bluuebunny/crossref_metadata_2025 huggingface dataset:
2015-LB: Actionable Pharmacogenomic Variants in the Kuwaiti Population
Authors: JOHN SUMI E. , CHANNANATH ARSHAD M. , MALIK ZUBBAIR , NIZAM RASHEEBA , AL-MULLA FAHD , THANGAVEL ALPHONSE T.
Published: June 2024

Pharmacogenomics plays a pivotal role in advancing precision medicine by addressing critical public health concerns like Adverse Drug Reactions (ADRs) and dosage regulations. The emergence of Next Generation Sequencing (NGS) techniques, coupled with the rapid expansion of pharmacogenomic data, offers a unique opportunity to accelerate progress in this field. This study aims to investigate the frequency and classification of actionable pharmacogenomic findings in the Kuwaiti population. Exome sequence data from 474 individuals of Kuwaiti descent were analyzed to evaluate the quantity and clinical relevance of incidental pharmacogenomic variants. Using a panel of 293 pharmacogenomic genes, the dataset was filtered, and resulting variants were categorized based on variant type, population frequency, functional impact, pathogenicity, and annotations from PharmGKB and ClinVar databases. In Clinvar, 33 missense variants related to drug response were identified. Additionally, 591 rare pharmacogenomic variants were detected in this population, predicted to be pathogenic using pathogenicity prediction tools. We observed 15 known pharmacogenomic variants classified as actionable (PharmGKB 1A or 1B level of evidence), impacting approximately 16 drugs. In conclusion, this study provides a comprehensive examination of known pharmacogenomic variants in the Kuwaiti population, highlighting their potential impact on drug response. We observed a higher frequency of genetic variants affecting drug response to medications like Ivacaftor, Tramadol, Efavirenz, and Capecitabine compared to global populations. Notably, a prominent actionable variant identified in this population is a VKORC1 variant associated with warfarin dosage. These findings underscore the significance of pharmacogenomic considerations in optimizing drug therapy for Kuwaiti individuals.

Disclosure

S.E. John: None. A.M. Channanath: None. Z. Malik: None. R. Nizam: None. F. Al-Mulla: None. A.T. Thangavel: None.
2016-LB: Uptake Kinetics and Presentation of Donor Alloantigen by Lymph Node Stromal Cells for Attenuating the Alloimmune Response in Pancreatic Islet Transplantation
Authors: LI CHRIS , MULLIGAN CALLIE , TELES LEONOR N. , GONZALEZ GRISELL , UMLAND OLIVER , TOMEI ALICE A.
Published: June 2024

Objective & Background: Pancreatic islet transplantation requires lifelong immunosuppression, reducing its applicability. We aim to eliminate the need for immunosuppression by co-transplanting fibroblastic reticular cells (FRCs), a lymph node stromal cell subtype. FRCs are unconventional antigen-presenting cells that contribute to restraining autoreactive T cells and could be used in transplantation to prevent alloreactive T cell activation. We hypothesize that autologous FRCs co-transplanted with allogeneic donor islets can uptake alloantigen and reprogram the recipient’s alloimmune response toward inactivation/anergy.

Methods: In all experiments, recipient-matched C57BL/6 FRCs were pre-conditioned with or without 10ng/mL interferon-γ (IFNγ) for 72h. FRCs were incubated with CellTrace-labeled NIT1 (fully mismatched to B6) cell lysate or 50µM OVA257-264 (SIINFEKL) peptide overnight. No, low (7.5:1 NIT1:FRC cells), or high (75:1) doses of NIT1 cell lysate were administered. For kinetics, cells were cultured in regular media after overnight treatment. Flow cytometry was used to detect labeled lysate uptake and anti-SIINFEKL-H2Kb for antigen presentation. Data was analyzed by two-way ANOVA. Three biologically distinct cell lines were tested.

Results: With NIT1 lysate, FRC viability was not affected. Uptake of fluorescent lysate was dose-dependent, and 96.3±2.6% of FRCs took up NIT1 lysate at high dose. Confocal microscopy demonstrated donor antigen localization within lysosomes. Donor antigen was cleared from FRCs by 72h. IFNγ potentiates SIINFEKL presentation and 99.9±0.1% of IFNγ-treated FRCs presented SIINFEKL.

Conclusion: In vitro, FRCs can acquire exogenous antigen and present in MHC I. These results predict that FRCs can uptake allogeneic donor cell antigen and can present to alloreactive recipient T cells in in vitro co-culture studies and in vivo co-transplantation.

Disclosure

C. Li: None. C. Mulligan: None. G. Gonzalez: None. O. Umland: None. A.A. Tomei: Other Relationship; Isla Technologies, Sernova, Corp.

Funding

National Institutes of Health (F30 DK136276-01); National Institutes of Health (R01 DK109929-01); Juvenile Diabetes Research Foundation (3-SRA-2024-1477-S-B).
2021-LB: FABULINUS—A Randomized, Controlled Trial with FrexalimAB, to Assess Endogenous Insulin Secretion in New-Onset Stage 3 Type 1 Diabetes Adults and Adolescents
Authors: HALLER MICHAEL J. , ROTTHAEUSER BAERBEL , CHERKAS ANDRIY , COUDERT MATHIEU , LABARD PASCALE , BACCARA-DINET MARIE , BOKA GABOR , RESCHKE FELIX
Published: June 2024

Introduction: Type 1 diabetes (T1D) is caused by autoimmune destruction of pancreatic β-cells. The CD40/CD40L immune checkpoint leads to activation of both innate and adaptive immune cells. Frexalimab is the first second-generation antibody against CD40L to be studied in T1D.

Objective: To demonstrate the efficacy and safety of different doses of frexalimab on endogenous insulin secretion in participants with newly diagnosed T1D.

Methods: FABULINUS (NCT06111586) is a 52-week randomized (2:1), double-blind, placebo-controlled phase 2b study with a 52-week blinded extension conducted in the US and Europe. It consists of 2 parts: Part A evaluates the safety of the highest dose of frexalimab in adults (18 - 35 years). In Part B, which is based on 3-month safety data from Part A, adolescents, and young adults (12 - 21 years) are treated with 3 sequentially escalated doses of frexalimab or placebo. Study entry criteria include diagnosis of Stage 3 T1D according to American Diabetes Association standards, initiation of insulin therapy < 90 days prior to screening and random C-peptide levels ≥0.2 nmol/L. Change from baseline to Week 52 in the mean 2h stimulated AUC C-peptide concentration is used as a primary efficacy endpoint. Secondary endpoints include time in range (TIR, 70-180 mg/dL blood glucose), insulin dose, glycated hemoglobin A1c (HbA1c), remission, and safety.

Results: The study design of FABULINUS ensures the stepwise assessment of anti-CD40L antibodies in adults and then adolescents with type 1 diabetes.

Conclusion: FABULINUS is an innovative combined proof-of-concept and dose-finding study tailored to specific clinical development requirements for ß-cell preservation in T1D.

Disclosure

M.J. Haller: Consultant; Sanofi. Advisory Panel; SAB Biotherapeutics, Inc. Consultant; MannKind Corporation. B. Rotthaeuser: None. A. Cherkas: Employee; Sanofi-Aventis Deutschland GmbH. Stock/Shareholder; Sanofi. M. Coudert: None. P. Labard: None. M. Baccara-Dinet: Employee; Sanofi. G. Boka: None. F. Reschke: None.

Funding

Sanofi
2022-LB: Diabetes Primes Neutrophils for Neutrophil Extracellular Trap by Metabolic Reprogramming
Authors: JEON JAE-HAN , KIM MI-KYUNG , LEE IN-KYU
Published: June 2024

Neutrophils are primed for neutrophil extracellular trap (NET) formation during diabetes and excessive NET formation from primed neutrophils compromises wound healing in patients with diabetes. Here, we demonstrate that trained immunity mediates diabetes-induced NET priming in neutrophils. Under diabetic conditions, neutrophils exhibit robust metabolic reprogramming comprising enhanced glycolysis via the pentose phosphate pathway and fatty acid oxidation, which result in the accumulation of acetyl-coenzyme A (CoA). ATP-citrate lyase (ACLY)-mediated accumulation of acetyl-CoA and histone acetyltransferases (HATs) further induce the acetylation of lysine residues on histone 3 (AcH3K9, AcH3K14, and AcH3K27) and histone 4 (AcH4K8). The pharmacological inhibition of ACLY and HATs completely inhibited high glucose-induced NET priming. The trained immunity of neutrophils was further confirmed in neutrophils isolated from patients with diabetes. Our findings suggest that trained immunity mediates functional changes in neutrophils in diabetic environments, and targeting neutrophil-trained immunity may be a potential therapeutic target for controlling inflammatory complications of diabetes.

Disclosure

J. Jeon: None. M. Kim: None. I. Lee: None.
2024-LB: Reversal of Diabetes by Human Stem Cell–Derived Islets Implanted with an Immunomodulatory Microgel in a Retrievable Site
Authors: RECH TONDIN ARTHUR , YOLCU ESMA S. , HERRING SARAH K. , HESTER DENNIS M. , GADEA YELENA , VEGA GREYCY , SZUST JOEL , REVEL ARIEL , SHIRWAN HAVAL , GARCIA ANDRÉS , JAPOUR ANTHONY , REVEL MICHEL , MOLAKANDOV KFIR , RICORDI CAMILLO , LANZONI GIACOMO
Published: June 2024

Introduction & Objective: Islet transplantation for T1D is limited by donor availability and need for immunosuppression. Stem cell-derived islets could represent a solution as an unlimited source, but chronic immunosuppression remains a critical barrier. Immunomodulatory SA-FasL engineered microgel (iTOL-100, iTolerance Inc) represents a viable option to eliminate chronic immunosuppression. This study aimed to investigate the effect of human stem cell-derived islets (IsletRx, Kadimastem Ltd) co-transplanted with SA-FasL microgel in streptozotocin-diabetic immunodeficient NSG mice, to assess potential clinical translation.

Methods: IsletRx cell clusters were shipped via intercontinental flight. IsletRx was implanted in the epidydimal fat pad at doses from 3 to 9 kIEQ per mouse, alone or with iTOL-100. Over three months of follow-up, animal body weight and glycemia were monitored to assess transplantation effects. Human C-peptide levels were periodically measured and Intraperitoneal Glucose Tolerance Tests (IPGTT) performed.

Results: The study demonstrated that IsletRx engrafted, resulting in substantial human C-peptide release and normalization of blood glucose levels. At the highest IsletRx dose (9 kIEQ, approximately 5 million cells), glycemic control improved over 3 months, reaching euglycemia. Importantly, iTOL-100 did not adversely affect stem cell-derived IsletRx function. Histological analyses of the grafts revealed well-preserved stem cell-derived islets.

Conclusion: The results indicate the potential of IsletRx as a stem cell-derived islet candidate for the treatment of subjects with T1D. Notably, IsletRx can be shipped intercontinentally, and thus could be delivered worldwide as a functionally competent clinical product. Additionally, our findings indicate that the combination of stem cell-derived IsletRx with the immunomodulatory iTOL-100 microgel does not compromise beta cell function and reversal of diabetes.

Disclosure

A. Rech Tondin: None. E.S. Yolcu: None. D.M. Hester: None. Y. Gadea: None. G. Vega: None. J. Szust: None. A. revel: None. H. Shirwan: None. A. Garcia: Board Member; iTolerance. Stock/Shareholder; iTolerance, CorAmi. A. Japour: None. M. Revel: Employee; Kadimastem Ltd, Nes Ziona, Israel. C. Ricordi: Advisory Panel; Vertex Pharmaceuticals Incorporated. Consultant; iTolerance, Inc. G. Lanzoni: Stock/Shareholder; Novo Nordisk, Eli Lilly and Company, Pfizer Inc., Medtronic, UnitedHealth Group, Provention Bio, Inc.

Funding

iTolerance, Inc. (ITOL-SOW-00018263)
2025-LB: Anti-apoptotic BCL2 Delivery to Protect Stem Cell–Derived Beta Cells from Transplantation-Induced Cell Death
Authors: BAKER ALEXANDER , CASTRO GUTIERREZ ROBERTO , KRATZ AUSTIN T. , RUSS HOLGER A.
Published: June 2024

Cadaveric islet transplantation in most type 1 diabetic (T1D) patients restores euglycemia. However, cadaveric islets are limited, transplantation often requires multiple organ donors, and significant apoptotic cell death shortly after transplantation prevents widespread implementation of this curative approach. Recent improvements in the differentiation of stem cell-derived beta cells (sBC) provide an abundant source of functional beta cells, with the first clinical trials evaluating the efficacy and safety of sBCs. Similar to cadaveric islets, sBCs experience severe apoptotic cell death following transplantation with the majority of graft mass lost within the first day following transplantation. We hypothesize that temporarily arresting the intrinsic apoptotic pathway by expression of BCL2 in transplanted sBCs can prevent significant cell death and improve graft survival. Using genome engineering strategies, we inserted a doxycycline inducible BCL2 expression cassette into a human induced pluripotent stem cell line. Under nutrient deprivation conditions, cells with induced BCL2 expression displayed a 60% increase in viable cells after treatment, this increase in viability was also observed in complementary in vitro models of apoptosis and radical oxygen species. These results give evidence to the role of BCL2 in saving cells under intrinsic apoptosis stress conditions. Future experiments will evaluate if BCL2 can similarly rescue sBCs cell death after transplant in vivo. Rescuing transplanted sBCs from apoptotic cell death will increase the efficacy of islet transplantation therapy for T1D patients by reducing the total beta cell mass needed to achieve insulin independence.

Disclosure

A. Baker: None. R. Castro Gutierrez: None. A.T. Kratz: None. H.A. Russ: Advisory Panel; Sigilon Therapeutics, Inc. Consultant; Minutia. Advisory Panel; Prellis Biologics. Consultant; Eli Lilly and Company.
203-OR: Metabolic and Clinical Outcomes with One Abnormal Value on Carpenter Coustan Criteria
Authors: SCIFRES CHRISTINA M. , DAVIS ESA , COSTACOU TINA , ORRIS STEVEN R. , LALAMA CHRISTINA M. , ABEBE KALEAB , CATALANO PATRICK
Published: June 2024

Objective: To examine the metabolic profile and neonatal outcomes of 1 abnormal (1ABNL) value on a 100g OGTT using Carpenter Coustan (CC) compared to no GDM (NGDM) and treated GDM (GDM) by the IADPSG or CC Criteria.

Methods: This is a secondary analysis of an RCT of GDM diagnosis using the IADPSG or CC criteria. Those with 1ABNL on CC GDM were not treated and compared to NGDM and GDM. Propensity score models with inverse probability of treatment weighing (IPTW) were used to balance groups.

Results: Of 827 participants 82 (10%) had 1 ABNL, 80 (10%) had GDM (22% CC, 78% IADPSG), and 665 (80%) NGDM. After IPTW, glucose and insulin were significantly higher whereas insulin sensitivity and beta cell response were lower in 1ABNL vs. NGDM. Insulin sensitivity/resistance and glucose/insulin AUC were similar between 1ABNL vs. GDM (Table) After IPTW, LGA (OR 1.4, 95% CI 1.0-2.0) and maternal composite (OR 2.0, 95% CI 1.6-2.6) were higher while neonatal composite (OR 0.5, 95% CI 0.4-0.7) and SGA (OR 0.1, 95% CI 0.1-0.2) were lower when comparing untreated 1 ABNL vs. NGDM. Compared to GDM, 1ABNL was associated with higher LGA (OR 3.4, 95% CI 1.4-8.4) and lower risk for SGA (OR 0.2, 95% CI 0.1-0.8), and neonatal composite (OR 0.3, 95% CI 0.2-0.6).

Conclusions: Women with 1ABNL on a 100g OGTT have a similar metabolic profile compared to GDM but metabolic dysfunction compared to NGDM resulting in increased fetal growth compared to both NGDM and treated GDM.

Disclosure

C.M. Scifres: None. E. Davis: None. T. Costacou: None. S.R. Orris: None. C.M. Lalama: None. K. Abebe: None. P. Catalano: None.

Funding

National Institutes of Health (1R01HD079647)
2030-LB: Matairesinol and Its Metabolite Enterolactone Promote Glucose Uptake in 3T3-L1 Adipocytes via a Glut4/Akt-Dependent Mechanism
Authors: MILLER ROCHELLE , FROMMACK ABIGAIL , WOODFIN SETH F. , CHAPPLE BROOKE , BONES MEGAN , JAMPOLE SHELBY , MOORE WILLIAM
Published: June 2024

Type-2 diabetes (T2D) is marked by dysregulated glucose homeostasis resulting in chronic fasting hyperglycemia and insulin resistance. Previous studies indicate that habitual coffee consumption is negatively correlated with the development of T2D. Matairesinol (MA) is a low molecular weight polyphenol that is found in coffee. MA and its gut microbial metabolite, enterolactone (ENL), have previously been shown to elicit anti-diabetic properties in studies analyzing skeletal muscle. However, their effects have not been demonstrated in adipocytes. In this study, 3T3-L1 adipocytes were treated with either MA or ENL in a dose-dependent manner and subsequently assayed for glucose uptake efficacy. We found that 1 and 10 µM ENL as well as 10, 15, 50, and 100 µM MA significantly increased glucose uptake in 3T3-L1 adipocytes compared to the vehicle. We also demonstrated that both MA- and ENL-stimulated glucose uptake were blunted by selective chemical inhibitors of Glut4, but not Glut1, thus indicating a potential Glut4-dependent mechanism. In addition, we show that ENL (50 µM) significantly increases Akt phosphorylation compared to the vehicle and to an extent that is statistically indistinguishable from the effects of insulin. Our data indicate that these compounds work through an Akt/Glut4-dependent mechanism thus warranting continued investigation into the molecular mechanisms by which they promote glucose uptake.

Disclosure

R. Miller: None. A. Frommack: None. S.F. Woodfin: None. B. Chapple: None. M. Bones: None. S. Jampole: None. W. Moore: None.
2033-LB: Dulaglutide Improves Metabolic Dysfunction–Associated Steatohepatitis (MASH), but Not Atherosclerosis, Independent of Weight Loss in Middle-Age LDLR-/- Mice
Authors: SHANTARAM DHARTI , RIMA XILAL Y. , BRADLEY DAVID , LIU JOEY Z. , WRIGHT VALERIE P. , AMARI ANASTASIIA , ROTTINGHAUS JOSEPH , FERNANDES JADEN M. , HSUEH WILLA
Published: June 2024

Clinical trials have demonstrated that glucagon-like peptide-1 receptor agonist (GLP-1 RA) reduces atherosclerosis risk in individuals with obesity independent of their diabetes status and is currently under investigation as a treatment for metabolic dysfunction-associated steatohepatitis (MASH). Several studies have associated weight loss with improvements in metabolic comorbidities, such as metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes (T2D). To determine the contribution of weight loss to the effect of dulaglutide; a GLP-1 RA, on atherosclerosis and MASH, we pair-fed western high-fat diet (WHFD) to middle-aged low-density lipoprotein receptor knockout (LDLR-/-) mice which develop accelerated atherosclerosis and MASH, compared to fatty streaks and simple steatosis in younger LDLR-/- mice. We administered dulaglutide and a placebo twice a week for the last 6 weeks of 12 weeks of WHFD. As a result, both dulaglutide and placebo-treated mice gained weight equally which was maintained throughout the study. Atherosclerosis extent measured with en-face analysis was similar between dulaglutide vs. placebo (18± 5% vs.14± 4% aorta covered by plaque), but dulaglutide-treated mice showed reduced liver fat by 50% (p<0.01), MASH pathology grade by 30% (p<0.05), and liver function testing by 50% (p<0.05). Furthermore, dulaglutide improved glucose tolerance but did not impact insulin sensitivity between the two groups. In addition, dulaglutide treatment substantially reduced the expression of de novo lipogenesis and inflammation genes in the liver. Together, these results reveal that weight loss contributes to the anti-atherosclerosis effects of GLP-1 RAs, but reduced liver fat accumulation and MASH are independent of weight loss.

Disclosure

D. Shantaram: None. X.Y. Rima: None. D. Bradley: None. J.Z. Liu: None. V.P. Wright: None. A. Amari: None. J. Rottinghaus: None. W. Hsueh: None.
204-OR: Social Vulnerability, Rurality, and Prevalence of Obesity and Inactivity in U.S. Counties, 2004–2019
Authors: VARGHESE BEN T. , LAHR BRIAN , VELLA ADRIAN , MIELKE MICHELLE , BAILEY KENT R. , DUGANI SAGAR B.
Published: June 2024

Introduction: Obesity and inactivity increase cardiovascular risk and are more prevalent in rural counties. The objective was to evaluate the association of county social vulnerability index (SVI) with obesity and inactivity, independent of rurality.

Method: We used CDC data (2004-2019; 97.5% of 3226 US counties) on county prevalence of obesity (BMI ≥30 kg/m2) and leisure-time inactivity. CDC SVI included 4 themes (socioeconomic status, household composition & disability, minority status & language, housing type & transportation) and was scored from 0 to 1 (low to high vulnerability). We used weighted least squares regression with restricted cubic splines to model the association of SVI with obesity and inactivity (median of 2004-2019). We adjusted for sociodemographic factors and rurality and reported the partial effects of SVI with F statistics and prevalence ratios (95% CI).

Result: SVI showed strong, monotonic, and independent associations with prevalence of obesity and inactivity (both, P<.001), after adjusting for sociodemographic factors and rurality. A change in SVI from the 25th to 75th percentile was associated with an 11% higher rate of obesity (1.11 [1.09-1.12]) and a 16% higher rate of inactivity (1.16 [1.14-1.18]). (Figure)

Conclusion: US counties with higher SVI have higher prevalence of obesity and inactivity, independent of rurality. SVI may identify counties for targeted intervention.

Disclosure

B.T. Varghese: None. B. Lahr: None. A. Vella: Research Support; Novo Nordisk. Consultant; Hanmi Pharm. Co., Ltd., Crinetics Pharmaceuticals, Inc. Advisory Panel; Rezolute, Inc. M. Mielke: Consultant; Biogen. Advisory Panel; Eisai Inc., Merck & Co., Inc. Consultant; Eli Lilly and Company. Advisory Panel; Roche Diagnostics. K.R. Bailey: None. S.B. Dugani: None.

Funding

National Institutes of Health (K23 MD106230)
2044-LB: IGF2 Deficiency Promotes Obesity by Inhibiting Testosterone Synthesis through Suppression of Autophagy
Authors: LIN XIHUA , ZHOU CAIPING , WU FANG , GUI WEIWEI
Published: June 2024

Objective: This study aims to investigate the role of Insulin-like Growth Factor 2 (IGF2) deficiency in promoting obesity through suppressed testosterone synthesis in Leydig cells by modulating autophagy flux.

Methods: Conditional hepatocyte-specific Igf2 knockout mice (Igf2 ΔHep) were generated. Body weight gain, serum testosterone, and glucose-lipid metabolic indicators were compared between Igf2 ΔHep and control mice. Transcriptomic sequencing was conducted on liver samples, and a combined analysis was done on publicly available single-cell sequencing data from testicular tissues. Autophagy levels and autolysosomes changes in Leydig cells were measured via autophagy marker protein LC3 and transmission electron microscopy (TEM). Key testosterone synthesis enzymes HSD17B and CYP17A1 expressions were quantified, followed by assessing cholesterol uptake using the BODIPY-cholesterol probe.

Results: Hepatocyte-specific Igf2 deletion mice exhibited accelerated weight gain compared to controls, coupled with significantly lower serum testosterone levels. Single-cell transcriptomics and immunofluorescence confirmed predominant expression of IGF2 and IGF2R in Leydig cells within the testes. Transcriptomic analysis disclosed downregulated genes in cholesterol metabolism and steroidogenesis pathways in Igf2 ΔHep mice. Immunofluorescence assays verified reduced expression of LC3 and TEM revealed a significant decrease in autolysosomes in Leydig cells of Igf2 ΔHep mice. Fluorescent co-staining and BODIPY-cholesterol assays indicated downregulated expression of testosterone synthesis enzymes HSD17B/CYP17A1 and decreased cholesterol uptake in IGF2-deficient mice.

Conclusion: This research demonstrated that IGF2 deficiency suppresses testosterone synthesis by regulating autophagy in Leydig cells, affecting cholesterol uptake and utilization, thereby potentially lowering testosterone levels and increasing obesity risk in males.

Disclosure

W. Gui: None.

Funding

National Natural Science Foundation of China (82370846)
2045-LB: Target-Derived Factors Decrease Sympathetic Innervation of Brown Adipose Tissue in a Critical Period of Development
Authors: FOHN ALEXIS , NERI DANIELE , RAMOS-LOBO ANGELA , LEDUC CHARLES A. , ODLE ANGELA , ZELTSER LORI M.
Published: June 2024

A wide range of developmental exposures can influence the establishment of sympathetic nervous system (SNS) tone onto metabolically relevant organs, but little is known about the underlying mechanism. Rearing mice at an ambient temperature of 30°C vs. 22°C from birth to 8 weeks of life programs lasting effects on SNS tone onto brown adipose tissue (BAT) and the capacity to respond to chronic cold challenges. We used this system to identify a critical period of development and potential molecular mediators of these effects. Utilizing cholera toxin B retrograde tracing we visualized sympathetic neurons in the stellate ganglion innervating BAT (SGBAT). By comparing the number of SGBAT neurons in mice reared at 30°C vs. 22°C across the first 8 weeks of life, we defined a time window when rearing at 30°C is associated with a marked decrease in innervation. Analyses of transcriptional profiles from bulk RNA-sequencing of BAT during this critical period revealed several signaling molecules that are differentially expressed at 30°C vs. 22°C. Complementary gain- and loss-of-function studies are underway to test the contribution of these candidate factors to the establishment of BAT SNS tone during development. Mechanisms identified here will provide a framework for analogous studies in other organs that are also implicated in developmental programming of health and disease.

Disclosure

A. Fohn: None. D. Neri: None. A. Ramos-Lobo: None. C.A. LeDuc: None. A. Odle: None. L.M. Zeltser: None.

Funding

National Institutes of Health (R01-DK125094)
206-OR: Assessing Connection to Outpatient Care among Patients Screening Positive for Previously Undiagnosed Diabetes in the Emergency Department
Authors: ANNEM VIDHYASAI , FAN CATHERINE , GANSUKH ENKHJIN , JOY QUINN , KAO DENIKA , KULIS NATALIA , NUNEZ CHRISTOPHER , TING KAILA S. , UPPAL DIVYA W. , REDDY HARITA , KOZIATEK CHRISTIAN A. , LEE DAVID C.
Published: June 2024

Introduction & Objective: Patients with frequent emergency department (ED) use often have poor connection to primary care, which limits their access to the preventive screening necessary to diagnose diabetes early. Our objective was to assess how frequently patients connected with outpatient care after a new diagnosis of diabetes through an ED-based screening program.

Methods: We performed a survey of all ED patients with newly diagnosed diabetes in 2022 at our health system, which now screens all ED patients aged 35 to 70 years old with a BMI ≥ 25 that do not have a prior history of diabetes in our records. HbA1c tests are added among those already receiving blood work as part of their care. We contacted each of these patients at least 6 months after they had been screened to participate in a phone-based survey about awareness of their new diagnosis, follow-up for outpatient care, and changes in health behaviors.

Results: In 2022, we screened 9,897 ED patients and found that 615 (6.2%) had a HbA1c ≥ 6.5%. After 3 rounds of phone calls, we successfully surveyed 307 for a response rate of 50%. We found that 44% of these patients had a pre-existing history of diabetes not reflected in our health records when they were screened. Analyzing the 171 ED patients with newly diagnosed with diabetes that were successfully surveyed, we found that 79% met with an outpatient provider after screening positive for diabetes, however, only 46% remembered being diagnosed. Of those with a new diagnosis, 65% reported improving their diet, 35% reported exercising more, and 52% reported starting medications for diabetes.

Conclusion: Connection to outpatient care after a new diagnosis of diabetes in the ED was more robust than anticipated, at least among those successfully surveyed. However, we identified key gaps: many patients did not remember their diagnosis, some reported barriers to outpatient care, and several patients were not started any medications despite a high HbA1c.

Disclosure

V. Annem: None. C. Fan: None. E. Gansukh: None. Q. Joy: None. D. Kao: None. N. Kulis: None. C. Nunez: None. K.S. Ting: None. D.W. Uppal: None. H. Reddy: None. C.A. Koziatek: None. D.C. Lee: None.

Funding

National Institutes of Diabetes and Digestive and Kidney Diseases (R01DK134668)
2062-LB: Disparity in Glucose Metabolic Regulation between Sleeve Gastrectomy and Gastroplasty
Authors: MOKADEM MOHAMAD
Published: June 2024

Sleeve gastrectomy (SG) and Endoscopic gastroplasty, are 2 effective weight loss interventions. This study assessed the impact of these interventions on weight loss, glucose homeostasis, and behavioral and hormonal parameters in mice. Both SG and gastroplasty induced significant weight loss, with SG showing lower food intake and improved feeding efficiency (Fig1). SG also showed better glucose and insulin tolerance, lower liver triglyceride levels, and reduced agouti-related protein levels compared to gastroplasty. Despite comparable weight reduction, SG demonstrated additional molecular improvements, suggesting potential for non-invasive interventions to replicate the benefits of invasive procedures (Fig2). This study highlights the potential of less invasive procedures as alternatives for treating severe obesity.

Disclosure

M. Mokadem: None.

Funding

VA Merit Award (I01 BX004774)
2066-LB: Potential to Optimize Weight Loss with Enobosarm—Meta-analysis of Body Composition from Three Randomized Clinical Trials Support the Ability of Enobosarm to Preserve Muscle while Reducing Fat
Authors: CRAWFORD JEFFREY , DOBS ADRIAN S. , EVANS WILLIAM J. , PRADO CARLA , RODRIGUEZ DOMINGO , SHALEV ITAY , GARY BARNETTE K. , STEINER MITCHELL
Published: June 2024

Background: Enobosarm, a novel oral selective androgen receptor modulator, combined with a GLP-1 receptor agonist (RA) may prevent muscle loss, while preferentially reducing fat resulting in a higher quality weight loss. A meta-analysis was conducted of three randomized clinical studies of enobosarm involving older men, postmenopausal women, and older patients who have muscle loss due to advanced cancer. Loss of appetite occurs with advanced cancer inducing a starvation state similar to GLP-1 RA therapy.

Methods: Meta-analysis was conducted of 3 randomized clinical trials evaluating enobosarm 3mg q day versus placebo and who had a Day 84 DXA scan to assess body composition: Phase 2 study in older males (>60 yo) and postmenopausal women (n=48), Phase 2 study in patients with muscle wasting because of advanced cancer (n=61), and Phase 3 study in patients with advanced lung cancer (n=258).

Results: At Day 84, DXA scan showed an absolute increase in lean mass of 1.5 kg in enobosarm treated vs placebo (p=0.00004) and % change in lean mass of a 4.04 % in enobosarm vs placebo (p=0.00007). Absolute decrease in fat mass was 0.758 kg in enobosarm treated vs placebo (p=0.015) and % change in fat mass was a loss -4.04 % in enobosarm vs placebo (p=0.006). Enobosarm was generally well tolerated with no increase in gastrointestinal side effects.

Conclusion: In meta-analysis of 367 older men, postmenopausal women, and older patients with muscle loss from advanced cancer, enobosarm therapy resulted in reductions in fat mass while preserving lean mass. Meta-analysis supports the potential for enobosarm when combined with a GLP-1 RA may preserve muscle, while preferentially reducing fat resulting in a higher quality weight loss in overweight and obese patients. A Phase 2b randomized controlled trial is currently underway to evaluate enobosarm in older patients receiving a GLP-1 RA for weight loss.

Disclosure

J. Crawford: Advisory Panel; Pfizer Inc. Research Support; Pfizer Inc., AstraZeneca, helsinn. Advisory Panel; BioAtla. Consultant; Actimed. Advisory Panel; G1 Therapeutics, Enzychem. Consultant; Faraday. Advisory Panel; Jazz. A.S. Dobs: Speaker's Bureau; Halozyme. W.J. Evans: None. C. Prado: Speaker's Bureau; Abbott Nutrition, Nestlé Health Science, Nutricia, Amra medical. Advisory Panel; Pfizer Inc. D. Rodriguez: Employee; Veru. I. Shalev: Employee; Veru. K. Barnette: None. M. Steiner: Stock/Shareholder; Veru, Inc.
2067-LB: Pooled Safety Analysis of Enobosarm from Phase 2 and Phase 3 Placebo-Controlled Clinical Trials
Authors: CRAWFORD JEFFREY , DOBS ADRIAN S. , EVANS WILLIAM J. , PRADO CARLA , RODRIGUEZ DOMINGO , SHALEV ITAY , GARY BARNETTE K. , STEINER MITCHELL
Published: June 2024

Background: Enobosarm is a novel oral selective androgen receptor modulator shown to increase lean mass and decrease fat mass. Enobosarm may benefit patients on GLP-1 RA for weight loss by preserving muscle while augmenting fat loss. A pooled analysis was conducted from 4 randomized clinical trials (RCT) to evaluate the safety profile of enobosarm.

Methods: The pooled safety analysis of enobosarm (3mg) included: Ph2 study in older males (>60 yo) and postmenopausal women (n=48), two Ph3 studies in patients with advanced lung cancer (n=651), and a Ph2 stress urinary incontinence study (n=328).

Results: TEAEs observed with enobosarm were comparable to the placebo group. Most common AEs for enobosarm were nausea (26.6% vs 26.0% in placebo), anemia (25.6% vs 23.9% in placebo), and vomiting (14.8% vs 14.6% in placebo), which were similar to the placebo groups. Notably, there was no increase in gastrointestinal AEs and no evidence of drug induced liver injury with enobosarm compared to placebo treatment. The incidence of deep vein thrombosis was higher (3.3%) in placebo compared to the enobosarm group (1%).

Conclusion: In pooled analysis of 1027 older men, postmenopausal women, and older patients with muscle loss from advanced cancer, enobosarm was well tolerated with an AE profile comparable to the control patients. A Ph2b randomized trial is underway to evaluate enobosarm in older patients on a GLP-1 RA for weight loss.

Disclosure

J. Crawford: Advisory Panel; Pfizer Inc. Research Support; Pfizer Inc., AstraZeneca, helsinn. Advisory Panel; BioAtla. Consultant; Actimed. Advisory Panel; G1 Therapeutics, Enzychem. Consultant; Faraday. Advisory Panel; Jazz. A.S. Dobs: Speaker's Bureau; Halozyme. W.J. Evans: None. C. Prado: Speaker's Bureau; Abbott Nutrition, Nestlé Health Science, Nutricia, Amra medical. Advisory Panel; Pfizer Inc. D. Rodriguez: Employee; Veru. I. Shalev: Employee; Veru. K. Barnette: None. M. Steiner: Stock/Shareholder; Veru, Inc.
2070-LB: Enhancing Metabolic Health in Obesity via Testosterone Replacement—Insights from a Meta-analysis of Controlled Trials
Authors: LIU YAOXIA , ZHANG MIN , FAN ZHEN , WANG TAO
Published: June 2024

Objective: This systematic review aimed to assess the efficacy and safety of testosterone replacement therapy (TRT) in obese men with testosterone deficiency.

Materials and Methods: A comprehensive computer-based search was conducted in Cochrane Library, PubMed, Embase, Web of Science, Scopus, Open SIGLE database, China National Knowledge Infrastructure, Wanfang Data, VIP database, and China Biology Medicine database to identify RCTs involving obese men with testosterone deficiency treated with TRT. Methodological quality was assessed using the risk of bias assessment tool in RevMan 5.3.

Results: A total of 10 RCTs were included, involving 665 subjects at baseline. Meta-analysis demonstrated that TRT resulted in a decrease in BMI by 0.57 kg/m²(P=0.002), a reduction in waist circumference(WC) by 2.78 cm(P=0.009), an increase in lean body mass by 1.96 kg(P=0.027), a decrease in fasting blood glucose by 0.53 mmol/L(P=0.002), a decrease in HOMA-IR by 1.89 (P=0.003), a decrease in HbA1c by 0.52% (P=0.0006), and a decrease in triglycerides(TG) by 0.22 mmol/L(P=0.003). There were no statistically differences in body weight, body fat mass, non-fat body mass, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol between the groups. However, TRT was associated with a statistically increase in hematocrit by 3.19% (P<0.00001).

Conclusions: The study suggests that testosterone replacement therapy in obese men with testosterone deficiency can improve metabolic parameters. TRT leads to reductions in BMI, WC and TG, while increasing lean body mass and improving insulin resistance. There is a risk of increased hematocrit, and it is recommended to consider the indications for TRT and cardiovascular risks. These findings suggest a potential role for TRT in the broader management strategy for obesity-related metabolic disorders.

Disclosure

Y. Liu: None. M. Zhang: None. Z. Fan: None. T. Wang: None.
2075-LB: Identification and Characterization of Two Novel Data-Driven Subtypes of Human Obesity
Authors: FAGNOCCHI LUCA , ANDREW POSPISILIK J.
Published: June 2024

Introduction & Objective: Obesity affects ~890 million adults and causes an estimated 5 million deaths each year. However, other than BMI and several clinical severity scales, there is no accepted framework for stratifying obesity into clinically actionable or etiologically distinct subtypes. Here, we identify and characterize two major subtypes of human obesity using a data-driven approach.

Methods: We performed multi-dimensional discordance analysis on adipose tissue gene expression profiles and morphological data from monozyogtic twins and validated the resulting two data-driven obesity subtypes against independent cohorts containing a wide range of clinical covariates.

Results: We identified two novel data-driven subtypes of human obesity, Type-A and -B, comprising ~90% of all patients with obesity. Type-A and -B are molecularly, epigenetically, morphologically, and physiologically distinct. At any given BMI, Type-B individuals exhibit relative hyperinsulinemia, relative lean mass increase, higher adipose tissue inflammation, and deregulated lipid homeostasis/adipogenesis gene expression. Mouse models and twin studies suggest that Type-B resembles a developmentally programmed obesity. These subtypes validated in the Leipzig Child Adipose Tissue cohort and in silico analysis reveal that Type-A/-B signatures can be found across the spectrum of obesity presentation. Our latest unpublished findings, integrating data available across several major obesity cohorts, indicate that Type-B obesity is reduced in insulin-responsive adipocytes (AdipoPLIN), and enriched for cardiometabolic comorbidities, irrespective of where the individuals are on the landscape of obesity.

Conclusion: Type-A and -B obesity define a major axis of human obesity heterogeneity, which might direct specific clinical intervention on patients. Type-B represents a higher risk form of obesity linked to incidence of comorbidities and suggestive of a potentially insulin-driven etiology.

Disclosure

L. Fagnocchi: None. J. Pospisilik: None.
2080-LB: Metabolite Profiles of Liver Fat and BMI in the MultiEthnic Study of Atherosclerosis (MESA) and Mediators of Atherosclerosis in South Asians Living in America (MASALA) studies
Authors: GADGIL MEGHANA D. , STROEBEL BENJAMIN M. , KANAYA ALKA M. , WOOD ALEXIS , GUO XIUQING , ROTTER JEROME I. , GREENLAND PHILIP , HERRINGTON DAVID M.
Published: June 2024

Introduction: Hepatic steatosis occurs across the body mass index (BMI) spectrum. We aimed to identify a metabolite signature for hepatic steatosis and BMI in a diverse population.

Methods: We included participants from the MESA (n=1,226) and MASALA (N=668) cohorts with untargeted LC-MS metabolomics and abdominal computed tomography data at baseline, excluding those with cirrhosis, prevalent HIV, alcohol use > 14 drinks/week or routine use of steatosis-inducing medications. There were 143 concordant metabolites between two cohorts. Log-transformed and mean-centered metabolites were used for elastic net regularized regression to select an optimal subset associated with inverse hepatic attenuation or BMI, adjusted for age, gender and BMI for hepatic steatosis analysis.

Results: There were 185 (10%) participants with hepatic steatosis, of which 48% were women, mean BMI 31 kg/m2 and 26% had prevalent diabetes. In elastic net analyses, 30 metabolites were selected for BMI, and 25 metabolites for intrahepatic fat with 6 in common. (Table)

Conclusions: Circulating triglycerides and lower lysophosphatidylcholines were predominant for hepatic steatosis while medium and long-chain acylcarnitines were related to BMI, suggesting differences in glucose and fat metabolism, respectively, between these states of excess adiposity.

Disclosure

M.D. Gadgil: Stock/Shareholder; LumosFit. B.M. Stroebel: None. A.M. Kanaya: None. A. Wood: Research Support; Beef Checkoff. Consultant; The Lundquist Institute. X. Guo: None. J.I. Rotter: None. P. Greenland: None. D.M. Herrington: None.

Funding

NIH-NIDDKK (23DK119404), NIH-NHLBI (R01HL093009), NCATS (UL1RR024131). COMBI-BIO Research supported by EU COMBI-BIO project (FP7, 305422), and NIH/NHLBI (R01HL133932). NIH-NHLBI contracts (75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169). NCATS grants (UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420).
2087-LB: Novel Human Islet Spheroid Models of Type 1 Diabetes
Authors: TITLE ALEXANDRA C. , RUFER CHANTAL , JAWUREK SAYRO , FORSCHLER FELIX , KODIYAN BEN , YESILDAG BURCAK
Published: June 2024

Recently, it has emerged that β-cells co-orchestrate their own demise by increasing their visibility to the immune system, stressing the importance of studying both the immune and the β-cell components of T1D simultaneously. To enable accurate, high-throughput and longer-term studies of these mechanisms in vitro, we established three islet-immune injury models by culturing spheroids derived from primary human islets with proinflammatory cytokines, activated peripheral blood mononuclear cells or HLA-A2-restricted preproinsulin-specific cytotoxic T lymphocytes. We developed a wide variety of biochemical and 3D microscopy based-methods to assess dynamic and static insulin release, insulin production, β-cell survival, cytokine secretion and T cell infiltration, at a single islet resolution. In all models, the decline in β-cell health manifested as increased basal and decreased glucose-stimulated insulin release (GSIS), and decreased intracellular insulin content. Additional hallmarks of T1D progression such as loss of the first-phase insulin response (FFIR), increased proinsulin-to-insulin ratios, HLA-class I expression, and inflammatory cytokine release were also observed. Using these models, we evaluated the effects of multiple intervention strategies including a glucagon-like peptide 1 (GLP-1) receptor agonists and HLA Class I inhibition, on human islets under T1D-relevant stress. We were able to successfully prevent the loss of GSIS under cytokine- and immune-mediated stress, notably by increasing β-cell survival, preserving the FFIR, decreasing immune cell infiltration and cytokine secretion. Our results support the anti-inflammatory effect of GLP-1R agonists and importance of HLA Class I modulation for protecting β-cells from the immune-mediated attack that leads to T1D. The described biomimetic islet-immune assays represent ideal in vitro models for long-term, high-throughput and precise study of early-stage T1D immunopathology and β-cell dysfunction.

Disclosure

A.C. Title: Other Relationship; Biomea Fusion, Inc., Boehringer-Ingelheim, Novo Nordisk, Merck & Co., Inc. C. Rufer: Other Relationship; Boehringer-Ingelheim, Novo Nordisk, Merck & Co., Inc., Biomea Fusion, Inc. S. Jawurek: Other Relationship; Boehringer-Ingelheim, Merck & Co., Inc., Biomea Fusion, Inc., Novo Nordisk. F. Forschler: Other Relationship; Biomea Fusion, Inc., Boehringer-Ingelheim, Merck & Co., Inc., Novo Nordisk. B. Kodiyan: Other Relationship; Biomea Fusion, Inc., Novo Nordisk, Boehringer-Ingelheim, Merck & Co., Inc. B. Yesildag: Other Relationship; Novo Nordisk, Boehringer-Ingelheim, Biomea Fusion, Inc., Merck & Co., Inc.
2092-LB: Receptor-Mediated G12 Signaling Strongly Promotes Insulin Secretion from Pancreatic Beta Cells
Authors: PITTALA SRINIVAS , HASPULA DHANUSH , LIU LIU , CUI YINGHONG , WESS JÜRGEN
Published: June 2024

Type 2 diabetes (T2D) has emerged as a major threat to human health in most parts of the world. The inability of pancreatic β-cells to release enough insulin is key pathological sign. Glucose-induced insulin secretion is regulated by G protein-coupled receptors (GPCRs) located on the cell surface of pancreatic β-cells. Because of the lack of GPCRs that can selectively interact with G proteins of the G12 family (G12/G13), it remains unknown whether G12 signaling has a positive impact on β-cell function. To address this question, we generated a new mouse line that expressed a CNO (clozapine-N-oxide)-sensitive, G12-coupled designer GPCR (G12 DREADD; DREADD = designer receptor exclusively activated by a designer drug) selectively in β-cells (beta-G12D mice). CNO is a small synthetic molecule that can selectively activate the G12 DREADD but is otherwise pharmacologically inert. In addition, we generated a mouse model lacking the α-subunits of G12 and G13 selectively in β-cells (beta-G12/13 KO mice). We then subjected these mutant mice, together with their control littermates, to a series of metabolic tests. We found that selective activation of β-cell G12 signaling strongly enhanced glucose-stimulated insulin secretion, leading to improved glucose tolerance in both lean and obese mice. In obese mice, activation of β-cell G12 signaling counteracted the deficits in glucose homeostasis caused by increased adiposity. The G12D-mediated simulation of insulin release was virtually abolished in beta-G12/13 KO mice. Mechanistic studies with perifused pancreatic islets demonstrated that the increase in insulin release triggered by stimulation of β-cell G12 signaling required the activation of ROCK1, leading to structural changes in the actin cytoskeleton that promoted insulin secretion. Our data strongly suggest that strategies aimed at stimulating β-cell G12 signaling could become clinically useful for the treatment of T2D and related metabolic disorders.

Disclosure

S. Pittala: None. D. Haspula: None. L. Liu: None. Y. Cui: None. J. Wess: None.

Funding

NIH Intramural Research Program