bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative Renin Status Indicate the Clinical Outcome of Aldosterone-Producing Adenoma
Authors: Xu Felicity , Song Ying , Luo Ting , Li Qifu
Published: May 2021

Primary aldosteronism is widely recognized as renin-independent hypersecretion of aldosterone and aldosterone-producing adenoma(APA) represents the typical clinical subtype. Plasma renin below detection levels was considered as an important indicator for PA, and the suppressed renin level after confirmatory tests was considered to be a prerequisite when interpreting the results of confirmatory tests, before making the diagnosis of PA. Strictly, there is no specific definition of suppressed renin level in patients with PA. Clinically, the renin level of patients with APA varied greatly within the low to normal range. However, the clinical characteristics and outcomes in patients with APA having different renin status remain unclear. This retrospective study included 274 patients with APA who underwent unilateral laparoscopic adrenalectomy with at least a 12-month follow-up postoperatively. Patients were classified into the following 2 groups: low renin and non-low renin groups measured at 8.2 mU/L, according to the widely used criteria(defined as plasma renin activity<1ng/ml/h≈PRC 8.2 mU/L). Only patients with two consecutive PRC less than 8.2 mU/L could be classified into the low renin group. For the screening test and the confirmatory tests, antihypertensive medication was withheld or changed according to the guideline. Chemiluminescence immunoassays showed the range of the plasma renin concentration as 0.4–41.5mU/L. Non-low renin APA patients (n=26) had higher presurgical SBP(p=0.028), DBP(p=0.001) and PRC post confirmatory tests(p<0.001), compared with low renin APA patients(n=248). There was no significant difference in baseline PAC(p=0.507) and serum potassium(p=0.348) between the two groups. Intriguingly, non-low renin APA patients had higher PAC(p<0.001) and PRC(p<0.001) and lower serum potassium(p<0.001) at follow-up. For non-low renin APA patients, the rate of complete clinical success after surgery was 42.3%, 25% lower than that of low renin APA

patients. APA patients with PRC<0.5mU/L had the highest rate of complete clinical success(75%), followed by PRC 0.5~8.2 mU/L(65%) and 8.2~20 mU/L(50%), with the lowest rate in patients with PRC>20 mU/L(33%). Multivariable logistic regression showed that the presence of baseline PRC>8.2 mU/L was a strong independent predictor for the lack of complete clinical success[OR 3.7(1.5–8.9),p=0.004]. Plasma renin concentration is closely related to the clinical outcome of APA patients postoperatively. APA patients with higher baseline renin status are at high likelihood of persistent hypertension after surgery, in whom strengthened monitoring of blood pressure is necessary.
Rates of Primary Aldosteronism Screening Among High-Risk Populations
Authors: Grigoryan Seda , Konzen Sonja Marie , Turcu Adina F
Published: May 2021

Background: Primary aldosteronism (PA) is the most common form of secondary hypertension. PA is associated with higher cardiovascular and renal morbidity and mortality than equivalent essential hypertension. Data on PA screening rates are scarce.

Objective: To evaluate the rates of PA screening among at-risk populations.

Methods: We conducted a retrospective review of adult patients (age ≥ 18 years) with hypertension (HTN) seen in a University setting outpatient clinics between 2010–2019 who had: 1) resistant HTN; 2) HTN and hypokalemia; 3) HTN at age <40; 4) HTN and known adrenal mass; or 5) HTN and obstructive sleep apnea (OSA). We excluded patients with known high-renin HTN, renovascular HTN, or congenital adrenal hyperplasia.

Results: We identified 11,627 patients with HTN meeting at least one of the inclusion criteria. Of these, only 3.27% were ever screened for PA. Patients screened were younger (47.5 ± 17.8 vs. 51.3 ±16.9, p <0.0001), more often women (55.28% vs. 45.71%, p=0.0003), had lower serum K+ (3.4 ± 0.5 vs. 3.7 ± 0.4, p<0.0001), and were more likely to have chronic kidney disease (29.27% vs. 17.5%, p<0.0001) and cerebrovascular accidents (9.21% vs. 6.16%, p= 0.02) than those never screened. While most patients in this cohort were white (79.9% vs. 15.3% black, and 2.3% Asian), screening rates were overall higher in Asian (8.4%) and black (6.1%) than in white Americans (2.8%, p<0.0001). Of the different indications for PA screening, the rates were highest among patients with adrenal nodules (35%) and lowest in patients with HTN and OSA (2.1%). The rates of screening were similar in patients younger vs. older than age 40 (3.2%, p=0.9). Among patients with resistant hypertension, those screened were on average 10 years younger (58.5 ± 14.0 vs. 68.7 ± 12.8, p<0.0001) and twice as often black (20.7% vs. 10.1%) compared to those not screened for PA. Conversely, in patients with adrenal masses, there were no sex, age, or race differences between those screened vs. not screened for PA. PA screening was initiated most often by general internists (53.9%), followed by endocrinologists (15.8%), and rarely by nephrologists (9.5%), or cardiologists (4.2%).

Conclusions: Despite its high prevalence and associated cardio-renal morbidity, PA screening is pursued in only 3% of high-risk populations. While patients screened are generally younger and more often black than those not screened, the diagnosis is often suspected after complications have already developed. These data indicate that initiatives to encourage PA screening are crucial for preventing cardiovascular and renal morbidity in many patients with HTN.
Visualization of Ca Channel Blocker on Human Adrenal Tissue by Mass Spectrometry Imaging ~Its Predominant Distribution at Aldosterone-Producing Cells ~
Authors: Motomura Naoki , Yamazaki Yuto , Xin Gao , Tezuka Yuta , Omata Kei , Ono Yoshikiyo , Morimoto Ryo , Satoh Fumitoshi , Nakamura Yasuhiro , Sasano Hironobu
Published: May 2021

Primary aldosteronism (PA) is the main cause of secondary hypertension, accounting for approximately 5–10% of all hypertension. Amlodipine, a third-generation calcium channel blocker, is one of the most frequently administered pharmaceuticals medications of hypertension, binds specifically to Cav1.2, a calcium channel primarily localized in the cardiovascular system, and exerts antihypertensive effects through inhibiting calcium influx into the vascular smooth muscle cells. In addition, calcium influx also plays important roles in aldosterone production and amlodipine was also reported to influence in vitro functions of Cav1.3, a calcium channel involved in aldosterone secretion. Ca channel blockers were also reported to reduce plasma aldosterone concentration by some clinical studies although with mild degrees. However, in vivo effects of amlodipine to aldosterone secretion has remained virtually unknown. A novel technique “Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI)” has been recently developed, which did make it possible to visualize non-labeled small molecules on tissue sections. Therefore, in this study, we firstly applied MALDI-MSI to visualize amlodipine on human adrenal glands including aldosterone producing adenoma (APA). We performed selective imaging of amlodipine using MALDI-MSI on the resected adrenal tissues from APA patients. Frozen sections containing whole representative tumor area were coated with a matrix called CHCA (α-Cyano-4-hydroxycinnamic acid) by deposition as a pretreatment. We subsequently analyzed and detected a precursor ion with MS at m/z 407.1 and then an amlodipine-specific ion with MS/MS at m/z 318.1. We also examined the concordance of amlodipine distribution obtained by this method with immunohistochemistry. Human resected adrenal tissues obtained from the patients APAs treated with and without amlodipine before adrenalectomy were examined. Periadrenal adipose tissues were also analyzed as a control tissue of non-aldosterone-producing tissues. Amlodipine was specifically detected and visualized only in the administered cases. Amlodipine was more abundantly detected in adrenal tissues than periadrenal adipose tissues. On the other hand, significant different was not detected between tumors and adjacent adrenal glands by semi-quantification using MALDI-MSI. In this study, we firstly visualized amlodipine directly in human tissue sections using MALDI-MSI. Increased accumulation of amlodipine in APAs treated with amlodipine did indicate direct effects of amlodipine on aldosterone production but further investigations are required for clarification between neoplastic and non-neoplastic aldosterone producing cells.
Targeted Therapeutic Approach in Patients With Familial Partial Lipodystrophy Type 3
Authors: Cohen Benjamin , Mathias Priyanka , Stein Daniel T
Published: May 2021

Introduction: Familial partial lipodystrophy (FPLD) syndromes are genetic disorders characterized by selective lipoatrophy affecting the upper and lower extremities leading to severe insulin resistance and metabolic complications. We describe a patient diagnosed with a pathogenic variant in the peroxisome proliferator-activated receptor γ (PPARγ) gene that causes FPLD type 3 (FPLD3) subsequently treated with pioglitazone with excellent response.

Clinical Case: A 52-year-old Hispanic woman with type 2 diabetes mellitus and hypertension presented with epigastric pain and vomiting. Workup revealed elevated lipase to 1889 U/L and triglycerides to 4117 mg/dL, consistent with hypertriglyceridemia-induced pancreatitis. CT abdomen showed acute pancreatitis with hepatic steatosis. Family history was significant for hypertension, diabetes, and hyperlipidemia in her father, mother, and five siblings. Examination revealed facial and truncal obesity, lipoatrophy of her limbs and buttocks, acanthosis nigricans, and hepatomegaly. The patient was treated with an insulin drip with decline in triglyceride levels (450 mg/dL) and discharged on atorvastatin, fenofibrate, metformin, and pioglitazone. Laboratory evaluation revealed an HbA1c of 9%, normal thyroid and liver function tests, and a serum leptin of 1.2 ng/ ml (N females: 4.7–23.7 ng/ml). Lipoprotein electrophoresis showed type 4 lipoproteinemia. A liver fibroscan showed hepatic steatosis with portal fibrosis. Genetic testing was notable for an autosomal dominant pathogenic heterozygous loss-of-function mutation in the ligand binding domain AF-2 region of PPARγ (c.452 A>G) confirming FPLD3. Pioglitazone was increased to 30mg/day with improvement in HbA1c to 8.3% and dyslipidemia at three-month follow up.

Conclusion: FPLD3 is caused by loss-of-function mutations in PPARγ, a transcription factor involved in adipogenesis1. FPLD is estimated to affect 1 per 1 million, with FPLD3 reported in approximately 30 individuals worldwide per National Organization for Rare Disorders. Treatment is currently directed at reducing insulin resistance, dyslipidemia, and their sequelae of pancreatitis and cardiovascular disease. Thiazolidinediones (TZDs), PPARγ agonists targeting insulin sensitivity and adipocyte differentiation, have been used in FPLD with variable results. Different mutations in the ligand-binding domains of PPARγ may affect the binding capacity to synthetic agonists, affecting clinical response. Use of TZDs in individuals with PPARγ mutations (R308P, A261E) have been shown to improve hyperglycemia and dyslipidemia2. Our patient was treated with pioglitazone with excellent response to therapy in three months. TZDs may offer a targeted approach to treat FPLD3 based on PPARγ ligand-dependent responsiveness.

References:

(1) Garg A. JCEM 2011;96:3313–3325(2) Agostini M. Diabetes. 2018;67(6):1086–1092
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

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

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 < 1 nM in cell-based assays of receptor activation and selectivity > 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

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

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<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 >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

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

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 <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(<=29.1), proinsulin of 19.7 pmol/L (<=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 <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 >50 u/mL (normal <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

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

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.
Development of Diabetes Type 3 After SARS-COV-2 Pancreatic B Cell Injury
Authors: Zayas Francisco Jose , Hernandez-Negron Marianne , Garcia Michelle Marie Mangual
Published: May 2021

SARS-COV-2 has caused millions of deaths in less than one year, yet little is known about the long-term consequences survivors may suffer. The novel coronavirus uses the ACE2 receptor to infect human cells, allowing it to target organ systems with such receptors including the respiratory, cardiovascular, gastrointestinal and endocrine system. The purpose of this case report is to describe the long-term implications COVID-19 may cause in the endocrine system. A 46-year-old woman was referred to our clinic due to abrupt uncontrolled blood glucose levels ranging from 200-550mg/dL after being infected with COVID-19 for approximately 10 weeks. She has a past medical history of Diabetes Mellitus Type 2 which was diagnosed 3 years ago and was well controlled with diet. Present history reveals polyuria, polydipsia, tiredness and a decreased appetite. Laboratory values show HbA1C 12, negative islet cell antibodies/GAD antibodies, low C-peptide, high TSH, normal FT4 and positive anti-TPO antibodies/thyroglobulin antibodies. The sudden loss of blood glucose control along with low c peptide levels without evidence of autoimmunity support the diagnosis of Pancreatic Diabetes. SARS-COV-2 infection may cause Diabetes Type 3, rendering a patient dependent on insulin use for life. Covid-19 survivors, with or without a previous history of endocrinopathy, should be evaluated for possible long-term sequels of infection as the virus targets tissues throughout the body.
Diabetic Ketoacidosis With Alpelisib
Authors: Jeun Rebecca , Lavis Victor Ralph , Thosani Sonali
Published: May 2021

Background: Hyperglycemia is a frequently reported adverse effect of alpelisib, an isoform specific phosphoinositide 3 kinase inhibitor, which is recently approved for use in hormone receptor positive advanced or metastatic breast cancer. Though two patients in clinical trials with alpelisib developed diabetic ketoacidosis (DKA), there have been no case reports to date characterizing this complication after drug approval. We present the first case of DKA in patients on alpelisib therapy.

Clinical Case: A 55-year-old woman with a history of hormone-receptor positive metastatic breast cancer was started on treatment with fulvestrant and alpelisib. The patient did not have any previous history of diabetes nor gestational diabetes, though she had evidence of prediabetes prior to starting treatment. Patient was non-obese and had a family history of type 2 diabetes. Baseline hemoglobin A1c was 5.6% (n <5.7%) with impaired fasting glucose of 108 mg/dl (n<105 mg/dL) immediately prior to starting therapy. One week after starting alpelisib, she presented to the emergency center in diabetic ketoacidosis. Initial laboratory evaluation showed serum glucose 690 mg/dl, anion gap metabolic acidosis, with undetectable serum bicarbonate and ketonuria. C-peptide on hospital day 1 was found to be 2.8 ng/ml (n 0.5 - 3.4 ng/ml) with a concurrent glucose of 479 mg/dl. GAD65 and Islet Antigen 2 antibodies were negative. Diabetic ketoacidosis quickly resolved with continuous insulin infusion and stopping alpelisib. The patient was able to come off all insulin therapy prior to discharge and was discharged on metformin with adequate glycemic control.

Conclusions: Current manufacturer guidelines for alpelisib recommend screening for diabetes mellitus at baseline and monitoring blood glucose and/or fasting plasma glucose weekly for the first two weeks of treatment and monthly thereafter. However, patients with no pre-existing history of diabetes mellitus may be at risk for life-threatening hyperglycemic crises which may develop within a week of initiation of alpelisib and more frequent monitoring may be indicated. The hyperglycemic effect of alpelisib appears to be reversible upon stopping the drug.
Diabetic Myonecrosis: A Rare Complication of Uncontrolled Diabetes Mellitus
Authors: Tumyan Gayane , Oubre Aaron , Feldman Mark
Published: May 2021

Background: Diabetic myonecrosis is a rare complication of long-standing, poorly controlled diabetes mellitus, and is more common in patients with microvascular complications. The diagnosis is frequently missed due to symptoms mimicking other conditions associated with diabetes mellitus.

Clinical Case: A 31-year-old woman with a past medical history of long-standing type I diabetes mellitus, end-stage renal disease, diabetic retinopathy, and cataracts presented to our hospital with a chief complaint of right thigh pain and swelling for a week. She did not have any other relevant symptoms and denied a history of trauma. On admission, physical examination revealed right thigh edema, induration, tenderness on palpation, more pronounced in the medial aspect of the thigh, and decreased range of motion of the right hip. Laboratory analysis showed leukocytosis of 13.29 k/uL (normal = 4.23 - 9.71 k/uL) with neutrophilic predominance of 91.4 %, elevated inflammatory markers (ESR > 130 mm/h (normal = 0 - 30 mm/h), CRP 33.84 mg/dL (normal <= 0.49 mg/dL)) and elevated CK levels of 1675 U/L (normal = 29 - 168 U/L). Additionally, the patient was anemic with a hemoglobin level of 8.4 g/dL (normal = 11.0 - 15.0 g/dL) and had a creatinine level of 2.67 mg/dL (normal = 0.55 - 1.11 mg/dL). Hemoglobin A1C level was 10.8 % (normal = 4.0 - 6.0 %). Blood cultures were drawn and did not grow any organisms. A doppler ultrasound of the right leg was negative for a deep venous thrombosis. CT angiogram of right lower extremity revealed diffuse calcifications in the walls of small and medium vessels and edematous changes in thigh musculature associated with subcutaneous edema. Noncontrast MRI revealed localized edema within the vastus medialis, sartorius, and right thigh adductor muscles. The patient improved with analgesics, rest, and gentle physical therapy. She was counseled on compliance with insulin and advised for a close follow up with her endocrinologist.

Conclusion: This case reinforces the importance of including diabetic myonecrosis in the differential diagnosis of acute to subacute nontraumatic muscular pain in diabetic patients, particularly in patients with poor glycemic control and known complications. While muscle biopsy can be performed for histological confirmation, the typical imaging findings and clinical presentation can lead to the diagnosis, making further invasive testing unnecessary. In most described cases, the course of this condition is self-limiting.
Hemi Chorea and Hemi Balllismus: A Rare Presentation of Prolonged Uncontrolled Hyperglycemia
Authors: Karam Jocelyne Georges , Eze-Raphael Chinenye Uchenna , Calliste Chrystel
Published: May 2021

Background: Hemi chorea and hemiballismus interestingly, are rare presentations of severe chronic persistent hyperglycemia which resolves with correction of hyperglycemia in most cases.

Clinical Case: Here we report a case of a 67 YO woman with a PMH of prolonged uncontrolled DM evidenced by average baseline HbA1c of 14.6% (n<5.7%) presenting with dance-like movements of the left arm and mouth deviation. Initially the patient presented as a stroke code. Vital signs were unremarkable. On Physical exam, there was mild L face weakness and obvious abnormal hand movement. Other neurological exams were unremarkable for stroke. MRI showed the typical decreased T2/flair signal within the right frontal lobe, white matter, right caudate head, and bilateral lenticular nucleus with mild increased T1 signal of the right caudate and lenticular nucleus compatible with hyperglycemic nonketotic hemichorea hemiballismus. Her significant admission lab values of random blood glucose of 306mg/dl (n 74-200mg/dl), HbA1c of 18.7% (n<5.7%), urine sugar >1000 (n neg mg/dl), absence of ketonuria and acidosis also support the diagnosis. With improvement in her blood sugar control, there was a significant decrease in her abnormal hand movements. However, sugar control was not enough as there was the need for additional medications to improve the chorea such as risperidone and tetrabenazine. Eventually over the course of many months of tight glucose control, there was significant symptomatic improvement. While the exact etiology is unclear, the hyperintensity usually seen on head CT scan and the pathognomonic T1 hyperintensity of the basal ganglia on MRI is postulated to be related to metabolic abnormalities caused by hyper viscosity of the blood in the end arteries supplying the basal ganglia. Many case reports associated movement disorders to chronic persistent hyperglycemia but there are many other cases that described hemiballismus in acute cases of hyperglycemia or persisting despite adequate glycemic correction. Most of the patients described had an underlying markedly elevated HbA1c as a common factor which suggests that a prolonged period of uncontrolled hyperglycemia may be necessary to produce hemiballismus. When thinking of complications of diabetes, we often think of CAD, ESRD, CVD, DKA and HHS. We aim to create an awareness of this rare association and to recognize hemiballismus as one of the varying presentations of severe hyperglycemia in order to ensure early diagnosis and treatment of this condition.

Conclusion: Hemichorea and hemiballismus are increasingly becoming popular as one of the many complications of severe chronic or acute hyperglycemia. This warrants recognition in literature.
Hyperglycemia With Use of Vagal Nerve Stimulator
Authors: Castellanos-Diaz Jessica , Amole Morolake , Surabhi Swapna , Kadiyala Sushma
Published: May 2021

Introduction: In patient with diabetes and refractory epilepsy requiring vagal nerve stimulator (VNS), glycemic management can be challenging. Clinical experience is limited in this scenario. Case Report: A 67-year-old male, BMI 30 kg/m2, with history of type 2 diabetes and hemispheric hemangioma complicated by seizure disorder is referred to our diabetes clinic for evaluation of persistent hyperglycemia. The patient reports 25-year history of seizures that have been difficult to control with antiepileptic drugs alone and eventually requiring VNS placement. Patient has normal kidney (eGFR > 60mL/min) and liver function. His antiepileptic drug regimen consisted of gabapentin and as needed lorazepam. He was never on glucocorticoids. Glycated hemoglobin (HgA1c) at our initial evaluation was 10.1%. His anti-glycemic regimen consisted of glipizide monotherapy. Fasting and pre-prandial blood glucose were in the 200-400mg/dL range with occasional values higher than 500mg/dL. This was confirmed with 14-day continuous glucose monitoring that showed average blood glucose of 287mg/dL with 100 percent above target (higher than 180 mg/dL). We optimized therapy by adding once daily glargine, pioglitazone and continued glipizide. At follow up visit, HgA1c still remained high at 10.5%, despite medication adherence. Patient emphasized that hyperglycemia was related to VNS use and given documented hyperglycemia with blood glucose range 500–600 mg/dL when on higher output current of 2 milliamps, his neurologist approved a trial off VNS for 4 weeks. His glucose improved to average less than 200 mg/dL and HgA1c decreased to 9.1% on the same anti-glycemic regimen. Device was re-started due to recurrence of seizures, however the output current and “on time” were reduced to minimal effective range for optimizing seizure therapy while avoiding hyperglycemia. Subsequent HgA1C improved to 8.7%. Discussion: VNS is a FDA approved device for epilepsy and depression. It works by intermittent stimulation or “on/off” periods. In animal studies, elevation of blood glucose was noted with afferent stimulation. Conversely, efferent activation lowers blood glucose. There are limited human studies on the effects of vagal nerve stimulation on glycemic control. The few available, showed variation in blood glucose based on output current and length of on/off period. This should be factored in during glycemic evaluation and management and close collaboration with neurology is essential. Reference: (1) Strauss H, et al. Cervical Vagal Nerve Stimulation Impairs Glucose Tolerance and Suppresses Insulin Release in Conscious Rats. Physiological Reports 2018; 6(24): 1–9 (2) Strauss H, et al. Effect of Vagus Nerve Stimulation on Blood Glucose Concentration in Epilepsy Patients - Importance of Stimulation Parameters. Physiological Reports 2019; 7(14): 1–10