bluuebunny/crossref_metadata_2025 huggingface dataset:
ODP014 Safety and Efficacy of IBI362 (LY3305677) 9 mg and 10 mg in Chinese Adults with Overweight or Obesity
Authors: Ji Linong , Jiang Hongwei , Yang Jing , Yu Lei , Cai Chenghang , Liu Meng , Deng Huan , Feng Liqi , Qian Lei
Published: November 2022

Background

IBI362, a novel once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist, achieved 12-week weight loss up to 6.4% at doses up to 6 mg in Chinese participants with overweight or obesity. We further explored the safety and efficacy of IBI362 dosed up to 9 mg and 10 mg.

Methods

Two high-dose cohorts from a randomized, placebo-controlled, multiple ascending dose study (NCT04440345) enrolled adults with overweight (body mass index [BMI] ≥24 kg/m 2) accompanied by hyperphagia and/or at least one comorbidity or obesity (BMI≥28 kg/m 2) from five study centers in China. Eligible participants were randomized 2: 1 within each cohort to receive once-weekly subcutaneous IBI362 or placebo. The cohorts and dose-escalation regimens were: 9 mg cohort (3 mg weeks 1-4; 6 mg weeks 5-8; 9 mg weeks 9-12) and 10 mg cohort (2.5 mg weeks 1-4; 5 mg weeks 5-8; 7.5 mg weeks 9-12; 10 mg weeks 13-16). The primary endpoints were safety and tolerability of IBI362. The secondary endpoints included changes from baseline in body weight, waist circumference and BMI.

Results

A total of 24 participants (mean age 37.9 years, body weight 81. 0 kg, BMI 30.5 kg/m 2) were enrolled, with eight randomly assigned to IBI362 and four to placebo in each cohort. One participant receiving IBI362 and two receiving placebo in the 10 mg cohort withdrew consent and quitted the study. The other 21 participants (87.5%) completed the treatment and the study. No serious adverse event (AE) was reported and all AEs were mild or moderate in severity. The most commonly-reported AEs included diarrhea, nausea, vomiting and decreased appetite (each reported in six participants [37.5%] receiving IBI362). Mean percent changes from baseline to week 12 in body weight were−11.7% for participants receiving IBI362 in the 9 mg cohort and−1.8% for participants receiving placebo (estimated treatment difference [ETD]: −9.8%; 95% confidence interval (CI): −14.4,−5.3; P = 0. 0002). Mean percent changes from baseline to week 16 in body weight were−9.5% for participants receiving IBI362 in the 10 mg cohort and−3.3% for participants receiving placebo (ETD: −6.2%; 95% CI: −11.5,−0.9; P = 0. 0243). Four participants (50%) receiving IBI362 in each cohort achieved≥10% weight loss and two (25%) receiving IBI362 in each cohort achieved≥15% weight loss during the study, while no participant receiving placebo achieved≥5% weight loss. In addition, waist circumference and BMI were markedly decreased in participants receiving IBI362.

Conclusion

IBI362 dosed up to 9 mg and 10 mg was both well tolerated and showed a favorable safety profile. IBI362 dosed with the 3-6-9 mg escalation regimen demonstrated extraordinary efficacy on 12-week weight loss, suggesting that IBI362 would be a promising weight loss drug as the next generation GLP-1-based dual agonist.

Presentation: No date and time listed
OR10-1 Body Mass Index and Weight Reductions in Patients With Obesity Due to Heterozygous Variants in POMC, PCSK1, and LEPR After 1 Year of Setmelanotide
Authors: Farooqi Sadaf , Miller Jennifer , Ohayan Olga , Scimia Cecilia , Still Christopher , Yohn Marianne , Yuan Guojun , Argente Jesús , Buckley Brieana
Published: November 2022

Background

The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Heterozygous variants of the genes for proopiomelanocortin (POMC), leptin receptor (LEPR), and proprotein convertase subtilisin/kexin type 1 (PCSK1) upstream of MC4R can result in impaired signaling in the MC4R pathway. This impaired signaling can lead to hyperphagia and early-onset, severe obesity. Setmelanotide (SET), an MC4R agonist, reduced weight and hunger after 3 months in patients with obesity due to these heterozygous variants in an earlier Phase 2 study. The current analysis is the first to assess continued efficacy of an additional year of SET treatment in patients with obesity due to heterozygous affectation of POMC, PCSK1, and LEPR.

Methods

Patients aged ≥6 years with obesity due to heterozygous variants in POMC, PCSK1, and LEPR were eligible for this long-term extension (LTE) trial (NCT03651765) after completing an index trial in which they received SET and demonstrated clinical benefit and acceptable safety as determined by the investigator. Patients received a minimum of 4 months of SET treatment in the index trial and began the LTE immediately following the completion of the index trial. Study visits occurred every 3 months and evaluated changes in body weight measures and assessed safety and tolerability. The current analysis reports outcomes after 1 year total of SET treatment across the index and LTE trials, relative to index trial baseline.

Results

As of October 29, 2021, 35 patients with obesity heterozygous for POMC, PCSK1, and LEPR had enrolled in the index trial, with 16, 17, and 17 patients continuing into the LTE trial and receiving at least 6, 9, and 12 months of treatment with SET, respectively. At index trial baseline, mean (standard deviation [SD]) body mass index (BMI) for all index trial patients was 50.26 (9.41) kg/m2, body weight in patients ≥18 years old was 142.97 (28.70) kg, and BMI Z score in patients <18 years old was 4.04 (0.65). Mean (SD) percent change in BMI was −6.93% (9.13%; n=16), −8.14% (10.13%; n=17), and −7.83% (9.69%; n=17) after 6, 9, and 12 months of treatment, respectively. Of 15 patients ≥18 years old, the mean (SD) percent change in body weight was −10.24% (7.90%; n=15) after 12 months. For the 1 patient <18 years old, mean change in BMI Z score was 0.64 after 12 months. No new safety concerns emerged during the LTE and 1 patient discontinued due to an adverse event, likely unrelated to treatment.

Conclusions

Treatment with SET had continued efficacy in patients with obesity due to heterozygous variants in POMC, PCSK1, and LEPR after 1 year of treatment. These data support the continued investigation of SET in these patients, which is underway in the Phase 3 EMANATE trial (NCT05093634).

Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.
OR10-5 Fructose Consumption and NAFLD in US Adult Population of NHANES 17-18
Authors: Kermah Dulcie , Najjar Sonia , Puri Vishwajeet , Schrode Katrina , Shaheen Magda , Zarrinpar Ali , Friedman Theodore
Published: November 2022

Non-alcoholic fatty liver disease (NAFLD) is a serious condition whose prevalence differs by race/ethnicity. Studies have suggested that consumption of high-fructose corn syrup is likely a risk factor for NAFLD. We investigated the associations between fructose consumption and NAFLD, and its distribution by race/ethnicity in the adult US population using NHANES 2017-2018 data (n=3292). NAFLD was diagnosed by FibroScan® using controlled attenuation parameter (CAP) values of =>260 and no exclusion criteria. Fructose consumption was calculated from 24-hour dietary recall data in combination with USDA food nutritional content data files. Fructose consumption was categorized into tertiles (low= <=0.95 g, middle= >0.95-<=2.1 g, and high= >2.1 g). We analyzed data in SAS 9.4 using Chi squared tests and multinomial logistic regression, adjusting for demographics, behavioral, and laboratory data, and including sample weights and design. Of the 3292 participants, 31.3% were in the middle tertile of the fructose consumption and 35.5% were in the high tertile. There was no significant difference in the prevalence of NAFLD by fructose consumption group [low=44%; middle=48%, and high=51%] (p=0.094).

The highest percentage of participants in the high tertile of fructose consumption were in Mexican Americans (48%) and non-Hispanic Blacks (44%), with a much lower percentage of non-Hispanic Whites (33%) (p<0.0001). The highest prevalence of NAFLD was in Mexican Americans in the high tertile of fructose consumption (70%), which was significantly different than the prevalence in Mexican Americans in the low tertile (52%) (p=0.031). In the adjusted models, those in the high tertile of fructose consumption had higher odds of NAFLD relative to those in the low tertile (AOR = 1.6, 95%CI = 1.1 - 2.3, p=0.0224). Fructose consumption in the high tertile was associated with increased odds of NAFLD in non-Hispanic Whites (AOR = 2.0, 95%CI = 1.0 - 3.7, p=0.0387) and Mexican Americans (AOR = 1.8, 95%CI = 1.2 - 2.8, p=0.0050). We conclude that there is an association between fructose consumption and the odds of NAFLD. This association does not explain the racial/ethnic disparity in NAFLD. Interventions should aim to decrease consumption of fructose overall.

Presentation: Sunday, June 12, 2022 12:00 p.m. - 12:15 p.m.
OR23-2 Mild Maternal Undernutrition Results in Transcript Regulation in the Fat of Male Offspring that Correlates with Resistance to High Fat Diet Induced Weight Gain
Authors: Miles Tiffany
Published: November 2022

Maternal undernutrition (MU) during fetal development profoundly effects offspring metabolism, resulting in either blunting or premature shifting of the neonatal leptin surge, and can cause metabolic dysfunction in adulthood. We developed a mild MU model in FVB mice, where dams received 20% less caloric intake (underfed) compared to control, ad libitum fed (Fed) mice. As previously reported, underfed progeny exhibited a leptin surge that was 3 days earlier (PND8) than controls (PND11) and PND1 GH levels were 354% higher. However serum IGF-1 was 55% lower (p=0.027) at PND16 in underfed progeny, resulting in delayed puberty and growth deficiencies which persisted in the male offspring. At 3 months, fed and underfed offspring received either a 45% HFD or 10% fat (Control) diet for 16 weeks, resulting in a weight gain (>12 g) in progeny from fed dams. However, underfed females gained only 8.74 g on the HFD, [lower than fed females (p=0.03)]. More surprisingly, underfed males showed no weight gain in response to the HFD. The study was replicated, yielding the same results.

We hypothesize that resistance to HFD induced weight gain by underfed males may be due to altered transcriptome expression. We investigated this unusual response through RNA sequencing of the pituitary, fat and liver of both fed and underfed male progeny. Pituitary and liver transcriptome analysis are ongoing. This presentation focuses on changes in the fat transcriptome.

Fat from Fed HFD males had 592 upregulated and 153 downregulated transcripts when compared to controls. Strikingly, fat of underfed HFD males had only 3 upregulated and 3 downregulated transcripts when compared to underfed controls. To ascertain potential protective influences, transcripts in the fat of Fed HFD males were compared with those of underfed HFD males. Prelid3a, Peg3, and Thbs1 were differentially expressed in underfed HFD males compared to Fed HFD males. Prelid3a, (involved in mitochondrial lipid metabolism and transport) was downregulated 2.9 fold (0.035 adj. P) in underfed HFD fat. Peg3,(involved in fat accumulation when decreased) was increased in underfed HFD fat by 2.4 fold (0.0297 adj. P). Thbs1 was also increased by 2.7 fold (0.0476 adj. P) in underfed HFD fat. Thbs1 contributes to HFD weight gain when increased, but can also improve hepatic steatosis and promote a protective ER stress response. Pde3b, found to be protective against obesity, was reduced 1.4 fold (0.002 adj. P) in Fed HFD males, but unchanged in underfed HFD males.

These data indicate that mild undernutrition causes a premature leptin surge, marked by sex-specific differences in offspring growth and transcriptome regulation in the fat of male offspring that is beneficial to blunting HFD induced weight gain.

Presentation: Monday, June 13, 2022 11:30 a.m. - 11:45 a.m.
OR23-5 Exploring the Role of PARP7 in Adipogenesis
Authors: Lee Kraus W , Stokes MiKayla
Published: November 2022

Adipogenesis is a complex and tightly regulated process that plays a vital role in multiple aspects of human health. The molecular mechanisms regulating adipogenesis are incompletely understood, although key facets of the signaling and regulatory pathways have been defined. ADP-ribosylation – the process whereby ADP-ribose moieties are covalently transferred from NAD+ to substrate proteins – has been shown to control multiple components of the adipogenic regulatory machinery, including the transcription factor C/EBPb. In order to explore the role of mono(ADP-ribosyl)transferases (MARTs) during adipogenesis, we used an siRNA-mediated knockdown screen in mouse 3T3-L1 preadipocytes to determine which MARTs are required for the differentiation of the preadipocytes into mature adipocytes. This screen identified PARP7 the primary candidate. Using a variety of cell-based and biochemical assays, we have identified key aspects of PARP7's involvement throughout adipogenesis. We observed dynamic localization of PARP7 during adipogenesis, moving from the nucleus in early adipogenesis to the cytosol during mid to late adipogenesis. The requirement for PARP7, as determined by knockdown, was most evident in early stages of adipogenesis. Knockdown of PARP7 was rescued by a PPAR g agonist, suggesting that PARP7 acts before the onset of the later stages of adipogenesis leading to mature adipocytes. Together, these findings led us to hypothesize that PARP7 plays a critical role in the nucleus during early adipogenesis. Preliminary data have revealed that PARP7 binds to C/EBPb, a key "first wave" transcription factor that drives adipogenesis, during a time when C/EBPb is poly(ADP-ribosyl)ated by PARP1 in the nucleus. Ongoing investigations are exploring: (1) the mechanisms by which PARP7 binds to C/EBPb; (2) the impact of PARP7 binding on C/EBPb stability; and (3) the biological outcomes of PARP7-C/EBPb interactions. Collectively, these studies provide an avenue to better understand the role of PARP7 in the regulation of adipogenesis.

This work is supported by a grant from the NIH/NIDDK (R01 DK069710) and funds from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment to W.L.K., and a predoctoral fellowship from the American Heart Association to M.S.S.

Presentation: Monday, June 13, 2022 12:15 p.m. - 12:30 p.m.
PSUN124 Weight Loss from Combination Anti-Obesity Medications Including Glucagon-Like Peptide-1 Receptors Agonists can Approach that Achieved from Bariatric Surgery
Authors: Bomberg Eric M , Patel Priya , Bensignor Megan O , Fox Claudia K
Published: November 2022

Background

Obesity is a multifactorial chronic disease for which treatment remains challenging and combination anti-obesity medications including glucagon-like peptide-1 receptor agonists (GLP1-RAs) can be highly effective.

Clinical Case

We report the case of a 23-year-old male, previously followed in a pediatric weight management clinic, who presented to an adult weight management program with a body mass index (BMI) of 84.3 kg/m2 and impaired glucose tolerance. Factors contributing to his obesity status included a family history, strong hunger and food cravings, and binge eating tendencies. He lost 30% body weight after the addition of semaglutide (a GLP1-RA) 0.5 mg weekly to an anti-obesity medication regimen.

At his initial presentation to the adult weight management clinic, with a weight of 643 pounds and hemoglobin A1c 6.4%, he was started on phentermine 15 mg, topiramate 75 mg, and metformin 500 mg daily. Over the next year, he was followed virtually due to the COVID pandemic and, therefore, weight and BMI could not be ascertained. His dose of metformin was increased to 1000 mg, phentermine to 18.75 mg, and topiramate to 100 mg daily during this time. Additionally, extended release bupropion 150 mg daily was added given a history of depression, which was then increased to 300 mg daily. When he was able to return to the clinic in-person, his weight and BMI remained unchanged and, therefore, semaglutide 0.5 mg weekly was added, in addition to monthly virtual registered dietician (RD) visits and a low calorie diet. He reported a significant reduction in hunger after the addition of semaglutide. Eight months later, he had lost 193 pounds, his BMI had decreased to 66.5 kg/m2, and his hemoglobin A1c normalized. The 30% total body weight loss and improved glucose tolerance achieved in less than one year mirrors that typically achieved by metabolic/bariatric surgery.

Conclusion

This case highlights the potential benefit of combination anti-obesity medication regimens that include GLP1-RAs. Specifically, while some patients may experience suboptimal response to combination anti-obesity therapies, it may be that the addition of GLP1-RAs to such regimens, namely semaglutide, can provide a synergistic effect leading to substantial weight loss approaching that achieved from metabolic/bariatric surgery. This may result from targeting multiple eating behavior pathways simultaneously, including appetite, satiety, and binge eating tendencies. Further studies are needed to evaluate the efficacy of GLp1-RAs as part of combination anti-obesity medication regimens, especially among those who achieve suboptimal response to regimens not including GLP1-RAs.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN81 A novel case of congenital generalized lipodystrophy (CGL) with no genetic abnormalites in the AGPAT2, BSCL2, CAV1, and CAVIN1 genes.
Authors: Mericq Veronica , Idris Idris , Harris Basma , Syed Najeeb , Hussain Khalid
Published: November 2022

Congenital generalized lipodystrophy (CGL) is a genetic disorder charaterized by total body fat loss. The extent of fat loss is usually associated with the severity of the disease and patients typically develop metabolic complications such as hypertriglyceridemia, hepatic steatosis, insulin resistance, and diabetes mellitus. Mutations in the AGPAT2, BSCL2, CAV1, and CAVIN1 genes are known to cause CGL. We report a new case of CGL but where no genetic aetiology has yet been identified in the known genes that cause CGL. The patient is a female child born at 36 weeks gestation with a birth weight os 2.57 kg. Soon after birth she was diagnosed clinically with CGL with both the DEXA and MRI scans showing severely diminished adipose tissue and 0% body fat respectively. She had severe failure to thive and developed diabetes mellitus, hyperlipidaemia, hypertrophic cardiomyopathy, severe scalp seborrheic dermatitis and hepatic steotosis. At 2 years of age her weight was only 3.7kg and she died from an upper respiratory tract infection. Whole exome sequencing and trio analysis did not find any mutations or copy number variants (CNV) in the AGPAT2, BSCL2, CAV1, and CAVIN1 genes associated with CGL. De-novo variants were found in the genes PCNT, PDE4DIP and STAT3 which need further functional validation. This case suggests that other possibly novel genetic mechanisms may be responsible for the CGL observed in this patient.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN92 Type 1 Diabetes and Obesity: The Overlooked Epidemic
Authors: Burguera-Couce Ella , Pantalone Kevin
Published: November 2022

Introduction

The type 1 diabetes (T1D) cohort in the DCCT study (1983-1989) began with a 1.3% prevalence of obesity that climbed to 18.6% with intensive insulin therapy, and subsequently increased further to a prevalence of 31% in the EDIC observational study (2005).1, 2 The aim of this report was determine the prevalence of overweight and obesity in T1D patients seen at our institution.

Methods

The electronic health record system was used to create a cross-sectional summary of patients with T1D seen on or before the index date (8/12/2021). Patients were included if they were ≥18 years of age, with at least two outpatient encounters with primary care provider or endocrinologist within the past 18 months, along with an active diagnosis of T1D (ICD-9 or -10 code) on their problem list, or at least 2 encounter diagnosis for T1D in the past 18 months, or documentation of a positive glutamic acid decarboxylase (GAD)-65 antibody titer. Categorical and continuous variables were summarized using N (%) and median (IQR), respectively.

Results

A total of 2,165 patients were identified. The population was 51% female and 86% Caucasian, with median age of 44 years (33, 55). The median A1C (%) was 7.9% (6.9, 9.4), median income $63,381 ($49,611, $78,367), and insurance coverage was 50% commercial, 11% Medicaid, 23% Medicare, and 16% other. While the median BMI (kg/m2) was 26.7 (23.6, 30.5), the % with a BMI 25-29.9 or ≥30 were 37% and 28%, respectively.

Conclusion

There is a high prevalence of overweight and obesity in patients with T1D. While the prevalence of these comorbidities is less than what is observed in the general population, 31.1 and 42.4%, respectively (2017–2018)3, it signifies that the T1D population still has a heavy burden of these comorbidities that is contradictive to the stereotype T1D patients are lean. These results stand in stark comparison with the starting 1.3% prevalence of obesity in the DCCT study. Studies directed at the burden of overweight and obesity in T1D patients are necessary to optimize the treatment and prevention of these comorbidities.

Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14): 977–986.

Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005 Dec 22;353(25): 2643-53. doi: 10.1056/NEJMoa052187. PMID: 16371630; PMCID: PMC2637991.

Centers for Disease Control and Prevention. Obesity and Overweight. https://www.cdc.gov/nchs/fastats/obesity-overweight.htm. Last visited 1/12/2022.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN97 Regulation of melanocortin-3 and -4 receptors by isoforms of melanocortin-2 receptor accessory protein 1 and 2
Authors: Ji Ren-Lei , Tao Ya-Xiong
Published: November 2022

The neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), play essential non-redundant roles in the regulation of energy homeostasis. Interaction of neural MCRs and melanocortin-2 receptor accessory proteins (MRAPs, MRAP1 and MRAP2) is suggested to play pivotal roles in MC3R and MC4R signaling. In the present study, we identified two new MRAP2 splice variants, MRAP2b (465 bp open reading frame) and MRAP2c (381 bp open reading frame). Human (h) MRAP2s are different in C-termini. We investigated effects of hMRAP1a, hMRAP1b, hMRAP2a, hMRAP2b, and hMRAP2c on MC3R and MC4R pharmacology. At the hMC3R, hMRAP1a increased affinity to ACTH, and hMRAP1b decreased maximal binding (Bmax). All MRAPs decreased the maximal responses in response to ACTH. For hMC4R, hMRAP1a and hMRAP1b significantly decreased Bmax, and MRAP2a increased Bmax. Human MRAP1b significantly increased affinity to ACTH while MRAP2a decreased affinity to ACTH. Human MRAP1a increased ACTH potency. MRAPs also affected hMC4R basal activities, with hMRAP1s increasing and hMRAP2s decreasing the basal activities. In summary, the newly identified splicing variants, hMRAP2b and hMRAP2c, could regulate MC3R and MC4R pharmacology. The two MRAP1s and three MRAP2s had differential effects on MC3R and MC4R binding and signaling. These findings led to a better understanding of the regulation of neural MCRs by MRAP1s and MRAP2s.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF36 | PSUN93 A Role for Somatostatin in Regulating Weight Regain after Bariatric Surgery in Mice
Authors: Arad Yhara , Ben-Zvi Prof Danny , Kleiman Doron , Schyr Rachel Ben-Haroush
Published: November 2022

Somatostatin is an inhibitory neuropeptide expressed in several neural and endocrine systems. For example, Somatostatin represses the secretion of growth hormone from the pituitary gland, and the secretion of gastrointestinal and pancreatic hormones. It is therefore surprising that Somatostatin knockout (sst-ko) mice have a very mild metabolic phenotype under normal conditions.

Here, we studied the role of Somatostatin in weight gain and weight loss using sst-ko mice.

We found that sst-ko mice gained weight, lost weight, and regained weight at an equal rate to heterozygous siblings following dietary interventions. However, overweight sst-ko mice did not regain weight after sleeve gastrectomy bariatric surgery compared to heterozygous siblings that underwent the same surgery. This phenotype persisted for three months after surgery, whilst a high-fat high-sucrose diet was provided. Mechanistically, the surgery led to hypersecretion of glucagon-like peptide 1 (Glp1), which was not observed in sham-operated sst-ko mice. Moreover, Glp1 hypersecretion was greater than that of heterozygotes sleeve gastrectomy operated mice. Sleeve gastrectomy sst-ko mice displayed lower levels of fasting insulin, and very rapid response to glucose loading. In conclusion, a metabolic and endocrine phenotype of sst-ko mice was exposed following bariatric surgery. These mice remained lean and increased Glp1 secretion, suggesting that somatostatin has an important role in regulating gastrointestinal hormone secretion, especially following bariatric surgery. Further study is required to determine whether pharmacological inhibition of somatostatin signaling can enhance the outcomes of bariatric surgery in mice and in patients.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:48 p.m. - 12:53 p.m.
PSAT033 Increased Risks of Atherosclerotic Heart Disease, Malignancy and Sleep Apnea with Primary Aldosteronism: A Case Report
Authors: Shakir Mohamed , Bonsu Osei , Vasanthakumar Vijaykiran , Hoang Thanh
Published: November 2022

Introduction

Primary aldosteronism (PA) demonstrates an increased risk of atherosclerotic heart disease. A less commonly known fact is that PA is often associated with increased risks of malignancy, especially renal cell carcinoma (RCC) and sleep apnea. We are reporting a 51-year-old male with a long history of untreated PA caused by an adenoma (APA) who developed coronary artery disease (CAD), RCC, and sleep apnea during the course of his illness.

Case presentation

A 51-year-old male was evaluated in the endocrine clinic for secondary hypertension. Patient developed hypertension and hypokalemia at the age of 39 years and laboratory tests showed plasma renin activity PRA 0.06 ng/mL/hr, aldosterone 6 ng/dL, plasma metanephrines 79 pg/mL (ref 0–145), normetanephrine 22 pg/mL (ref 0-62), a serum cortisol value of 0.8 mcg/dL after 1 mg dexamethasone suppression. Despite using several anti-hypertensive medications, including quinapril, amlodipine, and potassium chloride, both his hypertension and hypokalemia remained poorly controlled. He also was diagnosed with sleep apnea at the age of 44 years, treated with CPAP. Abdominal CT showed normal adrenals and angiomyolipoma involving the right interior pole of the kidney. At the age of 47 years, a diagnosis of Liddle syndrome was considered, and the patient was placed on amiloride. At the age of 48 years, the patient developed chest pain and further diagnostic tests confirmed coronary artery disease, and a stent was placed in the left anterior descending artery. Due to the poor control of hypertension, carvedilol and eplerenone were also added to the regimen. Another abdominal CT done at the age of 50 years showed a left adrenal adenoma 1.2 cm, left kidney lower pole cyst 2.9 cm, and atherosclerotic calcification of aorta. Family history was negative for endocrine diseases. Physical examination: HR 62/min, BP 160/90 mmHg, normal examination of the heart, lungs, and abdomen. No clinical features of Cushing syndrome was observed. Repeat laboratory evaluations showed plasma renin activity < 0.167 ng/ml/hr, plasma aldosterone 111.4 ng/dL, concerning for PA. A follow-up CT of the abdomen confirmed left adrenal adenoma and a 1.8 cm left renal lesion suggestive of RCC. The patient underwent an adrenal venous sampling, which localized the left adrenal adenoma as the cause of PA. The patient underwent left adrenalectomy and left partial nephrectomy and pathology confirmed left adrenal adenoma and RCC. One week after surgery plasma aldosterone was 1.9 ng/dL and his hypertension was controlled with fewer medications and he did not require potassium supplements.

Conclusion

Our case illustrates that delayed diagnosis of PA (poorly treated PA) may be associated with an increased risk of CAD, malignancy and sleep apnea. Early diagnosis and surgical intervention are recommended for PA, especially caused by an adenoma.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT050 An Unusual Case of Adrenal Insufficiency After Using Budesonide for Treatment of Microscopic Colitis
Authors: Barua Nabonita , Riaz Aiman , Osakwe Ibitoro
Published: November 2022

Introduction

Long term use of systemic glucocorticoids are a common cause of secondary adrenal insufficiency from 1.4-27.5% of cases. On the other hand, Budesonide, a non-halogenated steroid that is widely used for its low systemic absorption is rarely reported to cause secondary adrenal insufficiency.

Case

A 39-year-old female with significant medical history of anxiety, bipolar disorder, hypothyroidism, type 2 DM and lymphocytic colitis was admitted to the hospital with acute mental status change and lethargy. She reported a 3-week history of diffuse abdominal pain and diarrhea. She endorsed weight loss but denied any fever, vomiting, recent infection or any significant history of hepatitis. In ER, her vitals were notable for a BP of 105/68 mm Hg, Pulse 76 beats/min, temperature 97.5F, pulse oximetry 100% with 2 L nasal canula. On examination she appeared frail, alert but mildly confused. Admission labs showed sodium 143, potassium 4.3, bicarbonate 15, creatinine 1.2, GFR 57, blood glucose 67, Hemoglobin 6.3 and WBC 4.3, UA negative. During the ER course she became hypotensive with SBP in 80s. She was fluid resuscitated with a total of 4 L of normal saline and was eventually started on vasopressor support due to profound hypotension unresponsive to fluids. One unit of PRBC was transfused and she was transferred to MICU for further monitoring. Baseline cortisol level was drawn, and she was started on dexamethasone for presumed adrenal insufficiency, while awaiting the result of her labs. Her cortisol was subsequently confirmed to be 5.5mcg/dl. She was maintained on stress dose steroids and experienced dramatic improvements in her clinical status and BP. A review of her medical history revealed that she was diagnosed with microscopic colitis 5 months prior to the current admission and had been placed on budesonide 9mg/day, tapered slowly to the current dose of 3mg/day. She reported compliance with her budesonide up to the date of the admission.

Discussion

Iatrogenic adrenal insufficiency from Budesonide is rarely reported in the literature. Budesonide is a common choice for IBD, especially Crohn's disease and microscopic colitis. It has a high first pass metabolism (80-90%), thus limiting its systemic bioavailability to as low as 9-21%. Despite that, a few cases of chronic oral Budesonide use resulting in AI have been reported. As it is metabolized in the liver via CYP450 isoenzymes, concurrent use of CYP450 inhibitors or hepatic cirrhosis can also potentially interfere with its metabolism and increase its systemic bioavailability. According to literature there have been a few descriptions of patients developing AI without prior liver disease, similar to our patient. Caution should therefore be exercised in prescribing budesonide and physicians should have a high index of suspicion when patients on budesonide present with symptoms suggestive of adrenal insufficiency.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT054 Isolated ACTH Deficiency in a Patient on Epoprostenol
Authors: Riordan Marianne , Bauer Jessica , Panvelker Samir
Published: November 2022

Introduction

Epoprostenol is a prostacyclin analog used to treat severe pulmonary arterial hypertension (PAH). Endocrine abnormalities in patients on epoprostenol have been reported, most commonly autoimmune thyroid dysfunction.

Case Description

A 36-year-old woman with weight loss and dyspnea on exertion was diagnosed with pulmonary artery hypertension following right heart catheterization. Her symptoms initially improved after starting IV epoprostenol. Over the following two years, she experienced weight loss and anorexia. Due to concerns that her symptoms were caused by epoprostenol, her dose was reduced. After new-onset tremors and palpitations, thyroid studies were checked demonstrating TSH <0.01 (previously normal) and total T4 18.69 with anti-thyroid peroxidase >900.0 (≤8.9 IU/mL). Repeated thyroid studies 4 weeks later showed transition to the hypothyroid phase of Hashimoto's thyroiditis with TSH 6.65 and total T4 3.21. She was prescribed 50 mcg levothyroxine daily. Despite normalization in thyroid function, she continued to lose weight over the next year with ongoing nausea and anorexia unchanged by decreases in epoprostenol dosing. Her weight dropped to 76 lbs and she was admitted for further work-up. Repeat thyroid studies were normal but cortisol was <1.0 ug/dL and ACTH was <1.1 (7.2 - 63.3 pg/mL). Remainder of pituitary hormonal evaluation showed normal FSH & LH and low IGF-(63 ng/mL, Z-score -2.9). She denied recent steroid use. MRI head was normal as was CT of the adrenal glands. Her symptoms rapidly improved after initiation of 15 mg hydrocortisone. Repeat RHC showed marked improvement in hemodynamics.

Discussion

The association between autoimmune thyroid disease and PAH has been relatively well described and hypothyroidism seems to be more prevalent than hyperthyroidism. We found just 3 other cases of adrenal insufficiency in patients on epoprostenol. The mechanism for endocrinopathies in this population is unclear. In addition to their effects on endothelial cells, PGI2 analogs have been noted to have a role in T helper cell differentiation. Th17 cells are implicated in autoimmune diseases like multiple sclerosis, so prolonged use of PGI2 analogs may cause systemic inflammation and trigger autoimmunity. It is important for clinicians to be aware that diagnosing adrenal insufficiency in this population can be difficult as the side effects of epoprostenol (lightheadedness, nausea, vomiting, weight loss, and anorexia) are similar to the symptoms of adrenal insufficiency. With this in mind, it is important that adrenal insufficiency remains high on the differential diagnosis of patients presenting with such symptoms when on epoprostenol treatment to prevent delays in diagnosis.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT073 The Human Gonads Do Not Contribute to the Circulating Pool of 11-Oxygenated Androgens
Authors: Rabbah Amira , Davio Angela , Liu Haiping , Marko Xhorlina , Sherk William , Rege Juilee , Rainey William , Turcu Adina
Published: November 2022

Background

Androstenedione (A4) and testosterone (T) are produced by both the adrenal glands and the gonads. The adrenal enzyme steroid 11β-hydroxylase (CYP11B1) executes the last step in cortisol synthesis; CYP11B1 also uses A4 and T as substrates, generating 11-hydroxyadrostenedione (11OHA4) and 11-hydroxytestosterone (11OHT), respectively. 11OHA4 and 11OHT are further metabolized, primarily in periphery, to 11-ketoandrostenedione and 11-ketotestosterone. It has been suggested that CYP11B1 is expressed in the gonads, yet the circulating levels of all 11-oxygenated C19 steroids (11-oxyandrogens) are similar in males and females of reproductive ages, despite enormous differences in T.

Objective

To assess the gonadal contribution to the circulating pool of 11-oxyandrogens.

Methods

We used liquid chromatography-tandem mass spectrometry to measure 13 steroids, including traditional and 11-oxy-androgens in: (I) paired peripheral and gonadal vein serum samples from 11 patients (7 women), median age 37 years (range 31-51); and (II) 17 women, median age 57 years (range 41-81) before and after bilateral salpingo-oophorectomy (BSO). We also performed CYP11B1, 17α-hydroxylase/17,20-lyase, and cytochrome b5 immunohistochemistry in formalin-fixed paraffin-embedded ovaries and testes (10 each).

Results

A4, T, estradiol, estrone, progesterone, 17α- and 16α-hydroxyprogesterone were all higher in gonadal veins than in periphery (p<0.001 for all), while all 4 11-oxyandrogens were similar between matched peripheral and gonadal vein samples. Similarly, in women who underwent BSO, A4 (median [interquartile range]: 33 [24.5-49] ng/dL vs. 60 [47.5-71] ng/dL, p=0.0008) and T (15 [12.5-20] vs. 24 [15.5-33.5], p=0.0005) were lower after vs. before surgery, while the four 11-oxyandrogens were not significantly different. Immunohistochemistry staining for CYP11B1 was negative in both ovarian and testicular tissue.

Conclusion

Our results indicate that despite producing substantial amounts of both A4 and T, the human gonads are not important sources of 11-oxyandrogens.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT082 A Survey of Patients Living with CAH Assessing Their Perceptions on Glucocorticoid Regimen and Glucocorticoid-Associated Side Effects
Authors: Barnes Chris , Dias Rosh , Feather Melodie , Sherpa-Pine Nina
Published: November 2022

Background

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder characterized by insufficient cortisol production resulting in excess adrenal androgen production. The standard of care to replace the insufficient cortisol production is the lifelong use of glucocorticoids (GCs), usually at supraphysiologic levels to control hyperandrogenemia. Chronic use of supraphysiologic GCs is associated with long-term comorbidities. The degree of patient awareness of GC associated comorbidities is unknown and of critical importance to focus patient education.

Methods

An online survey was conducted in the US and promoted through a nationally known patient advocacy organization and through social media. Survey questions assessed the perceptions of patients living with CAH regarding their GC regimens, most common side effects associated with GCs, patients understanding of the risk and benefit of GC use and patients’ attitude about adjusting their GC regimen.

Results

A total of 113 patients living with CAH completed the online survey. Over 97.5% reported taking GCs at the time of the survey, with 75% being satisfied and 85% rating their regimen effective or very effective. Commonly reported side-effects associated with GC use included increased weight gain and appetite, fatigue, "moon face," thin skin that bruises easily, and mood changes or depression. Less common side effects included osteoporosis, muscle weakness, high blood pressure and increased infections. Approximately half reported discussing the long-term risks of GC treatment with their healthcare provider, with the remaining half reported not having this discussion or were unsure. Approximately 43% of respondents reported being in situations where they were not given enough information about the risk of supraphysiologic GC use to make an informed decision on treatment. A majority of respondents (67%) reported a willingness to change their current regimen if there was a safe and effective way to reduce their current GC dose closer to physiologic levels.

Conclusions

While a majority of patients living with CAH are satisfied with their current GC regimen, there is a general lack of patient awareness of the long-term side effects associated with supraphysiologic GCs. Patients may benefit from more patient education to make informed decisions with their healthcare providers.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSUN09 An Unusual Presentation of Pheochromocytoma with Persistent Hypoglycemia, A Case Report
Authors: Alnahas Zeinab , Horani Mohamad H
Published: November 2022

Introduction

Pheochromocytoma is a rare chromaffin cells tumor of the adrenal medulla characterized by excessive catecholamines production. It can be manifested by various clinical presentations, ranging from being asymptomatic to having sustained or paroxysmal hypertension, or the classical triad of paroxysmal headache, palpitations, and sweating. It may be sporadic or inherited as part of other familial syndromes, including hereditary paraganglioma syndromes, and multiple endocrine neoplasia 2. This case report shows an unusual presentation of pheochromocytoma in a patient with neurofibromatosis type 1.

Case Presentation

A 27-year-old normotensive woman with a past medical history significant for neurofibromatosis type 1 diagnosed at age 16 was involved in a single-vehicle rollover collision. She experienced a sudden episode of dizziness and presyncope associated with nausea while she was driving. She was found with altered mental status and a serum glucose level of 31 mg/dl (reference value 70-99mg/dL), indicating hypoglycemia which remained persistent after administering a glucose drip. The patient denied any recent febrile illness, previous episodes of dizziness, vertigo, syncope, or known hypoglycemia. Her CT abdomen with intravenous contrast showed a 4.8 cm lobulated heterogeneous mass involving the right adrenal glands concerning for pheochromocytoma. Her laboratory workup revealed HbA1C of 4.9%, serum-free insulin of 6 mcU/mL (reference range <17mcU/mL), C-peptide of 1 ng/mL (reference value 0.5-2 ng/mL), insulin autoantibodies of <0.4 nU/mL (reference value <95 nU/mL), random cortisol of 38.4 mcg/dL (reference value 5-25 mcg/dL), ACTH of <5 pmol/L (reference value 10-60 pmol/L), and a normal cosyntropin stimulation test. Further investigations showed high serum levels of normetanephrine of 8.02 nmol/L (reference range 0-0.89 nmol/L), metanephrines of 0.69 nmol/L (reference range 0-0.49 nmol/L), and chromogranin A of 300 ng/mL (reference range 0-95 ng/mL) which confirmed the diagnosis of pheochromocytoma.

Conclusion

Hypoglycemia is an unusual presentation of pheochromocytoma, which is usually associated with impaired glucose tolerance and hyperglycemia. Our case shows that pheochromocytoma associated with neurofibromatosis type 1 can present with persistent hypoglycemia.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN13 Transcriptional and epigenetic landscapes of adrenocortical tumors
Authors: Lerario Antonio , Mohan Dipika , Hammer Gary
Published: November 2022

Historically, our knowledge of adrenocortical tumorigenesis has been limited to clinical observations of genetic syndromes featuring benign and malignant adrenal disease. In the last two decades, the enormous boom in high-throughput approaches has transformed our understanding of adrenal pathophysiology. While benign adrenocortical tumors may be cured by surgery, adrenocortical carcinoma (ACC) continues to be associated with dismal clinical outcomes. Understanding the molecular pathogenesis of adrenocortical tumors and the programs that facilitate benign versus malignant trajectories is crucial for developing curative therapeutic approaches. Although numerous transcriptome, epigenome, and single cell datasets profiling physiologic adrenal cortex and adrenal tumors are publicly available, there is no analysis integrating the spectrum of physiologic to malignant disease. Through analysis of these datasets, including single center datasets and those published by ENCODE, ENSAT, and TCGA, we demonstrate that biologic processes involved in tissue differentiation are recurrently disrupted across tumorigenesis. While the dominant programs supporting benign tumors include intracellular signaling programs that stabilize steroidogenic identity, ACC is characterized by activation of proliferation, immune, and imprinting programs that restrict access to adrenocortical differentiation states. Taken together, these studies identify that loss of differentiation fidelity within the confines of putative cell of origin is the core determinant of benign versus malignant tumorigenesis in the adrenal cortex.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN22 Outcomes of Adrenalectomy for Adrenocortical Carcinoma at a Single Institution
Authors: Gurney Antonia , Kotwal Anupam , Patel Anery , Shank Jessica , Yuil-Valdes Ana , Pachigolla Srujana , Goldner Whitney , Fingeret Abbey
Published: November 2022

Background

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor overall prognosis. Complete surgical resection is the mainstay of therapy.

Methods

We performed a retrospective review of adult patients at a single institution undergoing index adrenalectomy for initial diagnosis of adrenocortical carcinoma from 2012 through 2021. Clinical and demographic variables were assessed.

Results

Fifteen patients were identified who underwent adrenalectomy for ACC during the study period with a mean age of 49.2 years (SD 17.8) with 6 (40%) male, 13 (87%) white, mean body mass index 29.5 kg/m2 (SD 7.5). On preoperative cross-sectional imaging nine (60%) were left sided tumors and the largest dimension was a mean of 11.1cm (SD 4.5), with pre-contrast density of 27.8 Hounsfield units (SD 9.6), five patients (36%) had evidence of local invasion and four patients (29%) had evidence of metastatic disease on imaging. Ten patients (67%) had biochemical evidence of hormone excess and eight had secretion of more than one cortical hormone, with overall ten (67%) glucocorticoid secretion, six (40%) androgen secretion, two (13%) mineralocorticoid secretion. Four patients (27%) had minimally invasive laparoscopic or robotic adrenalectomy. Three patients (20%) had a surgical complication including ileus, pancreatic leak and pleural effusion requiring intervention. Complications were not associated with hormone excess (p = 0.50). On final pathology, one patient (7%) was staged T0 who later presented with metastatic disease 18 months postoperatively, six (43%) were T2, 4 (29%) T3, and 3 (21%) T4. No patients had locoregional lymph node metastases. Ten patients (67%) had R0 resection with negative margins, 4 (27%) had microscopic positive margins, and 1 had grossly positive margins. Seven patients had Ki-67 assessed with a mean of 29% (SD 20.6). Ten patients (71%) received adjuvant mitotane, eight (53%) systemic chemotherapy, and 4 (27%) adjuvant radiation. Within the study period, nine patients (60%) had a recurrence and six patients died (40%) with a median survival of 24 months. Positive margin status was associated with mortality with mortality of one (10%) of patients with negative margins and 5 (100%) of those with positive margins (p = 0.002). Of the four patients who presented with initial evidence of metastatic disease on imaging, two died during the study period and the other two remain alive on therapy. Adjuvant treatment with mitotane, systemic chemotherapy, or radiation were not associated with survival.

Conclusions

In this cohort, complete surgical resection with negative margins was associated with improved survival compared with patients with microscopic or grossly positive margins. The overall median survival was 24 months. Differences in outcome by adjuvant therapy are limited by the sample size.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.