bluuebunny/crossref_metadata_2025_split 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

Abstract

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

Abstract

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 &lt;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 &lt;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

Abstract
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 =&gt;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= &lt;=0.95 g, middle= &gt;0.95-&lt;=2.1 g, and high= &gt;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&lt;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

Abstract
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 (&gt;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

Abstract
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

Abstract

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

Abstract
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

Abstract

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

Abstract
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.