bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Long-Term Safety and Efficacy of Metreleptin in Various Forms of Partial Lipodystrophy
Authors: Akinci Baris , Neidert Adam , Foss de Freitas Maria Cristina , Hench Rita , Oral Elif A 
Published: May 2021

Abstract
Metreleptin is an approved treatment for patients with generalized lipodystrophy but still under investigation for patients with partial forms of the disease in the US. This open-label single-arm study in partial lipodystrophy (PL) allowed continued treatment of patients who volunteered and completed treatment under our previous 1-year protocol and who derived significant clinical benefit. The primary outcome was percent change in fasting triglyceride levels and the secondary outcome was percent change in hemoglobin A1c levels (time frame: 5 years on metreleptin or last observation carried forward in both instances). The hypothesis was that these metabolic parameters would stay stable over the observation period. The study enrolled 11 participants (11 females; 3 ≤ 18 years; 8 between 18–65 years). Four patients had familial partial lipodystrophy type 2 (FPLD2) caused by LMNA pathogenic variants (R482Q in two subjects, R482W in one subject, and R349W in one subject), two patients had POLD1 associated PL (E1067K), four patients had FPLD1, and one patient had atypical PL. Variants of uncertain significance (VUS) in genes of interest were detected in two patients with FPLD1 and one patient with atypical PL. Four subjects completed 48 months (actual 60 months on metreleptin). Data from 3 subjects were excluded from final data analyses due to early loss to follow-up (n = 1), serious adverse event withdrawal (n = 1; development of persistent neutralizing antibody shortly after 18 months of drug exposure), and death (n = 1). The remaining 4 subjects withdrew from the study either through their own volition or due to the investigator decision (last observation carried forward in these 4 subjects). As expected, the median percent change from baseline triglyceride and hemoglobin A1c levels were not significant (55.76 percent (range: -66.79 to 203.80; p &gt; 0.05), and 2.55 percent (range: -27.52 to 25.00; p &gt; 0.05), respectively). Serious adverse events were reported in 8 of 11 patients and additional adverse events were observed in all patients. Apart from neutralizing antibody development in one subject causing substantial metabolic derangement, adverse events were considered not to be directly related to the study drug. Death was caused by a sudden cardiac event related to the specific molecular etiology (LMNA R349W) in one case. This interventional study provided valuable information on the efficacy and safety of long-term metreleptin in PL. Although nonsignificant fluctuations were observed in triglycerides, hemoglobin A1c levels were generally stable over time and the initial improvement seen in the first year were sustained. Adverse events were common but more likely due to the complex nature of the underlying disease. Although rare, neutralizing antibodies can develop in patients with PL treated with metreleptin.
Morbid Obesity Does Not Impact Mortality, Rate of Endoscopy in Patients With Biliary Acute Pancreatitis: A US Nationwide Analysis
Authors: Shaka Hafeez , Palomera-Tejeda Emmanuel , Achebe Ikechukwu , Asotibe Jennifer Chiagoziem , Pudasaini Garima , Essam Rashad , Warraich Muhammad-Sheharyar 
Published: May 2021

Abstract
Introduction: Morbid obesity (MO) is associated with increased mortality in various conditions including acute pancreatitis. Interventions are challenging in patients with MO due to higher prevalence of comorbidities that may affect airway and cardiopulmonary management. Biliary acute pancreatitis (BAP) is the most common etiology for acute pancreatitis in the US. Population-based studies on the effect of obesity on biliary acute pancreatitis are lacking. This study aimed to assess the impact of MO on outcomes of patients with BAP.
Methods: Data was obtained from the Nationwide Inpatient Sample database for 2016 and 2017. Hospital discharges of patients 18 years and over with a principal diagnosis of BAP were included. This cohort was divided based on BMI into nonobese patients (BMI &lt;30) and morbidly obese (MO) patients (BMI &gt;/=40.0). Patients with BMI between 30.0–39.9 were excluded. Primary outcome was inpatient mortality. Secondary outcomes included rate of endoscopic procedures, length of hospital stay (LOS), total hospital charges (THC), discharge diagnoses of hypocalcemia, septic shock, acute renal failure (AKI) and acute respiratory failure (ARF). Multivariate regression analysis was used to adjust for patients’ sociodemographic factors, Charlson comorbidity index as well as hospital characteristics as confounders.
Results: A total of 128995 hospitalizations were principally for BAP, with 75.7% and 12.0% of these patients classified as nonobese and MO respectively. There was a significantly higher proportion of females (66.1 vs 54.5%, p&lt;0.001) and lower mean age (50.1 vs 58.7 years, p&lt;0.001) in patients with MO. There was no significant difference in adjusted odds of mortality (aOR=1.34, 95% CI: 0.88 - 2.03, p=0.174), or rate of endoscopy (aOR 1.00 95% CI: 0.91 - 1.11, p=0.958), in MO compared with patients who were nonobese. However, MO patients had increased mean LOS of 0.8 days (95% CI: 0.5 - 1.0, p&lt;0.001), increased mean THC of $10760 (95% CI: 7077 - 14442, p&lt;0.001), increased odds of hypocalcemia (aOR=1.60, 95% CI: 1.22 - 2.09, p=0.001), septic shock (aOR=2.13, 95% CI: 1.39 - 3.25, p&lt;0.001), and AKI (aOR=1.48, 95% CI: 1.30 - 1.68, p&lt;0.001).
Conclusion: Even though we did not find any significative difference in mortality, patients with MO appear to have and increased LOS and THC, as well as more complications like septic shock, AKI, and hypocalcemia. This calls for a greater recognition of this association for further research studies and to recognize this potential association during clinical practice.
Refractory Hypoglycemia Related to Gastric Bypass Complicated by Hypothyroidism
Authors: Jain Akhil , Alukal Thomas J , Amakye Kingsley , Kagita Navyamani V D , Mustaqeem Ruqqiya , Alam Fahd , Jose Jose , Qiu Jack , Syed Asad , Sharma Sandeep 
Published: May 2021

Abstract
A 29-year-old African-American female was brought to the emergency department for sudden onset nausea, dizziness, and loss of consciousness at work. She was found to have low blood sugar and was fed with juice and crackers. She had history of similar episodes in the past, migraine headache, post-thyroidectomy hypothyroidism, seizures, generalized anxiety disorder, gastroesophageal reflux disease, and Roux-en-Y gastric bypass 9 months ago for morbid obesity related refractory Pseudotumor Cerebri (failed VP Shunting). She lost 41 kg, and had intolerance to foods from dumping syndrome. Her vital signs were within normal limits upon arrival to the ER. Laboratory parameters were remarkable for hypoglycemia of 52 mg/dL. She was immediately given dextrose intravenously. ECG showed sinus bradycardia. Though she regained consciousness, her blood sugar levels were persistently low, the lowest recording being 43 mg/dL. She was placed on a continuous D10 infusion. Further investigations revealed negative toxicology screens for 1st and 2nd generation sulfonylureas, and normal insulin levels at the time of the hypoglycemic event. Her TSH was found to be very high (99 nIU/mL). Her thyroglobulin (2.8 ng/mL), free T4 (0.25ng/dL), thyroglobulin antibody (99.18 uIU/mL), cortisol levels in morning (14.2 ug/mL), and evening (4.6 ug/dL) were found to be within normal range. Abdominal MRI did not reveal Insulinoma or any other pathology. Repeat ECG showed normal sinus rhythm with occasional PVCs. She was treated for nausea with ondansetron, promethazine, scopolamine, and dronabinol. Dextrose infusion was titrated down with rise in blood sugar levels. She confessed non-compliance to thyroid replacement. Therefore, she was initially treated with intravenous thyroxine replacement, which was later switched to oral therapy. Psychiatry evaluation ruled out any eating disorder. She was counselled to eat small frequent meals, increase dietary proteins, and restrict high glycemic index sugars. Educational value: National data indicates an increasing trend for admissions related to morbid obesity and bariatric procedures, especially laparoscopic (vertical) sleeve gastrectomy (see Fig 1). (1) Complex alteration in the signaling pathway to pancreas owing to changing metabolism causes hypoglycemia after bariatric surgery. When compounded by severe untreated hypothyroidism, as in our case, causes severe hypoglycemia needing hospitalization. Patient education for adjustment in dietary habits would have played a key role in preventing episodes of severe hypoglycemia.
Reference:
1.HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD. https://hcupnet.ahrq.gov/.
Fig 1: Trends for admissions for Morbid Obesity and Sleeve Gastrectomy
Severe Early-Onset Obesity in Three Adult Patients Harboring Inactivating Mutations of the Leptin Receptor Gene
Authors: Chaves Carolina Marques , Kay Teresa , Anselmo Joao 
Published: May 2021

Abstract
Background: Leptin is secreted by white adipocytes in response to fat storage and binds to leptin receptors (LEPR) expressed all over the body particularly in hypothalamic neurons. This hormone regulates several physiologic functions including energy expenditure and appetite. Clinical Case: We describe the clinical and hormonal findings in 3 adult brothers with body mass index (BMI) of 36.7, 50.7, and 46.1 kg/m2, respectively. There is no history of consanguinity in the family and none of the patients exhibited dysmorphic features. A rapid weight gain was noticed during their first few months of life, associated with permanent hyperphagia. At 2 years old, their BMI was already above 25 kg/m2 (&gt; +3SD), and at 10 years old, it was over 40 kg/m2 (&gt; +3SD). The linear growth was within the expected target heights for their parents. They did not seem to present cognitive impairment. The pubertal development began at 16 to 18 years old, and since then they maintained levels and FSH and LH above the upper limit of normal (15.6±3.7mUI/mL and 12.3±2.2mUI/mL, reference range 1.5–12.4 and 1.7–8.6, respectively), but with normal sexual steroids (estradiol 36.4±16.1pg/mL and total testosterone 445±401ng/dL, reference range 11–44 and 249–836, respectively). The thyroid function was normal and none of the patients suffered from dyslipidemia or diabetes, despite high serum insulin levels 26.4±15.8 mU/L (normal 5–10). Genetic sequencing identified a homozygous mutation of the leptin receptor gene in the 3 brothers: c.2357T&gt; C, p. (Leu786Pro). Their parents were heterozygous for the mutation as well as the patients’ daughters. Homozygous carriers of the mutation presented a significantly higher BMI than their heterozygous family members, 44.5±7.1 Kg/m2 vs 32.2±1.7 Kg/m2 (p=0.023), a significantly increased leptin levels, 80±36.4 ng/ml vs 26.3±9.3 ng/ml (p=0.028), and significantly higher weight, 134.6±16.9 vs 89.2±15,2 kg (p=0.021), respectively. Women had higher BMI than men (42.0 ±12.2 Kg/m2 vs 37.9±7.5 Kg/m2, p=0.496) and also higher percentage of fat (46.4±3.1% vs 34.9±6.8%, p=0.108). Serum levels of leptin in homozygous patients were not significantly higher than those measured in 10 patients with adult-onset morbid obesity, 80± 36.4 ng/ml vs 53.8±24.1 ng/ml, respectively (p=0.149). Therefore, serum leptin is not a useful discriminative maker of LEPR gene mutations. Conclusion: Patients with severe early-onset obesity should have a genetic diagnosis workup. Firstly, because clinical trials with MC4R-agonists have raised expectations regarding the treatment of patients with mutations of the LEPR gene. Secondly, and in contradiction to other reports in the literature, our patients were fertile. Therefore, identification of the mutation allows genetic counseling of these patients and their families, including the possibility of Pre-Natal Diagnosis or Pre-Implantation Genetic Diagnosis.
Endothelin-1 Receptor A Blockade Attenuates Metabolic and Proinflammatory Profile in Mice Fed a High Fat Diet
Authors: Rivera-Gonzalez Osvaldo , Taylor Erin , Speed Joshua S 
Published: May 2021

Abstract
Endothelin-1 (ET-1) is elevated in patients with obesity; however, its contribution to the pathophysiology related to obesity is not fully understood. Obesity is associated with dyslipidemia and insulin resistance, which may in part be mediated by inflammation and alterations to immune cell subsets within the adipose tissue. ET-1 promotes inflammation via the ET-1 type A (ETA) receptor, and blockade of ETA receptors improves dyslipidemia in patients with chronic kidney disease. We hypothesized that ET-1 causes dyslipidemia and inflammation within the adipose tissue of obese mice. To test this hypothesis, C57BL/6J mice were fed either normal diet (NMD) or high fat diet (HFD) for 8 weeks followed by 2 weeks of treatment with either vehicle or atrasentan (ETA receptor antagonist, 10mg/kg/day). HFD mice had significantly higher fat mass than NMD mice, with no significant effect of treatment with atrasentan. HFD mice had significantly higher circulating non-esterified free fatty acids, an effect that was ameliorated in mice treated with atrasentran (1.03±0.07 vs 0.58±0.02 mEq/L, p&lt;0.05). Atrasentan-treated mice had significantly attenuated increase in liver triglycerides compared to non-treated HFD mice (3.8±0.7 vs 7.5±1.3mg/dL respectively, p&lt;0.05). Mice treated with atrasentan had significantly improved glucose tolerance (10150±1031 vs 6563±975 AUC, p&lt;0.05) and insulin tolerance (-2796±386 vs -9825±319 AUC, p&lt;0.05) compared to non-treated insulin-resistant HFD mice. Plasma adiponectin, an insulin sensitizing adipokine that is inversely associated with adiposity and insulin resistance, was significantly increased in atrasentan-treated mice compared to non-treated HFD (4.8±0.1326 vs 6.5±0.3 µg/ml, p&lt;0.05), with no differences in plasma insulin levels. Gene expression analysis of visceral fat showed improved expression of genes negatively associated with insulin resistance that were downregulated in non-treated HFD mice vs. NMD (IRS-1, PPAR-gamma, GLUT4, and adiponectin). Flow cytometric analyses of visceral adipose tissue indicated that HFD mice had a significantly higher number of both CD4+ and CD8+ T cells compared to NMD mice, which was attenuated by treatment with atrasentan. Further, eosinophils, which are important in maintaining adipose tissue health and reducing inflammation, were significantly decreased in HFD mice compared to NMD. Atrasentan treatment abolished the decrease in eosinophils. Taken together, these data indicate that ETA receptor blockade improves peripheral glucose homeostasis, dyslipidemia, and liver triglyceride levels, and also attenuates the proinflammatory immune profile in visceral adipose tissue. These data suggest a potential use for ETA receptor blockers in the treatment of obesity-associated dyslipidemia and insulin resistance.
AM833, a Long Acting Amylin Analogue Induces Hypocalcemia in Young Rats via a Calcitonin Receptor Mediated Mechanism
Authors: Dahl Kirsten , John Linu M , Skyggebjerg Rikke B , Vegge Andreas , Andersen Ninette K , Raun Kirsten 
Published: May 2021

Abstract
Amylin is a peptide hormone that is co-secreted with insulin from pancreatic β-cells. It is member of the calcitonin family and activates amylin receptors (AMYRs) in the calcitonin receptor (CTR) family. During recent years, several AMYR agonists have been in clinical development for treatment of diabetes and obesity. In contrast to pramlintide, which is a short acting amylin analogue approved for use in combination with meal-time insulin in patients with diabetes, the more recent development candidates have been dual acting analogues activating both the CTR and the AMYRs. In rodents the CTR plays a significant role in calcium homeostasis, while in humans this has been associated with little long-term effect on the plasma calcium levels (Ganong, 1993; Longo et al., 2011); Rodents are usually chosen as first choice pre-clinical models for in vivo testing and introducing acute and profound hypocalcaemia can lead to general neurological and neuromuscular disturbances, which can be challenging in clinical development programs. AM833 (NNC0174-0833) is a long acting acylated dual acting amylin analogue activating both CTR and AMYRs. When combined with the long acting GLP-1 analogue semaglutide for weight management, both preclinical studies in rat models of obesity and clinical trials in humans with obesity have demonstrated significant weight loss potential. In young rats aged 7–9 weeks, single sc dose of 3–300 nmol/kg AM833 induced a reduction of total and ionized calcium of 40–50% from baseline with lowest level around 12 hours after dosing. A similar response was seen after administration of salmon calcitonin which also activates both CTR and AMYRs. Tachyphylaxis was introduced, with no effect on calcium found after sub chronic daily treatment for 2 weeks. Age played a key role in the sensitivity to calcium lowering with almost no effect found in 11 months old rats. When administering AM1213 (NNC0174-1213), a selective AMYR agonist with little activation of the CTR, no or little calcium lowering of around 10% was seen. These data indicated that the calcium lowering properties are CTR mediated. The induction of hypercalcemia was a rodent specific phenomenon as no calcium lowering outside of normal range was seen in young dogs and rabbits. Clinical data confirmed that CTR induced calcium lowering was not human relevant, but these data showed that understanding physiology and pharmacology in the animal models of investigation as well as human translational relevance is of outmost importance in the progress of an early development program. References: GaNong WF. Calcitonin. In: Review of medical physiology. 16th ed. Appleton & Lange. 1993. Longo DL et al. Calcitonin. In: Harrison’s principles of internal medicine. 18th ed. McGraw-Hill; 2011.
Defining the Contribution of Adipocyte Subpopulations to Dermal White Adipose Tissue
Authors: Leyendecker Mara , Sharma Rita , Luong Quyen , Powell Noah , Harper Brian , Lee Kevin Y 
Published: May 2021

Abstract
Introduction: Our lab has previously identified three distinct subtypes of developmentally and functionally white adipocytes and have shown that they each differentially contribute to adipose depots (Lee, KY et al. EMBO J. 2019). Dermal white adipose tissue (dWAT), a layer of adipocytes embedded in the skin below the dermis, has recently been shown to play a role in crucial physiologic processes including thermogenesis, the regulation of aging, scar formation, and wound healing. The purpose of this proposal is to investigate the contribution of three adipocyte subtypes to dWAT. Objectives: The primary objectives of this project are to determine the number of preadipocytes and adipocytes from each of three subtypes present in dWAT. Methodology: Lineage tracing analysis was performed by crossing transgenic mice harboring cre-recombinase under the control of promoter/enhancer elements of each of the three marker genes, Wilms tumor 1, transgelin, or myoxovirus 1 to dual- fluorescent reporter mice. These three mice lines mark Type 1–3 preadipocytes and adipocytes, respectively. dWAT was collected from X week old mice, and adipocyte identities were determined by confocal microscopy. Preadipocyte contribution of these subpopulations was determined by FACS analysis. Results: We found that Type 2 (~45%) and Type 3 (~25%), but not Type 1 preadipocytes significantly contributed to the dWAT preadipocyte cellular population. We also found a similar pattern for the adipocyte populations. Type 1, 2, and 3 adipocytes were found to comprise ~3%, 17%, and 7% of mature adipocytes, respectively. These studies demonstrate that Type 2 and Type 3 adipocytes contribute to the composition of dWAT. Summary/Conclusion: These studies demonstrate that Type 2 and Type 3 adipocytes and preadipocytes significantly contribute to the composition of dWAT. Since these adipocyte subpopulations have different functional properties, including metabolism and response to inflammatory cytokines, the contribution of these adipocyte subtypes may impact the crucial physiologic processes mediated by dWAT.
Distinct Calcium Signaling for Wildtype, Loss-of-Function and Gain-of-Function Human MC4R Variants
Authors: Kumar Shree S , Mountjoy Kathleen Grace 
Published: May 2021

Abstract
There is compelling evidence for human melanocortin-4-receptor (hMC4R) playing a critical function regulating energy balance; yet signal transduction pathways contributing to this are unclear. The hMC4R activates multiple signaling pathways, including induced increases in cAMP and mobilization of intracellular calcium ([Ca2+]i). Recent evidence showed cAMP signaling was not a good predictor for hMC4R variant-associated obesity. We hypothesize that hMC4R mobilization of [Ca2+]i plays an important role in regulating energy balance. To test this, we developed a robust high-throughput Fura-2 ratiometric fluorescent assay to quantitatively measure [Ca2+]i in vitro. We compared basal and α-melanocyte stimulating hormone (α-MSH) activation of [Ca2+]i for hMC4R-wildtype (WT) and hMC4R-variants stably expressed in HEK293 cells. The loss-of-function variants studied were two obesity-associated variants (R7H and R18L) known to exhibit cAMP signaling similar to WT, two obesity-associated variants (H76R and L250Q) known to exhibit cAMP-constitutive activity (CA) compared to WT, and one overweight-associated variant (H158R) known to exhibit cAMP-CA compared to WT. The gain-of-function variants (V103I and I251L) studied are known to exhibit cAMP signaling similar to WT. The data for basal [Ca2+]i were pooled from three independent experiments performed with WT and all variants in each assay. Data (mean ± SEM) were analyzed using one-way ANOVA with Dunnett’s multiple comparisons. The data (mean ± SEM) for α-MSH activation of hMC4R were pooled from three independent experiments and analyzed using non-parametric sum of squares F-test for maximum best-fit values and EC50. The α-MSH activated assays were performed with each hMC4R variant alongside WT. WT hMC4R and non-CA loss-of-function variants exhibited similar basal and α-MSH activated [Ca2+]i (WT: EC50 = 1.44 nM; R7H: EC50 = 1.40 nM; R18L: EC50 = 1.12 nM). The CA loss-of-function variants exhibited significantly (p &lt; 0.0001) increased basal [Ca2+]i compared with WT (WT = 97.6 ± 0.9 nM; H76R = 114.2 ± 1.7 nM; L250Q = 112.1 ± 2.6 nM; H158R = 110.7 ± 1.8 nM) and significantly lower EC50’s compared with WT (H76R: EC50 = 0.07 nM; p = 0.0019; L250Q: EC50 = 0.09 nM; p = 0.0066; H158R: EC50 = 0.14 nM; p = 0.0009). The gain-of-function hMC4R variants exhibited significantly (p &lt; 0.0001) decreased basal [Ca2+]i compared with WT (WT = 97.6 ± 0.9 nM; V103I: = 86.4 ± 0.9 nM; I251L = 87.5 ± 1.0 nM) and significantly (p = 0.0001) increased α-MSH stimulated maximum [Ca2+]i compared with WT (WT = 224.5 ± 13.6 nM; V103I = 288.2 ± 31.5 nM; I251L = 295.6 ± 20.0 nM). To summarize, we show three distinct patterns of hMC4R-associated calcium signaling; (1) WT and non-CA loss-of-function, (2) CA loss-of-function and (3) non-CA gain-of-function. Future studies are required to understand how hMC4R mobilization of [Ca2+]i might contribute to the regulation of energy balance.