bluuebunny/crossref_metadata_2025 huggingface dataset:
Euglycemic Diabetic Ketoacidosis Post Bariatric Surgery in Type II DM in the Setting of SGLT2-Inhibitor Use
Authors: Alfares Khalid , Gidda Harish , Proudan Nikoletta
Published: May 2021

Introduction: Current AACE recommendations is to stop the SGLT-2 inhibitor at least 24 hours prior to elective surgery, planned invasive procedures, or anticipated severe stressful physical activity. However, case reports suggest that the pharmacologic effects of SGLT2 inhibitors persist beyond 5 half-lives of elimination (2–3 days), with glucosuria and ketonemia lasting as long as 9 to 10 days after discontinuation.

Case: A 51 year old female with a past medical history of hypertension, morbid obesity, DM type II, admitted to the hospital electively for bariatric surgery. Post-op day 1, she became tachypneic and lethargic. However, alert, oriented and responding appropriately. Lab work showed blood glucose levels <200 mg/dl (70–200 mg/dl), pH 7.21 (7.35–7.45), anion gap of 36 (4–14 mol/L), bicarbonate of 3 (23–34 mmol/L), pCO2 of 6 (35–45) and Potassium of 2.6 (3.5–5.2 mmol). UA showed glucose >500 mg/dl (0 mg/dl) and ketones 80 mg/dl (0 mg/dl). She was transferred to SICU. After reviewing her home medications, she was on Canagliflozin which was stopped 2 days prior to surgery and Glargine/Lixisenatide which was stopped 2 weeks prior to surgery as recommended by her endocrinologist. Patient was then diagnosed with euglycemic DKA. She was started on an insulin drip following potassium replacement and IV fluids. Over the course of few days, she started to feel better. Her PH, bicarb, anion gap and potassium all trended toward normal limits. She was transitioned off insulin drip to basal-bolus insulin regimen and then she was discharged on post-operative day 7 with the instruction to not take any SGLT2 inhibitors.

Discussion: SGLT-2 inhibitors is known to cause euglycemic DKA and ketosis. Our case brings to attention that discontinuation of SGLT2 inhibitor treatment 48 hours prior to surgery may not be adequate specially giving the half-life of the medication. The optimal timing of discontinuation remains unknown. Further studies are needed to evaluate if longer withholding period may be necessary (1).

1.Yehuda Handelsman, Robert R. Henry, Zachary T. Bloomgarden, Sam Dagogo-Jack, Ralph A. DeFronzo, Daniel Einhorn, Ele Ferrannini, Vivian A. Fonseca, Alan J. Garber, George Grunberger, Derek LeRoith, Guillermo E. Umpierrez, and Matthew R. Weir (2016) AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF SGLT-2 INHIBITORS AND DIABETIC KETOACIDOSIS. Endocrine Practice: June 2016, Vol. 22, No. 6, pp. 753–762.
Euglycemic DKA Associated With SGLT2 Inhibitors
Authors: TakallooBakhtiari Asieh , Butina Julio Piedra , Funderburk Sheri A Gillis , Brundavanam Hari V
Published: May 2021

Background: DKA associated with SGLT2 inhibitors also known as Euglycemic DKA (EDKA) is a rare condition characterized by milder degrees of hyperglycemia with a blood glucose level < 200 mg/dl. Unfortunately, this unusual feature can often lead to missed or delayed diagnosis with potential life-threatening outcomes. Clinical Case: The patient is a 53-year-old Caucasian male with PMH of type 2 diabetes mellitus treating with Metformin and Empagliflozin. He presented to the emergency room with shortness of breath, flu-like symptoms, and decreased oral intake for a couple of days. Vital signs at presentation were: Temperature 98.2 °F, pulse rate 108 beats/min, respiratory rate 28 breaths/min, and blood pressure 134/72 mmHg. He was alert but ill-looking, moderately dehydrated with dry mucus membranes. The rest of the physical examination was unremarkable at the time of admission. In the initial blood work, sugar was found to be mildly elevated (163mg/dl), and hemoconcentration besides mild pre-renal acute kidney injury was detected. He was also found infected by the COVID-19 virus without hypoxemia or signs of pneumonia. Arterial blood gases showed metabolic acidosis with an elevated anion gap (PH 7.21, CO2 39.93mmHg, HCO3− 10mEq/L, anion gap 21mEq/L). Urine analysis was positive for ketones and glucose. After ruling out other causes of metabolic acidosis by screening for alcohols, salicylates, acetaminophen, lactic acid, and urine toxicology; the diagnosis of EDKA was made. He was treated with a 3L bolus of IV normal saline and an insulin drip with dextrose solution started as per the protocol based on his glucose levels and promptly admitted to the intensive care unit (ICU). Serial blood tests showed gradual resolution of ketoacidosis and anion gap normalized after 36 hours when insulin drip was stopped and replaced by subcutaneous insulin therapy. Conclusion: SGLT2 inhibitors increase the urinary excretion rate of glucose and subsequent fall in plasma glucose level. Thus, In the absence of exogenous insulin use, increase glucagon release resulting in upregulation of lipolysis and activation of the ketogenesis. Factors such as low oral intake, concurrent infection, and alcohol use can also exacerbate the process. Timely diagnosis of EDKA can be a challenge for physicians unfamiliar with this class of medications, additionally, ketone studies and blood gas analyses are not part of the routine workup for diabetic patients in the emergency department. We recommend all first-line care providers to consider ketosis in ill patients with diabetes and metabolic acidosis, despite the normal or near-normal serum glucose levels. EDKA is mainly a diagnosis of exclusion, but treatment is not different from DKA; correcting dehydration by using intravenous fluids and then, initiating insulin drip along with dextrose-containing solutions, and frequent monitoring of serum anion gap.
High Insulin Resistance in Pancreatic Adenocarcinoma
Authors: Murthi Swetha , Zarghamravanbakhsh Paria , Busta Agustin
Published: May 2021

Introduction: Diabetes mellitus and obesity is associated with increased risk of pancreatic cancer which has been postulated to be due to pancreatic beta cell dysfunction and increased insulin resistance. Pancreatic cancer also exerts its effect on pancreatic beta cells, reducing insulin secretion, affecting glucose uptake and increasing insulin resistance. We present a case of pancreatic adenocarcinoma with severe insulin resistance and uncontrolled diabetes which reversed after tumor removal.

Clinical Description: 79 year old male patient with no prior diagnosis of diabetes, history of hypertension, atrial fibrillation, cerebrovascular accident got admitted to the hospital with painless jaundice, dark colored urine and pruritus for a month. He also endorsed polyuria, polydipsia and weight loss for 2 months. He underwent Magnetic Resonance Cholangiopancreatography and was diagnosed with a 2.8 cm pancreatic head mass, consistent with adenocarcinoma along with intraductal papillary mucinous neoplasm. He was diagnosed with new onset of diabetes, A1c 12.6% during that hospitalization. He weighed about 75 kg and height 170cm (BMI 26.6). Labs showed normal renal function, deranged liver enzymes with direct hyperbilirubinemia, elevated transaminases and alkaline phosphatase. C-peptide level was 1.2 ng/ml for a blood glucose of 197 mg/dl. He was discharged on once daily insulin Glargine 25 units and mealtime insulin Lispro 10 units three times a day (TID) requiring 0.7 units/kg. During follow-up, his insulin requirement started to increase despite proper insulin injection technique and medication compliance. He required glargine 150 units/day and U500 insulin 50 units TID requiring about 4 units/kg. He underwent Whipple’s procedure, partial pancreas resection after a month of his diagnosis. Patient was started on clear liquid diet and his blood glucose started to get better on post-op day 1 with just correctional insulin. He was discharged on Repaglinide 0.5mg TID with each meal and all his insulin was discontinued. His blood glucose was in range of 80 to 160 mg/dl with Repaglinide during clinical follow-up with regular diabetic diet. His severe insulin resistance got reversed after the resection of pancreatic neoplasm.

Conclusion: The pathogenesis of pancreatic cancer associated diabetes has not been studied well. Basic science research found that adrenomedullin, an amionopeptide, is up-regulated in patients with pancreatic cancer and causes insulin resistance in β Cells. Cancer theories also found about metabolic reprogramming and metabolic cross talk happens between pancreatic cancer and peripheral tissue, inhibiting cellular glucose intake and inducing insulin resistance. More research is required to understand these paraneoplastic phenomenon caused by diabetogenic tumor-secreted product in pancreatic cancer associated diabetes.
Immunotherapy-Related Autoimmune Diabetes Mellitus and Exogenous Insulin Antibody Syndrome in a Patient With Metastatic Oral Squamous Cell Carcinoma
Authors: Bahlol Maimoona , Dai Yufei
Published: May 2021

Introduction: Exogenous insulin antibody syndrome (EIAS) is a rare condition characterized by wide glycemic excursions and recurrent hypoglycemia in the presence of high insulin antibody titers. It has been described in diabetic patients treated with exogenous insulin. Programmed death ligand 1 (PD-L1) inhibitors are known to cause autoimmune diabetes mellitus, but PD-L1-related EIAS has not yet been reported to our best knowledge. Case Description: A 63 years old Caucasian man with history of recurrent oral squamous cell cancer presented to emergency room with polyuria, polydipsia, nausea, and vomiting 3 months after initiation of immunotherapy (Durvalumab and cetuximab). He had no prior history of diabetes mellitus or hypoglycemia. He was admitted to hospital for management of diabetic ketoacidosis (Anion gap of 24 mEq/L, venous blood glucose of 805 mg/dL, Venous PH of 7.12, large urine ketone, A1C of 8.9%). After a brief hospital stay, the patient was discharged home on insulin glargine and metformin. His immunotherapy was resumed after hospital discharge. When the patient was seen by Endocrinologist in the clinic, metformin was discontinued and prandial insulin lispro was added. This basal-bolus insulin regimen improved his glycemic control initially. However, without significant changes in his lifestyle or medical condition, he developed worsening postprandial hyperglycemia and recurrent fasting hypoglycemia. Up-titration of his mealtime insulin did not lower postprandial hyperglycemia but possibly worsened fasting hypoglycemia. EIAS was suspected after reviewing his continuous glucose monitoring data. Further work up at this point revealed mildly elevated glutamic acid decarboxylase antibodies (5.9 units/mL, normal range 0.5 - 5.0) and markedly elevated insulin antibody level (77.0 µU/mL, normal range <5). His blood C-peptide was undetectable when his venous blood glucose was 252 mg/dl. In addition, his total insulin level (198 uU/mL) was much higher than his free insulin level (38 uU/mL) following an insulin lispro injection. The patient was diagnosed with EIAS. Switching insulin lispro to insulin aspart while he was on a different immunotherapy medication (Pembrolizumab) immediately reduced his average blood glucose and reduced his total daily insulin dosage by more than 50%. This improvement in glycemic control with insulin aspart only lasted for about 1 week. Unfortunately, the patient’s squamous cancer progressed on immunotherapy. He was referred to hospice care and passed away. Conclusion: Evaluation for EIAS would be reasonable in insulin-treated diabetic patients who develop wide glucose excursions and unexplained fasting hypoglycemia while on immunotherapy.
Is Spontaneous Hypoglycemia a Feature of XLID Type Nascimento?
Authors: Mardini Amin A L , Singh Ishita
Published: May 2021

Introduction: X-linked intellectual disability (XLID) type Nascimento is a rare, under-diagnosed genetic disorder caused by intragenic mutations in the UBE2A gene. The syndrome was first described in 2006 by Nascimento et el. It is characterized by intellectual disability, dysmorphic facial features, skin anomalies, hypotonia, impaired speech, and seizures. To date, there is no literature to suggest that it affects glucose homeostasis.

Case: A 63-year-old male with a history of XLID (mutation in UBE2A pL112P variant), seizures, dementia, stage II CKD, polycystic kidneys, and hyperkalemia presented to the emergency department with altered mental status and blood glucose (BG) of 22 mg/dL. Mental status improved after correction of hypoglycemia.

He had multiple admissions for hypoglycemia, however, no history of diabetes mellitus, or use of hypoglycemia inducing medications. Home medications included Patiromer for hyperkalemia. Family history was remarkable for XLID type Nascimento in his brother and sister’s son. Imaging and laboratory studies conducted on prior admissions were inconclusive. Abdominal CT scan showed a 6mm cyst in the head of the pancreas, but no mass. A 72-hour fast after holding dextrose infusion did not yield a clear biochemical differential. BG 51 mg/dL, Insulin <0.5 (3.0–25 mU/L), C-peptide 0.6 (1.1–4.4 ng/mL), pro-insulin 3.2 (0.0–10.0 pmol/L), β-hydroxybutyrate 0.2 (<0.6 mmol/L). BG increased to greater than 25 mg/dL with 1 mg IV glucagon. Insulin antibody was negative (<5 uU/ml). IGF-1, IGF-2 were low at 17 (49–188 ng/mL) and 142 (333-967ng/mL) respectively. Thyroid function and ACTH stimulation test were within normal limits. Aldosterone <0.1(0.0–30 ng/dL), renin 0.195 (0.167–5.38 ng/mL/hr). Urine metabolic screen, urine amino acid screen, plasma amino acid screen and white cell lysosomal enzymes were normal for the nephew and not performed in our patient. The patient’s family requested not pursuing a repeat 72-hour fast, additional imaging or invasive procedures. Dexamethasone 0.5mg orally at bedtime was started which improved blood sugars and patient was discharged. He presented 2 weeks later with recurrent hypoglycemia. Dexamethasone was titrated to 1.5 mg with no improvement. Diazoxide 3mg/kg/day was subsequently started while dexamethasone was tapered and discontinued. Hypoglycemia did not recur.

Conclusion: This is the first case report describing spontaneous hypoglycemia in an individual with XLID type Nascimento. Our patient also had hyporeninemic hypoaldosteronism which raises the question of endocrine abnormalities as a manifestation of XLID type Nascimento and if hypoglycemia is an inborn error of metabolism in this patient.
Precipitation of Euglycemic DKA (euDKA) From the Initiation of SGLT2 Inhibitor (SGLT2i) and 0-Carb Diet Inpatient
Authors: Popli Rakesh , Chao Jing H
Published: May 2021

Background: SGLT2i are increasingly prescribed for their cardiorenal benefits. Nationally renowned endocrinologists have begun to actively discuss the need for guidelines on safe use of SGLT2i inpatient, with the most common indication being treatment for advanced heart failure (HF). However, no consensus has been reached to date. While in the hospital, patients with HF who are taking SGLT2i are at an increased risk for developing euDKA due to volume depletion, critical illnesses, and restricted dietary intake. We present a case of euDKA inpatient in a man admitted for HF treated with empagliflozin (EMPA).

Clinical Case: A 54-year-old man with HF and non-ischemic cardiomyopathy was admitted for decompensated HF. The patient was also newly diagnosed with T2D on admission when he presented with an elevated blood glucose (BG) of 395 mg/dL (n 62–125 mg/dL) and an elevated A1C of 13.6% (n 4–6%). Cardiologists initiated EMPA 25 mg PO daily on hospital day (HD) 2, in addition to MDI insulin. On HD3, a 0-carb diet was started for a planned FDG PET/CT scan to assess the etiology of cardiomyopathy. With an extremely limited food selection, the patient became largely fasting between HD3-6 while awaiting the PET scan, eating only eggs once a day. On HD6, patient developed chest pain and hypotension and was found to be in euDKA with AKI. Labs were notable for arterial pH 7.14 (n 7.35–7.45), CO2 12 meq/L (n 22–32 meq/L), anion gap (AG) 23 (n 4–12), BG 238 mg/dL (n 62–125 mg/dL), beta-hydroxybutyrate 7.29 mmol/L (n <0.30 mmol/L), and an acute rise in creatinine from 0.8 to 1.4 mg/dL (n 0.51–1.18 mg/dL). In addition to stopping the EMPA, the patient required treatment with IV insulin and fluids for 24 hours, with resolution of euDKA, hypovolemia, and AKI. Patient was safely discharged on HD14 on MDI insulin and metformin.

Conclusion: While euDKA is increasingly recognized outpatient and perioperatively, it is under-recognized in the hospital setting. A study reported 94 patients at one center using SGLT2i inpatient experiencing no euDKA (1). However, hospitalized patients taking SGLT2i remain vulnerable to euDKA, especially with concurrent critical illnesses, volume depletion and restricted dietary intake. Zero-carb intake triggers energy production by ketosis, which greatly amplifies the risk of euDKA on SGLT2i. There are currently no guidelines for safe use of SGLT2i inpatient. When using SGLT2i inpatient, we advocate for clinicians to closely monitor patients’ symptoms and AG twice a day and consider holding SGLT2i with prolonged fasting of >24 hours to readily prevent, diagnose and treat euDKA. We recommend educating clinicians on the side effects associated with SGLT2i, developing EMR alerts, and involving endocrinologists with inpatient use of SGLT2i in high-risk patients.

References: (1) Palermo, N.E. et al. Use of SGLT2 Inhibitors in Hospitalized Patients in an Academic Center. Diabetes 2020; 69(S1):1200-P.
Prolonged Hypoglycemic Effect Due to Intentional Massive Insulin Glargine Overdose
Authors: Gill Kirit S , Arao Kevin A , Merolli Alisa
Published: May 2021

Introduction: Since its discovery in 1921, insulin has served as the mainstay of treatment for patients with both type 1 and insulin-dependent type 2 diabetes mellitus (T2DM). Insulin is available in both long and short acting formulations. Glargine, a long-acting insulin, has an onset of action in one to two hours and length of duration of 24 hours. Although generally well tolerated, when taken in overdose, insulin can lead to severe hypoglycemia, seizures, unconsciousness, or even death. We present a case of an insulin-dependent male with refractory hypoglycemia after an intentional glargine overdose.

Case: A 57-year-old man with past medical history of insulin-dependent T2DM, alcohol abuse, cirrhosis, and depression, presented to the hospital after a suicide attempt. The patient reported that after a night of drinking he experienced suicidal thoughts and injected himself with 8 vials of 100 Units (800 units) of insulin glargine. On initial presentation, the patient had a GCS of 15/15 and was in slight distress. The remainder of his exam was normal. Initial laboratory workup was pertinent for a blood glucose of 86mg/dL. Poison control was contacted and the patient was started on an intravenous infusion of 10% Dextrose with blood glucose checks every 15 minutes; subsequently reduced to every 60 minutes. Despite continuous glucose administration, the patient still suffered from severe hypoglycemic episodes (glucose < 70mg/dL) requiring glucose boluses in the first 96 hours of hospitalization. His glucose infusion was transitioned to D5 and then discontinued. Psychiatry determined the patient was no longer a risk to himself and outpatient therapy was warranted. His blood glucose was well controlled and he was not discharged with insulin.

Discussion: Insulin glargine is a long-acting human insulin analogue with a prolonged activity profile and no pronounced peak. At doses between 0.4 IU/kg to 0.8 IU/kg, insulin glargine is metabolized in 24 hours. However, in cases of insulin overdose, insulin effects and absorption are highly variable. Multiple studies have illustrated the unusual prolonged hypoglycemic effect of glargine after massive doses. The mechanism behind this is still unclear but several factors may result in this prolonged duration of action. Larger injection volumes create a larger depot that may have a mechanical effect on the microcirculation leading to delayed absorption. Presence of lipodystrophy from repeated insulin injection, hepatic impairment, and renal impairment may also alter insulin kinetics. Another contributing factor in our patient is obesity, which is associated with delayed insulin absorption.

Conclusion: Insulin glargine overdose can lead to prolonged hypoglycemic effect due to altered pharmacokinetics. Physicians should be cognizant about this and closely monitor blood glucose levels and anticipate the possibility for prolonged IV dextrose infusion.
Severe Hypoglycemia in a Non-Diabetic Patient
Authors: Thomas Melbin , Krug Esther
Published: May 2021

Introduction: Accidental ingestion of insulin secretagogue may result in severe life-threatening hypoglycemia. Patients in long-term care may be especially vulnerable if proper medication administration safety guidelines are not followed. Case: A 62-year-old woman who was staying at a residential living facility (RLF) for the homeless, presented to the emergency room with altered mental status. Her past medical history included hypertension, COPD, psoriasis, and alcohol abuse. Prior to arriving to the emergency room, she was drinking alcohol excessively. Head CT results were normal. Capillary blood glucose (FBG) level was noted to 38 on EMS arrival. Her FBG improved to 69 after glucagon and her mental status improved shortly afterwards. ED was planning on discharging her when she became unresponsive with tonic-clonic seizure-like activity. The FBG at that time was 17. She was given Ativan and 10% Dextrose IV followed by 5% Dextrose Normal Saline (D5NS) drip. She recovered consciousness and was admitted for further monitoring. Endocrinology was consulted for hypoglycemia (HG). The patient denied prior diagnosis of diabetes mellitus or access to diabetic medications. Her medications were dispensed to her daily by staff at RLF. We held D5NS in order to perform testing for HG. Within 30 minutes she developed symptoms of HG. Hypoglycemic profile labs including C-peptide, insulin, beta-hydroxybutyrate, pro-insulin, hypoglycemic agent screen, insulin antibodies were drawn prior to reversal of HG. Laboratory findings: Venous BG - 26 mg/dL. Beta-hydroxybutyrate level (BHB) - 0.02 mmol/L (n, 0.02–0.27). The insulin antibody - 6.9 ng/mL (n, <5). C-peptide - 8.5 uU/mL (n, 1.1–4.4), insulin level - 53.2 uIU/mL (n, 2.6–24.9). Proinsulin - 8.6 pmol/L (n, <10.0). She had normal GFR of 95.94 mL/min/1.73m2 (n, >60) and elevated liver enzymes. Abdominal ultrasound results were consisted with cirrhosis. HG resolved after 36 hours. HG drug screen performed at Mayo Clinic lab by highly sensitive LC/MS/MS assay was positive for Glimepiride. Discussion: This case illustrates importance of high degree of suspicion for drug-induced HG in a patient presenting with profound HG and no previous history of diabetes. Discharging this patient prematurely could have resulted in hypoglycemic coma and death. Severity of HG was not consistent with alcoholism and cirrhosis. Suppressed BHB level coupled with high-normal pro-insulin and markedly elevated C-peptide and insulin levels were consistent with endogenous hyperinsulinemia. Sulfonylureas are known to have a long half-life; hypoglycemic effect can last for 12 to 24 hours or longer, especially in patients with impaired kidney or hepatic dysfunction. Since results of HG work-up are typically not available for several days, clinical observation and avoidance of premature discharge following initial reversal of HG are very important.
Two Extremes of Dysglycemia- a Rare Case of Diabetes Complicated With a Non-Functional Pancreatic Neuroendocrine Tumor Transforming to an Insulinoma
Authors: Schleis Gregory , Rasouli Neda
Published: May 2021

Background: Diabetes is characterized by hyperglycemia with heterogeneous pathophysiological features and varied presentation and consequences. Here, we present a rare case of diabetes that was complicated with insulinoma making glycemia management complicated.

Clinical Case: A 48-year-old white man was diagnosed with diabetes when he presented with weight loss, polyuria and polydipsia and HbA1c of 11%. He was treated with oral agents for few months without a good response then switched to insulin. He was assumed to have type 1 diabetes and had fairly well controlled glycemia on multi daily injection of insulin. He was diagnosed with a metastatic non-functional pancreatic neuroendocrine tumor (PTEN) 9 years later. He presented with epigastric pain and CT scan showed a mass in the pancreas tail and multiple lesions in liver. The tumor was immunopositive for S100, synaptophysin, and chromogranin. He was first treated with sunitinib and later switched to Everolimus. He underwent treatment with SIR-spheres which was complicated with post-embolization syndrome and Diabetes Ketoacidosis (DKA). He was switched back to Everolimus and referred to the endocrinology clinic for management of diabetes with a recent DKA. At the initial evaluation by the endocrinology team, he had BMI of 25 kg/m2, no significant family history of diabetes, no diagnosis of dyslipidemia or hypertension. He had low C-peptide < 0.1 ng/mL (n: 0.8 - 5.2 ng/mL) and negative GAD antibody suggestive of non-immune mediated insulin deficient diabetes. He was treated with basal plus prandial insulin regimen and required about 0.6–0.7 unit/kg of insulin each day. Due to progression of PTEN, he was started on monthly Lanreotide while later Pembrolizumab was added resulting in hypothyroidism with a TSH of 75 mIU/L (n: 0.45 - 5.33 mIU/L) that was treated with Levothyroxine. Meanwhile, his diabetes care was complicated by recurrent hypoglycemic episodes and hypoglycemia unawareness. He gradually decreased the dose of insulin, stopped taking prandial insulin, and finally discontinued basal insulin due to recurrent hypoglycemia. He continued to have hypoglycemia despite stopping insulin. His C-peptide was found to be 3.3 ng/mL with a low BG of 62 mg/dl. Diazoxide was started and despite maximizing the dose, the patient continued experiencing hypoglycemia. He therefore decided to stop taking Diazoxide and only continued monthly Lanreotide. The patient is currently avoiding hypoglycemia by eating frequently (every 3 hours) and has regained his hypoglycemia awareness.

Conclusion: This is a rare case of non-immune mediated insulin deficient diabetes complicated by recurrent episodes of hypoglycemia due to a non-functioning PNET converting to a functional tumor producing insulin.
Fetuin-A as a Marker of NAFLD
Authors: Dharmalingam Mala , Pattabhi Ganavi
Published: May 2021

Fetuin-A has been implicated in the causation of metabolic disorders such as obesity, diabetes, and hepatic steatosis. There are numerous studies which have shown the association between levels of fetuin-A in Type 2 diabetes mellitus (T2DM) and Nonalcoholic fatty liver disease (NAFLD). The levels of fetuin-A in newly detected type 2 diabetic patients (NDD) and its correlation with presence of NAFLD has not been studied. Objective: To study the fetuin-A levels in patients with NDD and its correlation with NAFLD. Methods: A total of 60 newly diagnosed type 2 diabetes (NDD) were studied. Diagnosis of NAFLD was made on the basis of transient elastography. Serum fetuin-A and serum fasting insulin were measured along with other investigations. Results: Percentage of patients with NAFLD in NDD was 53.33%. Fetuin-A levels were significantly higher in NDD with NAFLD compared to those without NAFLD. There was no association of fetuin-A with age, both systolic and diastolic blood pressure, FBS, HbA1c, fasting insulin, HOMA-IR, QUICKI and markers of advanced fibrosis. Fetuin-A levels beyond 1166.5 mcg/ml could predict the development of NAFLD with OR of 4.33 (95%CI:1.364–13.77) which remained significant after adjustment for various confounding factors. Conclusion: Fetuin-A is a reliable marker of NAFLD in NDD and is positively associated with IR. The observation in this study suggests that high serum fetuin-A levels in patients with NAFLD do not merely reflect the effects of insulin resistance, but also a more extensive distortion of liver architecture.
Glycemic Control & Morbidity in Diabetics With COPD Exacerbation. A Retrospective Study
Authors: Naoum Ibrahim , Abedalhalim Abedalghani , Aker Amir , Khalaili Luai , Kassem Sameer
Published: May 2021

Background: Diabetes and chronic obstructive pulmonary disease (COPD) are widely prevalent and comorbidity with these diseases is quite common. However, there is limited data on the interrelation between glycemic control and COPD exacerbations in diabetic patients.

Objective: To study the association between pre-admission glycemic control and COPD clinical outcomes including mortality, risk of hospital readmission and the need for mechanical ventilation.

Methods: A retrospective population-based cohort study. We screened for patients with both diabetes and COPD exacerbation aged 35 years and above. Pre-admission glycemic control was defined by the last HBA1C level prior to hospitalization. Patients with HBA1C>8% were defined as uncontrolled. We evaluated the difference between controlled and uncontrolled groups in the rates of mortality, readmission and the need for mechanical ventilation. We examined demographic and clinical parameters that might reflect COPD severity including: COPD medication use, blood hemoglobin, platelets, LDH and CRP levels.

Results: 513 hospitalizations with diabetes and COPD were screened. 222 hospitalization were excluded either due to unestablished diagnosis of COPD or due to lack of HBA1C test in the preceding year. Of the remaining 291, 208 admissions were with controlled diabetes whereas 83 were uncontrolled. Although not statistically significant, the rate of re-hospitalization was higher in the uncontrolled group (OR 1.99, CI 0.99–4.0, p-value 0.051). There was no statistically significant difference in mortality (OR 1.6, CI 0.73–3.5, p-value 0.243). The use of oxygen and the need for noninvasive mechanical ventilation were significantly higher in the uncontrolled group (67.5% vs. 52.4%, p-value 0.019, 33.7% versus 18.8%, p-value 0.006, respectively). There was no significant difference in possible confounders tested between the groups.

Conclusion: Uncontrolled diabetes may adversely affect patients with COPD exacerbation. Larger studies are needed to conclusively determine the impact of glycemic control on COPD morbidity and mortality.
Immune Checkpoint Inhibitor Mediated Insulin Dependent Diabetes: Observations at a Cancer Center
Authors: Jeun Rebecca , Best Conor , Iyer Priyanka , Lavis Victor Ralph , Varghese Jeena Mary , Oliva Isabella Glitza , Dadu Ramona , Thosani Sonali
Published: May 2021

Immune checkpoint inhibitors (ICIs) have rapidly changed the landscape of oncologic care and are now often used in the front line setting for many types of cancers. These agents attempt to harness the immune system to target cancer cells (ICIs) by releasing inhibition of T cell response against tumor cells. With increasing use of ICIs, a new spectrum of immune-related adverse events (irAEs) has emerged including a number of endocrinopathies. A distinct form of ICI-mediated insulin dependent diabetes (ICI-DM) has become increasingly recognized. To better characterize this disease entity and longer-term consequences, we performed a retrospective review of medical records of patients diagnosed with ICI-DM between April 2014 and July 2020 at the MD Anderson Cancer Center. This cohort of 68 patients represent the largest single institution cohort described to date. Baseline characteristics of our cohort are consistent with what has been reported in other case series and meta-analyses with median age at presentation 61 years old (range 32–83 years old), slight male predominance (59% vs 41%), and strong association with anti-programmed cell death protein 1 (anti-PD-1) therapy (59%). Melanoma was the most commonly represented underlying malignancy (29%). The majority of patients (66%) presented with diabetic ketoacidosis. At presentation, median HbA1c was 7.8 % (n < 5.7%) and median C-peptide was 0.2 ng/ml (range <0.1–3.4). Pancreatic autoantibodies were present in 49% of patients. Median insulin dose was 0.54 units per kg per day[T1] (range 0.25 to 1.07 units per kg) at first follow up suggesting these patients may have varying levels of insulin sensitivity[T2]. On most recent follow up at a median[T3] of 40 weeks (range 8 to 261 weeks), median HbA1c was 7.9% and median insulin requirement remained 0.54 units per kg (range 0.14 to 1.2 units per kg). 22% of patients were on insulin pump therapy[T4]. ICI-DM is an irreversible immune-related adverse endocrinopathy characterized by frequent presentation with fulminant hyperglycemia and DKA, persistent beta cell dysfunction necessitating long term insulin therapy and mixed evidence of beta-cell autoimmunity. Median insulin requirement was more consistent with type 1 diabetes, but a wide range was present. Adequate glycemic control was generally achievable on insulin therapy.
Screening for Asymptomatic Coronary Artery Disease in People With Type2 Diabetes Mellitus in a Tertiary Care Center
Authors: Tewari Ajoy
Published: May 2021

Cardiovascular disease is the biggest driver of mortality in people with diabetes. Cardiovascular disease and diabetes share the same risk factors, the so-called “common soil” hypothesis. Asians and more specifically Indians are predisposed to cardiovascular disease, that too at an earlier age. The cost of management of cardiovascular disease in India is prohibitive. Thus, screening for asymptomatic coronary artery disease in people with type 2 diabetes and referring them for further evaluation will go a long way in preventing cardiovascular mortality. 560 consenting previously diagnosed people with type 2 diabetes, undergoing treatment for type 2 diabetes at our center, were recruited in the study. We used the risk score model for the assessment of coronary artery disease in asymptomatic patients with type 2 diabetes (1) because it was easy to use, specific for Asian population and validated with coronary computed tomographic angiography in asymptomatic people with type 2 diabetes. Questions regarding smoking, past history of stroke and duration of diabetes were recorded as per the risk score and accordingly the subjects were labelled low, intermediate and high risk. Anthropometric measurements were recorded, lipid profile was measured, neuropathy assessment was done using the DNS score. Results: 48.9%subjects were females,51.1% were males, mean duration of diabetes was 3.5 years, mean HbA1c was 8.5%, mean BMI 26.5kg/m2, mean age was 51.4 years, mean CAD score was 4.1 44.2% of the subjects were in a low risk category, 44.9% were in the intermediate risk category and 10.9% in the high-risk category. The maximum people had intermediate to high risk and were in the age group of 50–60 years (21.3%), followed by 13% in the 60–70 age group. Surprisingly, 12.6% people in the 40-50year age group had an intermediate to high risk score for ASCVD. The high prevalence of intermediate to high risk in relatively younger populations with shorter duration of diabetes (mean duration of diabetes 3.5 years) mandates universal screening for asymptomatic coronary artery disease in all people with type 2 diabetes mellitus. Our study highlights the importance of identifying asymptomatic coronary artery disease using locally relevant risk models and their timely referral to prevent excessive cardiovascular mortality in people with type 2 diabetes mellitus. This would ensure optimum utilization and prioritization of scarce resources in resource crunch situations. Keywords: Screening, asymptomatic CAD, type 2 diabetes mellitus. References: 1. Park G-M, An H, Lee S-W, Cho Y-R, Gil EH, Her SH, et al. Risk Score Model for the Assessment of Coronary Artery Disease in Asymptomatic Patients With Type 2 Diabetes. Medicine [Internet]. 2015 Jan [cited 2020 Oct 14];94(4):e508. Available from: https://journals.lww.com/md-journal/Fulltext/2015/01040/Risk_Score_Model_for_the_Assessment_of_Coronary.44.aspx
The Possible Link Between Serum Lipocalin-2 Level and Mild Cognitive Impairment in Adults With Metabolic Syndrome
Authors: Pinyopornpanish Kanokporn , Phrommintikul Arintaya , Angkurawaranon Chaisiri , Kumfu Sirinart , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: May 2021

Introduction: Metabolic syndrome (MetS) is associated with an increased risk of cognitive impairment. Lipocalin-2 (LCN2) or neutrophil gelatinase-associated lipocalin (NGAL), is an inflammatory protein, and participates in the innate immune response. LCN2 significantly decreased in the cerebrospinal fluid of individuals with mild cognitive impairment. A recent study reported that circulating lipocalin-2 is involved in early AD pathogenesis. However, the association of LCN2 and cognition in MetS patients are still unclear. Then, the present study aims to evaluate whether serum LCN2 levels are associated with the alteration of cognitive function in MetS subjects.

Methods: Participants with MetS, but without dementia or prior psychiatric problems, were enrolled to the study. The demographic data and physical examination were assembled. Blood samples were collected to evaluate the metabolic parameters. Levels of serum LCN2 were determined with ELISA assay. The global score of the Thai version of Montreal cognitive assessment (MoCA) was used to assess cognitive function. Multivariable regression analysis was used to determine the associations.

Results: Among 202 MetS participants, 111 (54.95 %) were female, and average age was 64.6 (SD 8.6). Mean serum LCN2 and MoCA score were 30.7 ng/ml (SD 17.6) and 19.3 (SD 4.8), respectively. Serum LCN2 levels were negatively associated with the MoCA scores in crude analysis (B=-0.053; 95%CI -0.090, -0.015; p 0.006). After adjustment for sex, age, waist circumference, and creatinine levels, there was an association between the higher serum LCN2 levels and the lower MoCA scores (B=-0.049; 95%CI -0.090, -0.008; p 0.019).

Conclusion: These findings suggest the association between serum LCN2 levels and MCI in MetS subjects. However, further longitudinal study should be investigated to support the link between serum LCN2 levels and cognitive impairment.
Integration of Flash Glucose Monitoring During the Transition of Care From Inpatient to Outpatient Settings in Patients With Type 2 Diabetes
Authors: Jaiswal Radhika , Zhang Meng , Zuniga Sharon , Myers Alyson K
Published: May 2021

Background: The use of continuous glucose monitoring (CGM) technology in the outpatient setting has been associated with both improved patient satisfaction1 and increased glucose monitoring2. It remains to be seen, how well this technology can be integrated during the transition from hospital discharge to outpatient settings. Here, we aim to assess the feasibility of introducing the FreeStyle Libre during the transition of care from inpatient to the outpatient environment in patients with Type 2 diabetes (T2D). We will assess CGM use as measured by the numbers of days used and frequency of daily scans. Methods: During the time period April and September 2020, 20 patients with T2D being discharged on multiple daily injections admitted to North Shore University Hospital were enrolled in this study. Exclusion criteria were those with adhesive allergy, CKD 4/5 or on dialysis and pregnant women. Participants were trained on how to use the FreeStyle Libre with the LibreLink mobile application. All patients received 2 Libre sensors at the time of discharge, one that was placed in the hospital and the other to be placed after 14 days. 1 participant died prior to discharge. Analyses included descriptive statistics, specifically categorical variables using frequencies and percentages while continuous variables using mean and standard deviation. Results: Among who used the mobile application, 10 were men and 9 were women. Majority of patients were Black (n=11, 57.9%) with a mean age of 52 years (range 31–76). The mean duration of diabetes was 9.7 years (range: 0 to 22) and mean Hemoglobin A1c of 11.2% (range: 5.5–15.5). 10 out of 19 persons used CGM for more than 2 weeks, while the remaining 9 utilized the CGM for less than 2 weeks. Mean average daily scans were 5 times per day (range: 1–12) with majority of the persons (n=15, 78.9%) scanning more frequently (3 or more times per day). The average glucose ranged from 62 to 268 mg/dl and the mean active CGM time was 52.05% (range 0–98). Mean glycemic variability was 29.17% (range: 14.5–56.7). Technical issues with the CGM included poor adhesion or issues connecting to the mobile application.

Conclusion: Our study found that the initiation of CGM during the transition from hospital discharge to the outpatient setting is feasible and a useful tool. A limitation of this study was the inability for all people to use the mobile application due to incompatible phones or operating systems. References: 1. Beck RW, Riddlesworth TD, Ruedy K, et al. Continuous Glucose Monitoring Versus Usual Care in Patients With Type 2 Diabetes Receiving Multiple Daily Insulin Injections. Ann Intern Med. 2017;167(6):365–374. doi:10.7326/M16-2855. 2. Shehav-Zaltzman G, Segal G, Konvalina N, Tirosh A. Remote Glucose Monitoring of Hospitalized, Quarantined Patients With Diabetes and COVID-19. Diabetes Care. 2020;43(7):e75-e76. doi:10.2337/dc20-0696.
Predicting the Need for Basal-Bolus Insulin in Hospitalized Patients With Hyperglycemia: Is Sliding Scale Sometimes the Answer?
Authors: Jankovic Ivana , Nguyen Minh , Kalesinskas Laurynas , Chen Jonathan H
Published: May 2021

Uncontrolled blood glucose (BG) is associated with increased risk of infection, complications, and mortality in hospitalized patients. American Diabetes Association guidelines currently recommend basal insulin for all hospitalized, non-critically ill patients requiring insulin and state that “use of only a sliding scale insulin regimen in the inpatient hospital setting is strongly discouraged”. In practice, however, sliding scale only is used not infrequently. Here, we challenge the recommendation for universal basal insulin use and leverage machine learning to predict which inpatients would indeed benefit from basal insulin at time of admission.

Querying inpatient electronic health record data for hospitalizations between 2008–2020, we identified a cohort of 16,868 unique patients who achieved a day of “good control”, defined as ≥ 3 BGs that were within 100–180 mg/dL without any values outside that range. Inclusion criteria were adult inpatients receiving subcutaneous insulin with BG of 100-180mg/dL on one calendar day. If patients had more than one “good day”, the first day of their most recent hospitalization was chosen. We excluded patients ordered for insulin pumps, insulin infusion, any insulin type that is rarely used (ordered < 25 times), TPN or PPN, or tube feeds. We also excluded patients with missing weights.

We aimed to predict which patients would require > 6 units of insulin. We chose this threshold clinically, as patients with a total daily dose (TDD) of insulin < 6 units could reasonably be managed on sliding scale insulin alone. Using the threshold of 6 units, we used an ensemble machine learning method, called SuperLearner, to model a binary classification for high vs. low insulin users. Features included in the algorithm were collected prior to prediction time, including weight, height, age, sex, race, insurance status, A1c categories (normal, high, panic high, and missing), creatinine, diet, steroid use in prior 48 hours, admission BG, summary statistics of BG, numerous counts of relevant lab values in quantiles, history of basal insulin use, and counts of major diagnosis code groups. Prior insulin doses were not considered to better simulate admission insulin dosing.

Compared to using only weight in the model, with an area under the receiver operating curve (AUROC) of 0.59, our machine learning algorithm showed excellent predictive ability, with an AUROC of 0.85 (95% CI: 0.84 - 0.87) and area under the precision recall curve (AUPRC) of .65 (95% CI: 0.64 - 0.68) vs 0.29 with the weight-only model. Although it will need to be validated prospectively, our algorithm could be used to emphasize basal-bolus insulin on admission in patients predicted to require more insulin, whereas those predicted to require less could be started on sliding scale insulin or considered for oral anti-hyperglycemics.
Insulin Resistance and Gender Define a Cell Autonomous Supernetworkof Protein Phosphorylation
Authors: Haider Nida , Lebastchi Jasmin , Jayavelu Ashok K , Batista Thiago M , Pan Hui , Dreyfuss Jonathan M , Carcamo-Orive Ivan , Knowles Joshua W , Mann Matthias , Kahn Carl Ronald
Published: May 2021

Many hormones and growth factors, including insulin, act through networks of protein phosphorylation. Insulin resistance is an important factor in the pathophysiology of many metabolic disorders. The aim of this study was to uncover the cell autonomous determinants of insulin action and protein phosphorylation using induced pluripotent stem cell (iPSC)-derived myoblasts (iMyos) in vitro. Here, we show that iMyos from non-diabetic individuals in the highest quintile of insulin resistance show impaired insulin signaling, defective insulin-stimulated glucose uptake and decreased glycogen synthase activity compared to iMyos from the insulin sensitive individuals, indicating these cells mirror in vitro the alterations seen in vivo. Global phosphoproteomic analysis uncovered a large network of proteins whose phosphorylation was altered in association with insulin resistance, most outside the canonical insulin-signaling cascade. More surprisingly, we also observed striking differences in the phosphoproteomic signature of iMyos derived from male versus female subjects, involving multiple pathways regulating diverse cellular functions, including DNA and RNA processing, GTPase signaling, and SUMOylation/ubiquitination. These findings provide new insights into the cell autonomous mechanisms underlying insulin resistance in the non-diabetic population and provide evidence of a major, previously unrecognized, supernetwork of cell signaling differences in males and females that must be considered in understanding the molecular basis of sex-based differences in normal physiology and disease.
Dipeptidyl Peptidase-4 (DPP-4) Inhibitor Therapy in the Management of Latent Autoimmune Diabetes in Adults (LADA): A Systematic Review and Meta Analysis
Authors: Alanes Escueta Luz Margaret , Jasul Gabriel Villaflor , Dampil Oliver Allan Castillo , Laforteza Alexis Roberto Yamane
Published: May 2021

Objective: Latent autoimmune diabetes in adults (LADA) has been shown in recent studies to have heterogeneous pathophysiology and phenotype. Although insulin is considered as the therapeutic choice for these patients, other antidiabetic drugs have been studied in terms of glycemic control and beta cell function preservation. In particular, dipeptidyl peptidase-4 (DPP-4) inhibitors have shown immunomodulatory effects in animal models since it was demonstrated a higher DPP-4 activity in patients with LADA compared to patients with Type 1 and Type 2 diabetes suggesting a possible effect on autoimmunity found in LADA. This study aims to review the outcomes of the included studies and evaluate the efficacy of DPP-4 inhibitors in the treatment of LADA. Methods: We searched Medline, Embase, PubMed and Cochrane Library Databases and ClinicalTrials.gov for studies concerning the use of DPP4 inhibitors in patients with latent autoimmune diabetes in adults (LADA). Results: Preclinical studies demonstrated drug’s immunomodulatory effects in terms of suppression of inflammatory processes and oxidative stress providing endothelial protection leading to improved metabolic control and prevention of vasculopathy. From this meta-analysis, pooled data from 8 randomized controlled trials revealed that the use of DPP-4 inhibitors in LADA patients resulted in an improved glycemic control, decreased insulin requirement and increased beta cell function as assessed by a decrease in GADA titers, increased C peptide levels and HOMA B. Conclusion: Beneficial effects of DPP4 inhibitors are shown by the included studies indicating that they are promising therapeutic agents for patients with LADA. However, caution should still be exercised since there is still much to learn about the disease itself and larger scale prospective randomized trials are needed to assess the efficacy and safety of DPP4 inhibitors for these patients.