless of previous insulin exposure, as a solitary autoimmune manifestation or in association with other autoimmune disorders. It can be induced by drugs that contain sulfhydryl group. Etiology of IAS is still not fully understood but there are theories that genetic predisposition such as class II Human Leukocyte Antigen (HLA) and environmental triggers such as medications, viruses, hematological diseases etc. might play a role. In our patient, failure to test IAA in past admissions and lack of continuity of care delayed the diagnosis.

Conclusion: IAS should be considered especially in those who have no clear etiology of hypoglycemia in order to avoid unnecessary diagnostic and therapeutic procedures. Gold standard test for definitive diagnosis is IAA. As IAS is frequently self-remitting, supportive management is usually recommended. In severe cases, pharmacotherapies that reduce insulin secretion and immunosuppressants are occasionally necessary. But there is still no study that compares different treatment measures.
A Case of Diabetic Keto Acidosis From Alpelisib
Authors: Thumma Soumya P , Manchala Venkata R , Motahari Hooman , Shah Aashka M , Menon Lakshmi
Published: May 2021

Introduction: Alpelisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor, approved for the treatment of hormone receptor positive, human epidermal growth factor receptor-2 negative, PIK3CA-mutated metastatic breast cancer. While hyperglycemia is a known side effect of this drug, diabetes ketoacidosis (DKA) is rare. Only one case was previously reported in the literature to our knowledge. Here, we report a patient with prediabetes who presented with DKA after initiation of Alpelisib. Case Presentation: A 48 y.o. woman with metastatic left breast cancer was started on Alpelisib 300mg/day. HbA1C prior to the initiation of Alpelisib was in the prediabetes range at 5.7% with a fasting glucose of 106 mg/dL. Three weeks later, she presented to the ER with abdominal pain, nausea and vomiting. Vitals were notable for sinus tachycardia of 130 bpm. Exam was notable for diminished lung sounds over left lower chest. Labs revealed elevated serum glucose of 302 mg/dL, anion gap metabolic acidosis (anion gap 19, bicarbonate 10) and elevated beta hydroxy butyrate of 7.58 (normal < 0.27 mmol/L) consistent with DKA. Intravenous insulin infusion per DKA protocol was initiated and Alpelisib was held. She was bridged and subsequently transitioned to insulin glargine with insulin lispro sliding scale. Her C-peptide was 1.47 ng/mL (normal 0.90 - 4.30 ng/mL) with negative anti-GAD antibody. She developed multiple episodes of symptomatic hypoglycemia despite reduced insulin doses, requiring eventual discontinuation of insulin, followed by stabilization of blood glucose levels. Subsequent hospital course was complicated by acute respiratory failure from malignant pleural effusion due to which hospice care was initiated. Discussion: Hyperglycemia, diarrhea, nausea and rash are common side effects of PI3K inhibitors. Insulin binds to insulin receptor substrate which activates PI3K, which in turn activates protein kinase B resulting in the translocation of the glucose transporter GLUT4 to the plasma membrane causing glucose uptake. Alpelisib inhibits PI3K resulting in hyperglycemia through decreased glucose uptake. Hyperglycemia was reported in 51–65% of the patients treated with Alpelisib. Patients with prediabetes are at increased risk of worsening hyperglycemia. Hyperosmolar and ketoacidotic states are rare, usually encountered in patients with pre-existing diabetes. DKA can be a presenting manifestation in patients with mildly impaired glucose tolerance as in our case, highlighting the importance of screening for diabetes prior to initiation and monitoring glycemic control during therapy. Once hyperglycemia is detected, prompt initiation of oral hypoglycemic agent metformin (first line) or insulin therapy is recommended depending on the severity of the hyperglycemia. Dose reduction or eventual discontinuation of Alpelisib therapy may be necessary based on the severity of hyperglycemia.
A Novel Homozygous WRN Mutation Identified in a Middle Aged Man With Diabetes Mellitus Complicated By Multiple Features of Accelerated Aging
Authors: Jaafar Batoul , Nasrallah Mona , Oshima Junko , Lessel Davor
Published: May 2021

Background: Werner syndrome (WS; MIM# 277700) is a rare genetic disorder characterized by accelerated aging and predisposition to cancers. The causal gene, WRN, encodes a multifunctional nuclear protein that belongs to the RecQ family of DNA helicases. The earliest sign of WS is short stature due to the lack of pubertal growth spurt. In addition to the aged-appearance, WS patients typically develop functional declines of multiple organs including the endocrine system in their middle ages. Frequent Endocrine disorders include Type 2 Diabetes (T2D), dyslipidemia (DL), hypothyroidism, hypogonadism and osteoporosis. Most common causes of deaths are myocardial infarction and cancers in their 50s. Clinical Case: A 54-year old man was admitted for right wrist septic arthritis. His medical history was pertinent for premature cataract diagnosed in his 2nd decade. He had uncontrolled T2D (peak HbA1C level 10%) since the age of 32 years, treated with oral hypoglycemics including glimepiride, sitagliptin and metformin then shifted to insulin over the past 2 years. He also had DL since the age of 41 years, characterized by hypertriglyceridemia (766 mg/dL) with very low HDL (7 mg/dL). At age 50, he was diagnosed with hypothyroidism and negative anti-TPO antibodies. Moreover, he had refractory bilateral leg ulcers that manifested at the age of 35 years requiring multiple debridments, premature coronary artery disease at the age of 38 years and ischemic cardiomyopathy. On examination, his height was 154 cm and weight 42 kgs. He had prominent eyes, a pinched nose, grey and sparse scalp hair with absence of eyebrows and eyelashes. Hoarse voice was easily noticeable. He had very thin limbs, flat feet, central fat distribution and muscle wasting. Skin was shiny, tight, and atrophic with overlying hypermelanosis. Old bilateral hyperkeratotic deep feet ulcers were noticed with variable necrosis. Blood chemistry testing showed: HbA1C 8.2%, disturbed lipid profile, TG 341 mg/dL, HDL 17 mg/dL, LDL 155 mg/dL, and TSH 21 µU/mL (0.2 - 4.2 µU/mL). MRI of the foot revealed Achilles’ tendon calcification. His parents were 2nd degree cousins and had normal features. Three of his siblings had similar features and premature death. His diabetes was atypical due to his low BMI, high insulin requirements and the relatively early onset. WS was suspected based on the overall features of accelerated aging with characteristic deep leg ulcers and the family history. Genetic sequence analysis revealed a novel pathogenic homozygous nonsense variant mutation c.1111G>T, p.Glu371* of the WRN gene.

Conclusion: Werner syndrome is a rare genetic disease, but it carries high morbidity and mortality burden, in addition to impaired quality of life. It should be highly suspected in patients with atypical T2D, DL, premature coronary disease, refractory leg ulcers with features of accelerated aging and short stature.
Alpelisib-Induced Hyperglycemia- A Small Case Series
Authors: Ekanayake Preethika Subashini , Gerwer Johanna Elizabeth , McCowen Karen Clare
Published: May 2021

The phosphoinositide-3-kinase (PI3K) family consists of highly conserved enzymes that are key intermediaries in signal transduction regulating cell survival and mitogenesis. This axis has been implicated in many types of cancers. In 2019 Alpelisib (Piqray), a reversible inhibitor specific to the PI3Kα subunit, in combination with fulvestrant, was approved to treat hormone receptor positive, human epidermal growth factor receptor 2 (Her2) negative, PI3K mutated breast cancer. This approval followed SOLAR-1 trial results showing a 35% risk reduction in cancer progression or death with alpelisib-fulvestrant compared to placebo in a cohort with PI3K mutated breast cancer. PI3K also plays a critical role in the insulin signaling pathway and alpelisib has been shown to cause a dose dependent rise in plasma glucose, insulin and c-peptide. Here we present a case series of severe hyperglycemia induced by alpelisib.

A 44-year-old woman with ER+/Her2(-)/PI3K positive metastatic breast cancer was started on alpelisib. Previously, HbA1C was 5.4%. Hyperglycemia developed and HbA1c rose to 9.0% within 6 months of alpelisib 300mg daily. She started metformin and empagliflozin, which she was unable to tolerate due to nausea and vomiting. Her self-monitored blood glucoses were 300-400mg/dL within hours after her morning alpelisib dose. We discontinued empagliflozin when she developed metabolic acidosis with an increased anion gap. However, prior to any dose reduction, oncology discontinued alpelisib due to evidence of cancer progression. A week later, her glucoses normalized.

Second case is of a 64-year-old woman with stage IV ER+/Her2(-)/PI3K mutated breast cancer with bony metastases, who was started on alpelisib 250mg. Her prior HbA1C was 5.5%. Ten days after initiation of alpelisib, she developed grade 3 hyperglycemia (blood glucoses 200-500mg/dL). She was started on metformin 2000mg with alpelisib dosed at noon. However, she noted a marked rise in blood glucose in the afternoon, few hours following alpelisib dose. Thus, moving the alpelisib to bedtime allowed better control of glycemia by using overnight basal insulin.

Similarly, a 37-year-old woman with a history of ER+/HER2(-) stage IV metastatic breast cancer to the liver, with PI3K mutation was found to have acute, severe hyperglycemia with blood glucose of 300mg/dL, despite HbA1C being only 4.7%. This was attributed to initiation of alpelisib 2 days prior to admission. Given the severity of her insulin resistance (requiring > 100 units of insulin daily), alpelisib dose was reduced from 300mg to 150mg/day. On discharge, she was placed on metformin, dulaglutide, and basal and prandial insulins. Her HbA1C rose to 9.4% within 3 months of alpelisib initiation.

This case series demonstrate the unique challenges in managing alpelisib induced reversible hyperglycemia.
An Atypical Case of Latent Autoimmune Diabetes of Adults
Authors: Kim Keun Young , Manem Raveena , Sun Chenyu , Qureshi Faisal
Published: May 2021

Introduction: Latent autoimmune diabetes of adults (LADA) is an adult-onset, slowly progressing subtype of autoimmune type 1 diabetes mellitus (T1DM), that is often misdiagnosed as T2DM. We present an atypical case of LADA that was presented in an uncommonly late age with high titres of anti-glutamic acid decarboxylase antibodies(GADA). Clinical Case: A 78 year old male presented with alcohol intoxication and hyperglycemia. His serum glucose was 441mg/dL with negative urine ketones. Arterial blood gas showed pH 7.36, HCO3- 20mmol/L, pCO2 37.1mmHg. Anion gap was 11. HbA1c level was 16%. His body weight was 43.2kg with a BMI of 16.6. He was having polyuria and polydipsia, and was recently diagnosed with T2DM. His low BMI and symptoms raised suspicion for LADA. GADA titres revealed to be greater than 250IU/mL. A diagnosis of LADA was made. He was discharged on insulin. Conclusion: LADA shares the same genetic and autoimmune profiles with T1DM, but its insidious presentation overlaps with that of T2DM, often delaying diagnosis and adequate treatment. Our case of confirmed LADA at a late age of 78 is atypical, but warrants that adults newly diagnosed with diabetes should be screened for LADA if there are atypical findings. Among the anti-islet antibodies, GADAs are the most sensitive self antigen-antibody markers of autoimmune diabetes. The GADA titre is often used to stratify the risk of progression to insulin dependence in LADA, as a higher titre suggests severe β-cell loss in the pancreas. High GADA titres at the time of diagnosis at an elderly age is also an uncommon finding for LADA. Autoimmune diseases with aggressive autoimmune responses present early, while indolent progressions lead to late onset of symptoms and diagnosis. Thus it is unusual for our patient to have significantly high GADA levels. As pathophysiology of LADA is yet to be understood, further research may reveal the autoimmune process of GADA and the role of titres in disease activity and progression. There are no current therapeutic guidelines for LADA. Our patient was eventually discharged on insulin given his high HbA1c with high titres of GADA, but there were questions regarding the use of oral glycemic control agents due to his history of noncompliance. The use of oral agents for LADA remains an area of ongoing research. The general understanding is that due to its autoimmune etiology, insulin is eventually required. Early insulin therapy preserves residual β-cell function, improves glycemic control, and reduces the risk of long-term complications. As treatment goals of LADA would be to improve glycemic control with preserving residual β-cell function, further research may establish treatment guidelines for LADA. Monitoring anti-islet antibodies and c-peptide titres may play a role in establishing the timing to introduce oral agents and/or insulin for optimal treatment of LADA.
Autoimmune Diabetes After Initiation of Nivolumab in a Patient With Hepatocellular Carcinoma
Authors: Cristiano Elizabeth A , Grdinovac Kristine , Bhattacharya Rajib
Published: May 2021

Background: Immune checkpoint inhibitors have become an integral part of oncologic treatment, and their role is rapidly evolving. Nivolumab is an immune checkpoint inhibitor to anti-programmed cell death protein-1 (PD-1), which blocks PD-L1 from binding to PD-1, allowing the T cell to activate. While nivolumab has been shown to improve outcomes in certain malignancies, anti-PD-1 therapy can cause multiple endocrinopathies, including autoimmune diabetes (AD). Case: Here we present a 60-year-old male with a past medical history of end-stage liver disease secondary to hepatitis C and hepatocellular carcinoma (HCC). After undergoing transarterial chemoembolization for HCC, nivolumab was initiated. The patient initially tolerated the immunotherapy well. However, after three cycles, the patient acutely developed nausea, vomiting, lethargy and confusion. On presentation, he was afebrile, blood pressure of 85/46 mmHg, and a heart rate of 92 bpm. Exam was significant for abnormal mentation, and diffuse guarding of the abdomen. Laboratory workup showed hyperglycemia (1,178 mg/dL), positive serum ketones (beta-hydroxybutyrate 11.4 mmol/L), anion gap metabolic acidosis (AG 31, CO2 7 mmol/L), anemia, thrombocytopenia, acute kidney injury, leukocytosis, and elevated lipase. He was admitted to the intensive care unit, and further workup for acute pancreatitis was unrevealing. C-peptide was low (0.8 ng/mL) with corresponding hyperglycemia (1,055 mg/dL). GAD-65, islet cell, and insulin antibodies were undetectable. Hemoglobin A1c was 8.0%. Blood sugars from the previous one and a half years were in normal range. The patient was ultimately diagnosed with DKA and AD secondary to anti-PD-1 therapy. Discussion: This case is representative of AD secondary to nivolumab. While there have been many cases of AD reported after nivolumab, this is the fifth case that has been reported in a patient being treated for HCC. Our patient presented acutely in DKA with no prior diagnosis of diabetes. His antibody testing was undetectable, C-peptide was low in the context of hyperglycemia, and he continued to require insulin therapy until his passing. Prior case reports have demonstrated that the majority of patients with AD related to anti-PD-1 therapy present in DKA, while less than half have detectable diabetes autoantibodies. Specific haplotypes and diabetes autoantibodies have been postulated as risk factors for AD secondary to anti-PD-1 therapy. However, this does not explain the pathology behind a number of patients who have neither of these risk factors. While AD is a rare complication of nivolumab (<1%), this case identifies the need for patients and clinicians to be aware of and discuss the risk of AD after starting nivolumab. Future research is needed to identify risk factors for patients at highest risk of developing AD related to anti-PD-1 therapy and reporting every case encountered is the first step.
Checkpoint Inhibitor-Associated Autoimmune Diabetes Mellitus: A Case Report
Authors: Gnanapragasam Helen Prathiba , Sharma Rajeev
Published: May 2021

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 <0.7 ng/mL (0.8–6), glucose 76 mg/dL, positive glutamic acid decarboxylase (GAD-65) antibodies of >25,000 nmol/mL (<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 >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

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 < 0.7 mg/dl), elevated lactate dehydrogenase [LDH] (672 U/L, n 100–170 U/L), high D-dimer (3420 ng/ml, n <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 <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

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 <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

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 >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 >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

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 >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

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

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

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.