bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trimethylaminuria and Vascular Complications
Authors: Oliveira-Filho Antonio Fernandes , Medeiros Paula F V , Velloso Renata N , Lima Erika C S , Aquino Ivna M , Nunes Adriana Bezerra 
Published: May 2021

Abstract
Background: Trimethylaminuria (Fish-Odour Syndrome) is a rare metabolic disorder characterized by an unpleasant odour in body secretions similar to rotting fish. The disorder is most commonly caused from mutations affecting the Flavin containing monooxygenase 3 (FMO3) gene, the vital enzyme for the metabolism of trimethylamine. Although uncommon, it is important to be conscious of this condition, which can be devastating psychosocially even with reliable diagnostic tests. We present here an individual with this syndrome who, in addition to the psychosocial difficulties, presented physical complications that we relate to the disease’s physiopathology. Case: R.M.F., 56 years old, lawyer, self-diagnosed at 25 after identifying himself with a disease description in a local newspaper. He describes fish odour symptoms from infancy and his mother used to demand excessive hygiene habits. He has always suffered from social disturbances. At 44, a physician’s investigation detected FMO3 mutation. The patient is not obese, has never smoked and denies any comorbidity, except erectile dysfunction for 10 years. He presented 4 years ago extensive acute venous thrombosis in the right lower limb femoral veins, lateral and medial gastrocnemius, solar and fibular popliteal veins. Laboratory investigation excluded other causes and negative antibodies. Besides, ENMG confirmed last year peripheral motor sensitive polyneuropathy, axonal pattern, distal both lower extremities. The patient failed treatment with modifications in diet and hygiene, but achieved symptomatic improvement after metronidazole. Genetic analysis showed a new homozygotic variant in the FMO3 gene, with substitution of adenine for cytosine and exchange of Threonine for proline at position 307 of the FMO3 protein with protein dysfunction computably predicted. Comments: Considering the deep venous thrombosis and symmetrical peripheral neuropathy developed by the patient, we searched for a possible association with TMAU but we did not find previous reports. However, Weifei Zhu et al. (Circulation, 135(17), 1671–73,2017) have shown TMAO generated by gut microbes contributing to platelet hyper reactivity and causing a prothrombotic phenotype in vivo. Plasma TMAO levels could predict incident thrombosis risk. Also, direct TMAO exposure enhanced platelet activation from multiple agonists stimulus. Although the “chemical sensor” for TMAO within platelets remains unknown, these findings could increase our understanding of the relationship between TMAO and CVD risk. Although the disorder might not appear to be a significant health problem, its social and psychological burden can be devastating, since the few treatments available provide modest benefits. In addition, it may be associated with other complications, including CVD, to which we would like to draw attention with this report
Selective Somatostatin 5 (SST5) and Somatostatin 2 (SST2) Nonpeptide Agonists Potently Suppress Glucose- and Tolbutamide-Stimulated Dynamic Insulin Secretion From Isolated Human Islets
Authors: Rico Elizabeth , Zhao Jian , Chen Mi , Kusnetzow Ana Karin , Zhu Yun Fei , Betz Stephen F 
Published: May 2021

Abstract
Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in newborns and infants and arises from dysregulated insulin secretion. Rapid recognition and treatment are vital to prevent seizures, permanent developmental delays, coma, or even death. Very few medical options exist to treat congenital HI patients: the KATP channel activator diazoxide, the injectable somatostatin receptor peptide agonists octreotide and lanreotide, or chronic glucose infusions. However, side effects and/or limited efficacy render these therapies inadequate for many patients.
Somatostatin is a 14-amino acid peptide hormone with a broad spectrum of biological actions, which are regulated through five somatostatin receptor subtypes (SST1-SST5). Somatostatin’s common physiological role is to down-regulate secretion of other hormones in various tissues. Its role in the maintenance of euglycemia is to regulate insulin and glucagon secretion from pancreatic β- and α-cells, respectively. Somatostatin regulates insulin secretion by decreasing the intracellular levels of cAMP, inhibition of voltage-gated calcium channels (VGCC), activation of the G protein-activated inward rectifier K+ channel (GIRK), and direct inhibition of insulin exocytosis.
Several studies have evaluated the effect of somatostatin, somatostatin peptide analogs, and a limited number of nonpeptide somatostatin receptor agonists on insulin secretion in static assays using isolated human islets. However, the lack of highly selective agonists has made the interpretation of the contribution of SST receptor sub-types difficult to discern. Our programs for the treatment of hyperinsulinism, acromegaly, and other indications have led to the development of selective nonpeptide SST2, SST3, SST4, and SST5 agonists, possessing EC50s &lt; 1 nM in cell-based assays of receptor activation and selectivity &gt; 130 times over the other members of the family. The ability of these selective nonpeptide agonists to regulate glucose- and tolbutamide-stimulated dynamic insulin secretion from human islets was evaluated using a perifusion system (Biorep, FL).
We found that selective SST2 and SST5 agonists potently suppressed dynamic insulin secretion in contrast to SST3 or SST4 selective agonists. Importantly, SST5 agonists were shown to have a greater effect than selective SST2 agonists or diazoxide, demonstrating their potential utility in human conditions such as congenital HI. In addition, SST5 activation is also known to have a smaller effect on glucagon secretion and is also less prone to agonist-driven desensitization than SST2 activation. Taken together, these studies support our program to identify, characterize, and develop potent, nonpeptide, orally-bioavailable, selective SST5 agonists with appropriate pharmaceutical and safety characteristics for the treatment of congenital HI.
Basal Insulin Fc (BIF), A Novel Insulin Suited For Once Weekly Dosing For The Treatment of Patients With Diabetes Mellitus
Authors: Heise Tim , Chien Jenny , Beals John , Benson Charles , Klein Oliver , Moyers Julie S , Haupt Axel , Pratt Edward J 
Published: May 2021

Abstract
An optimally designed once-weekly basal insulin with reduced day-to-day pharmacokinetic (PK)/pharmacodynamic (PD) fluctuations compared to daily basal insulins should have a low peak-to-trough ratio at steady state. An insulin with this flat profile could improve glycemic efficacy while reducing hypoglycemia. Basal insulin Fc (BIF; LY3209590) is an insulin IgG Fc-fusion protein developed for once weekly dosing. The results of the first in-human studies of BIF assessing the safety, tolerability, PK, and PD following single and once-weekly doses of BIF are presented below. The single ascending dose (SAD) study assessed 6 dose levels of BIF, administered to healthy subjects or patients with type 2 diabetes mellitus (T2DM). In the multiple ascending dose (MAD) study, patients with T2DM previously treated with basal insulin received a one-time loading dose at Week 1 followed by a once-weekly maintenance dose for 5 additional weeks. Four fixed-dose maintenance dose levels were evaluated. The loading dose was implemented to rapidly achieve steady-state BIF concentration at each dose level. Patients with T2DM in the control group received insulin glargine at the same dose as their previous daily insulin dose. Key objectives were safety and tolerability, PK endpoints with a focus on half-life and peak-to-trough ratio at steady state, and finally PD measures. The SAD study included 57 patients with T2DM and 16 healthy subjects. The mean age of patients with T2DM was 58.4 years and the mean BMI was 29.5±3.2 kg/m2. The mean age of healthy subjects was 35.8±9.3 years and the mean BMI was 26.1±3.1 kg/m2. In the SAD study, BIF demonstrated linear PK with dose-proportional concentration profiles in healthy subjects and patients with T2DM. The maximum BIF concentration was reached on Day 4. BIF had a mean half-life of approximately 17 days in patients with T2DM. Following a single dose of BIF, a decrease in FBG was observed on Day 1 and was sustained until at least 5 days post-dose. In the MAD study in 33 subjects with T2DM aged between 40 and 69 years, BIF demonstrated a nearly peak-less PK profile over a one-week dosing interval with a peak-to-trough ratio of ~1.1 at steady state. This flat profile is in contrast to insulin glargine. Following once-daily dosing, insulin glargine has a daily peak-to-trough ratio of ~2. Over the 6-week duration, the 7-point glucose profiles remained constant over time and were similar to insulin glargine profiles. BIF was well tolerated and had a safety profile similar to insulin glargine-treated subjects. In particular, hypoglycemia rates were also similar to insulin glargine and there was no occurrence of hypoglycemic events with cognitive dysfunction. These data support continued development of BIF as a once-weekly insulin treatment of diabetes mellitus.
Is DPP-4 Use Associated With a Decreased Mortality for COVID-19 Diabetic Patients? A Meta-Analysis
Authors: Sun Chenyu , Kim Keun Young , Ahmed Mubashir Ayaz , Manem Reveena , Bhan Chandur , Cheng Ce 
Published: May 2021

Abstract
Introduction: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Dipeptidyl peptidase-4 (DPP-4) is a multi-expressed glycoprotein that is speculated to be a functional SARS-CoV-2 receptor. Previous studies remain controversial regarding whether DPP-4 use is associated with reduced risk for COVID-19 diabetic patients. Thus, this meta-analysis is performed. Method: A comprehensive literature search on PubMed was conducted to identify all relevant studies published prior to October 2020. This meta-analysis was reported in conformity to the Preferred Reporting Project declared by the Systematic Review and Meta-Analysis (PRISMA). The quality assessment was performed by the Newcastle-Ottawa Scale (NOS). The pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated. Random-effect model or fixed-effect model was used based on heterogeneity. Subgroup analyses were performed based on types of diabetes, geographic locations, study designs, and different sample sizes. Sensitivity analysis and publication bias detection were also performed. All statistical analyses were performed using RevMan and STATA 12.0 statistical software, and all P values were two-tailed, the test level was 0.05. Result: 69 articles were obtained. 5 articles involving 49,989 participants were included. All included studies were considered moderate to high quality. No decreased mortality of COVID-19 diabetic patients was found among DPP-4 users (OR 0.86, 95%CI: 0.22,3.41, P=0.083, I2=81%). In the subgroup analysis, studies in Asia (OR 3.11, 95%CI: 0.78, 12.34, P=0.001, I2=70%) did not found reduced mortality, whereas studies in Europe (OR 0.36, 95%CI: 0.23, 0.56, P&lt;0.00001, I2=0%) were associated with reduced mortality. Based on study designs, the four case-control studies (OR 1.27, 95%CI: 0.27, 5.93, P=0.76, I2=89%) did not find reduced mortality, but one cohort study (OR 0.13, 95%CI: 0.02, 0.84, P=0.03) showed a reduced mortality. The four studies investigating Type 2 Diabetes Mellitus (T2DM) did found reduced mortality (OR 0.74, 95%CI: 0.13, 4.24, P=0.73, I2=90%). For sample size &gt;200, reduced risk of mortality (OR 0.28, 95%CI: 0.07, 1.15, P=0.08, I2=32%) was found, however, for sample ≤200, no statistically significant association (OR 1.44, 95%CI: 0.23, 8.89, P=0.70, I2=93%) was found. Sensitivity analysis by changing models and omitting each study at a time confirm the stability of the result. Begg’s test (z=-0.24, P=1.000) and Egger’s test (t=0.56, P=0.618) did not detect a significant risk of publication bias. Conclusion: The current meta-analysis did not find reduced mortality for COVID-19 diabetic patients who take DPP-4. However, subgroup-analyses found reduced mortality in Europe. More high-quality original studies are needed to further explore the association between DPP-4 use and the mortality risk of COVID-19.
‘” Hyper-Warburg“ Phenomenon - A Rare Complication
Authors: Nallu Ravali , Emott Molly Morgan 
Published: May 2021

Abstract
Background: Malignant cells rewire metabolism to promote growth and survival through fermentation of glucose to lactate known as Warburg phenomenon; this process occurs even in aerobic conditions. To produce enough ATP the cells must increase the rate of glucose uptake. We report a fatal case of severe hypoglycemia and progressive lactic acidosis in a patient with lymphoma thought to be from Hyper-Warburgism.
Case: 57-year-old male with no past medical history presented with diarrhea, abdominal cramping, nausea, vomiting of 1-week duration. At presentation he was hemodynamically stable except for mild tachycardia. Biochemical evaluation showed normal renal function, glucose of 115 mg/dl, sodium of 126 mmol/dL, mild leukocytosis and anemia. CT scan of the abdomen and pelvis showed large retroperitoneal mesenteric portacaval and periportal nodes, biopsy of which revealed CD 30 + T- cell lymphoma. He was discharged with outpatient oncology follow up but re-presented within 1 week with weakness. He was noted to be hypoglycemic with a serum glucose of 55 mg/dl, which was corrected with D50. Laboratory work up showed anemia, mild leukocytosis. Lactic acid was elevated at 5 mmol/dl (0.5–2.2). Chest X ray showed increased peri-hilar markings and he was admitted for presumed sepsis secondary to community acquired pneumonia. Throughout the hospitalization he had persistent hypoglycemia with a serum glucose as low as 33 mg/dl but with only mild neurocognitive symptoms. He was started on a continuous glucose infusion up to 20 g/hr with no significant improvement of the hypoglycemia. He was started on stress dose steroids again without much improvement. Lab evaluation to rule out insulin mediated hypoglycemia was limited an IGF level 1.3 mcg/ml (3.4–6.9), insulin level 2.4 uIU/ml (2.5- 25) with a corresponding serum glucose of 119 mg/dl. He had negative urine and blood cultures. Lactate level continued to increase throughout the hospitalization to as high as 11.3 mmol/dl with the continuous glucose infusion. He unfortunately suffered a cardiac arrest and passed away.
Discussion: Warburg phenomenon is an adaptive form of metabolism where malignant cells utilize glucose via the glycolytic pathway irrespective of the oxygen content. This process requires increased glucose uptake to sustain energy production and, in some cases, can result in clinically asymptomatic hypoglycemia and concurrent lactic acidosis. Infusions of dextrose are thought to ‘feed’ the cycle. This severe complication is very rare and associated more commonly with lymphoproliferative disorders as demonstrated in this case. Hypoglycemia and lactic acidosis has been shown to improve only after institution of chemotherapy for treatment of the underlying malignancy. It is important to maintain a high index of suspicion as this cause of hypoglycemia has important therapeutic implications.
A Curious Case of Hypoglycemia: A Rare Occurrence of Insulin Autoimmune Syndrome
Authors: Ellangovan Rithikaa , Mundada Rachana , Kulkarni Ajinkya , Ries Robert A , Konduru Sudheer , Ruby Edward B 
Published: May 2021

Abstract
Background: Hypoglycemia can be challenging, requiring close monitoring and evaluation. Although treating diabetes can cause hypoglycemia, the coexistence of autoimmune syndromes contributes to rare etiologies. They are characterized by elevated insulin levels with either insulin autoantibodies (IAA) or insulin receptor antibodies (IRA). It has been observed commonly in Japan but is scarce among non-Asian groups. We present a unique case of insulin autoimmune syndrome (IAS) that posed a diagnostic challenge in an African American male. Case: A 73-year-old African American male was admitted with altered mental status. Medical history included type 2 diabetes, hypertension, and hyperlipidemia. Home medications were carvedilol and simvastatin. On arrival, vital signs were normal. A fingerstick glucose was 52 mg/dL with a serum level of 68 mg/dL (70–110). Other labs were normal. Given symptomatic hypoglycemia, an IV dextrose infusion was initiated. Once his mentation improved, a diet was started. Despite this, he had recurrent hypoglycemia with glucose levels as low as 22 mg/dL, predominantly in fasting state with sporadic hyperglycemia. On rare occasions, he received correctional insulin for the same. An HbA1c was &lt;4% (4–6). Thyroid function test and AM cortisol were normal. A cosyntropin stimulation test was negative for adrenal insufficiency. A hypoglycemia panel showed inappropriately high levels of insulin, highest at 77.4 μIU/mL(&lt;=29.1), proinsulin of 19.7 pmol/L (&lt;=8), and C-peptide of 5.6 (0.8–3.69 ng/mL) when serum glucose was 25 mg/dL. An MRI abdomen was normal. Octreotide study was negative for insulinoma. He had a normal response to IM glucagon, inferring normal glycogen stores. He was started on Diazoxide 160 mg thrice a day for recurrent hypoglycemia. An endoscopic ultrasound and DOTATATE scan were negative. He had no hypoglycemia for a few days, attributable to lingering effects of diazoxide. Eventually, his serum glucose was 52 mg/dL. Labs prior to glucose correction included an insulin level elevated at 1,000 (normal &lt;3 mcIU/mL), c-peptide at 0.90 ng/mL, and proinsulin of 5.6 pmol/L. Given exceedingly high insulin levels, we measured an IAA level. This was &gt;50 u/mL (normal &lt;0.4 u/mL). With negative imaging and high IAAs, a diagnosis of IAS was made. Discussion: IAS or Hirata disease is a rare condition with hyperinsulinemic hypoglycemia and high titers of antibodies to endogenous insulin. The binding kinetics of endogenous insulin to these antibodies causes physiologically inappropriate levels of bioavailable insulin, causing either hyper- or hypoglycemia. IAA should be measured in patients with high insulin levels that are inconsistent with C peptide levels. We believe this to be the first African American patient to have been diagnosed with Hirata disease. Making a correct diagnosis may spare a hypoglycemic patient from unnecessary pancreatic surgical intervention.
Accelerated Progression of Prediabetes to Insulin-Dependent Diabetes After 9 Cycles of Nivolumab
Authors: Swaid Bakr 
Published: May 2021

Abstract
Introduction: Diabetes mellitus have been reported in around 1% of patients receiving immune checkpoint inhibitors (ICI) resultingin immune checkpoint inhibitor induced diabetes mellitus (ICI-DM). 4 phenotypes of ICI-DM exist: acute autoimmuneinsulin-dependent diabetes, decompensation of prediabetes or type 2 diabetes, autoimmune pancreatitis, andautoimmune lipoatrophy. Clinical Case: A 52-year-old man was diagnosed with stage IIIb malignant melanoma. Two months following local excision, he wasstarted on nivolumab every 4 weeks planned for 1 year. His past medical history was significant for prediabetes,hypertension, obesity (BMI 33.27 kg/m²), primary hypogonadism, adult attention deficit disorder, obstructive sleepapnea, gastric ulcer, and gastroesophageal reflux disease. He denied tobacco use but reported semi-daily use ofmarijuana and alcohol. His baseline HbA1c was 6.0%. After the 8th cycle of nivolumab, he reported several bloodglucose readings in the 200 mg/dL range. He was thought to have progressed to type 2 diabetes and metformin wasstarted. Glipizide was added shortly thereafter due to persistent hyperglycemia. At the 9th cycle of nivolumab, hisHbA1c was 8.2%. In 1 week from this time, the patient developed abdominal pain, nausea, and persistent vomiting. Hewas found to be in DKA with blood glucose of 278 mg/dL, bicarbonate of 9.3 mmol/L, anion gap of 21, and arterial pHof 7.22. He was treated in the ICU per standard DKA care. His C-peptide was 0.5 ng/mL (reference 0.8–3.5) withconcomitant plasma glucose of 229 mg/dL. Autoantibody screening was negative including glutamic aciddecarboxylase antibody (anti-GAD), insulin antibody, insulin antigen-2 (IA-2) autoantibody, and zinc transporter 8antibody. The patient was discharged home on multiple daily injections of insulin but he struggled with diabetes carewhich proved to be of brittle nature requiring CGM use. Two months after completion of nivolumab treatment, thepatient reported epigastric abdominal pain with frequent nausea and occasional vomiting of few weeks duration. He wasdiagnosed with subacute pancreatitis based on symptoms and elevated lipase. There was no evidence of gallstones. Although immunotherapy-related pancreatitis was considered, we decided to try alcohol cessation first hoping to avoidthe need to use prednisone. Over several weeks, lipase normalized and his symptoms completely resolved. Conclusion: In this case, nivolumab resulted in progressive beta-cell failure and complete insulin dependence in a person with ahistory of prediabetes. Not all pancreatitis cases in the settings of immunotherapy use are immune-related adverseevents (irAE). Usual causes, e.g. alcohol, should still be considered. With cessation of alcohol, pancreatitis fullyresolved leading to avoidance of prednisone which would likely have worsened diabetes management in this patientwith brittle diabetes.
Atypical Diabetes Mellitus Associated With Kabuki Syndrome: A Model of Epigenetic Disturbance in Insulin Resistance?
Authors: Thewjitcharoen Yotsapon , Wanothayaroj Ekgaluck , Nakasatien Soontaree , Krittiyawong Sirinate , Khurana Ishant , El-Osta Assam , Himathongkam Thep 
Published: May 2021

Abstract
Background: Kabuki syndrome (KS) is a genetically heterogeneous disorder characterized by striking facial features similar to make-up of actors in Japanese Kabuki performance together with multi-organ defects. The first identified and most frequently involved gene is KMT2D which encodes a histone H3K4 methyltransferase. Even though KS is a rare syndrome and associated diabetes has been rarely reported, both type 1 DM and type 2 DM had been previously reported. Understanding the function of the genes that lead to KS opens up the possibility of targeted therapies for diabetes.
Clinical Case: A 27-year-old male with unconfirmed diagnosis of Fragile X syndrome since childhood came to attend our diabetes clinic due to uncontrolled hyperglycemia (A1C 8.5%). He was a preterm baby born at 7 months and had been clinically diagnosed with Fragile X syndrome due to delayed development and moderate mental retardation from another hospital. At the age of 11 months, he underwent right nephrectomy from severe hydronephrosis. He later developed hypertension due to coarctation of aorta at the age of 14. At the age of 19, he presented with polyuria and lost 10 kilograms within 6 months (baseline BMI at 26.3 kg/m2). Laboratory data showed A1C 14.7%, plasma glucose 432 mg/dL, no ketonemia. At that time, youth-onset type 2 DM had been diagnosed and insulin treatment had been given for a few months before switching to oral medications. He presented at our hospital at the age of 27. Based on his facial features and multi-organ involvements, KS was clinically suspected and then was confirmed to have heterozygous frameshift deletion mutation (c.7524 deletion) of the KMT2D gene. Evaluation of beta-cell function revealed preserved beta-cell with stimulated C-peptide at 8.7 ng/mL. HOMA-IR score suggested severe insulin resistance (HOMA-IR 5.5). Pancreatic auto-antibodies revealed negative results. Currently, his diabetes has been fairly controlled (A1C varied from 6.8–8.5%).
Conclusions: Our case highlights the importance of clinical recognizable phenotype in patients with diabetes. To study and decipher mechanistic studies of the role of epigenetic regulations in this syndrome toward insulin signaling pathways would provide an opportunity for novel insights into pathogenesis of epigenetic defects in Kabuki syndrome.