bluuebunny/crossref_metadata_2025 huggingface dataset:
1941-LB: Effect of the Community-Based Multicomponent Strategy for Diabetes Self-Care
Authors: SONG YOUNGSHIN , SHIN HYUNKYUNG
Published: June 2024

Introduction & Objective: Although there are many studies to confirm the effectiveness of single interventions for diabetes self-care, but patients’ real world experiences are complex, including education, counseling, and access to mHealth. The purpose of this study is to identify the effect of multicomponent self-care strategy among various interventions applied to patients with diabetes in community.

Methods: A matched sample study design was conducted. Participants were recruited at the Diabetes Registration and Education Center of Public Health Center in S-City of Korea. Three different A, B, C interventions (A: non-face to face health literacy education & tailored counseling, B: mHealth & motivational telephone counseling, C: conventional group education & telephone checkup) were applied to groups of 109 patients with diabetes in community for 3 months each. Diabetes self-care behaviors, knowledge, and self-efficacy were measured as outcome variables. Descriptive statistics, χ2-test, and F-test were used to analyze the differences between groups.

Results: Homogeneity for demographics was confirmed among groups. The difference in diabetes self-care scores before and after intervention was significantly highest in group A, followed by groups B and C. In terms of knowledge, group A had the largest difference in scores before and after intervention, but not significant. In diabetes self-efficacy, the difference in scores before and after the intervention was larger in group B than in group A.

Conclusion: Non-face to face health literacy education & counseling were most effective in community setting. Based on this, it is necessary to develop strategies that can be used in reality.

Disclosure

Y. Song: None. H. Shin: None.
1948-LB: Effect of N-Acetyl Cysteine on Thrombo-inflammation in Children with Metabolic Dysfunction–Associated Steatotic Liver Disease
Authors: GURNURKAR SHILPA , MCGOOGAN KATHERINE , SHAH CHETAN C. , UPPAL VIKAS , JOBAYER HOSSAIN MD , BALAGOPAL BABU
Published: June 2024

Background: Obesity (OB)-related pro-thrombo-inflammatory state sets the basis for cardiometabolic disease including type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) in children. The aims were to explore in children with OB and MASLD (i) the role of gamma prime (γ′) fibrinogen (GPF), a novel marker of thrombo-inflammation, and selected metabolic parameters and (ii) the effect of N-acetyl cysteine (NAC) on GPF and metabolic parameters.

Methods: 16-week randomized, double-blind, placebo-controlled trial of oral NAC treatment. Participants (n=13) with OB (BMI-percentile>95) and MASLD (NAS Score >2) were randomized to one of the two groups of NAC (600mg NAC/day or 1200mg NAC/day) and placebo. GPF, leptin, spexin, glucose, insulin and body composition were measured. Data on high-sensitivity c-reactive protein (hs-CRP), interleukin-6 (IL-6), liver enzymes, liver fat fraction (LFF) and liver stiffness (LS) were previously reported. Because of the small sample size and that the response to both doses of NAC was similar, merged data of the two intervention groups were used for statistical analysis, which included 2-sample t-test and analysis of covariance (ANCOVA).

Results: GPF was elevated (p=0.01) in those with MASLD vs normal weight (NW) and OB [GPF data from age and sex matched children with NW and OB from our previous study]. Leptin was higher and spexin lower in MASLD. GPF and leptin decreased (p=0.01 and 0.03) and spexin increased (p=0.02) in response to NAC treatment. Substantial decrease in liver enzymes, LFF, and LS were previously reported.

Conclusion: 16-week NAC treatment led to improvements in the pro-thrombo-inflammatory state present in children with OB and MASLD along with beneficial liver outcomes. Further investigation on the role of thrombo-inflammation in children with MASLD, particularly in those with T2D is warranted because of the higher incidence and severity of MASLD in those with T2D.

Disclosure

K. McGoogan: Research Support; AbbVie Inc., Pfizer Inc. Advisory Panel; Mirum Pharmaceuticals. Research Support; Retrophin. V. Uppal: None. M. Hossain: None. B. Balagopal: None.

Funding

American Diabetes Association (1-14-CE-04)
1950-LB: Real-World Use of Tirzepatide among People without Type 2 Diabetes—Results from Optum’s Deidentified Clinformatics Data Mart Database
Authors: HUNTER GIBBLE THERESA , CHINTHAMMIT CHANADDA , MEEKS ALEXANDRA , LIAO BIRONG , WARD JENNIFER , HANKOSKY EMILY R.
Published: June 2024

Objective: Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide and glucagonlike peptide-1 (GLP-1) receptor agonist (RA) approved for treatment of adults with type 2 diabetes (T2D) and obesity. This study aimed to understand the real-world use of tirzepatide among people without T2D.

Methods: This retrospective, claims-based study was conducted using Optum’s de-identified Clinformatics® Data Mart Database. The index date was the first observed claim of tirzepatide (NDC for Mounjaro™) during the index period (May 13, 2022-March 31, 2023). Adults without a T2D diagnosis during the 12-month (mo) pre index period and with continuous medical and pharmacy enrollment (12 mo pre index and 6 mo post index) were included. Tirzepatide was only approved for the treatment of T2D during the index period, therefore any use of tirzepatide by individuals without T2D during this time was off-label and solely at the discretion of their prescribing physician. Baseline demographic and clinical characteristics and post-index treatment patterns were assessed using descriptive analyses.

Results: 1,756 people without T2D diagnosis codes initiated tirzepatide. Mean age was 53.4 yrs, and 68.6% were female. Top prescribing providers were primary care physicians (77.5%). Dyslipidemia (46.6%), hypertension (46.1%), and prediabetes (31.2%) were the most common comorbidities, and 74.0% had ≥1 obesity-related comorbidity (ORC). During the 12-mo pre-index period, 1.4% had ≥1 claim for an anti-obesity medication (AOM). Additionally, 21.3% had ≥1 claim for metformin, while 14.5% had ≥1 claim for a non-AOM GLP-1 RA. Of 1,756 people initiating tirzepatide, 77.9% were persistent (treatment discontinuation was considered as >60 untreated days on tirzepatide for ≥6 mo).

Conclusion: Most people initiating tirzepatide without T2D diagnosis codes had ≥1 ORC, were naïve to AOMs and non-AOM GLP-1 RAs and were persistent on tirzepatide at 6 mo post index.

Disclosure

T. Gibble: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. C. Chinthammit: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. A. Meeks: Employee; Eli Lilly and Company. B. Liao: Employee; Eli Lilly and Company. J. Ward: Employee; Eli Lilly and Company. E.R. Hankosky: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.
1953-LB: Assessing Continuous Glucose Monitor Accuracy for Diabetes Management in Hospitalized Children
Authors: GARG NEHA , LEWIS KAMRYN R. , WHITE PERRIN C. , ADHIKARI SOUMYA
Published: June 2024

Introduction & Objectives: The adoption of continuous glucose monitors (CGM) in inpatient settings in the pediatric population has remained slow due to a scarcity of data on their reliability in hospitalized children.

Methods: We retrospectively reviewed the accuracy of the Dexcom G6 CGM system in pediatric patients with diabetes admitted to our academic children’s hospital from March 2018-September 2023. We cross referenced our institutional Dexcom Clarity database against an internal database of inpatient admissions to identify all children admitted to the hospital with CGM data. We then recorded sensor glucose readings from Clarity and values for blood glucose (BG), blood urea nitrogen, and pH from the electronic medical record.

Results: There were 3,200 admissions of children with diabetes in this period, of which 295 (from 211 patients 2-18 years old) had associated CGM data. A total of 3,952 paired CGM and BG measurements (serum and point-of-care, POC) (40-400 mg/dl) were compared resulting in a mean absolute relative difference (MARD) of 15.6%, with 96.5% of the values in zones A+B of Clarke error grid analysis. The MARD for POC BG vs CGM (n=3,518 pairs) was 15.5%, and for serum BG vs CGM (n=434 pairs), 17%. MARD varied by degree of hyperglycemia (Glucose 70-180 mg/dL: n=1866 pairs, MARD 16.4%; Glucose 181-250: n=1023, MARD 13.2%; Glucose 251-400: n=831, MARD 12.7%, p <0.0001), but not by degree of acidosis (pH 7.3-7.5: n=611, MARD 15.8%, pH 7.1-7.3: n=330, MARD 16.1%, pH <7.1: n=12, MARD 14.8%). We performed linear regression, and pH, sodium, and BUN had no impact on CGM accuracy.

Conclusion: Based on our retrospective data, CGMs demonstrated high clinical reliability in hospitalized children with diabetes.

Disclosure

N. Garg: None. P.C. White: Consultant; Provention Bio, Inc. Research Support; MannKind Corporation, National Institute of Diabetes and Digestive and Kidney Diseases. S. Adhikari: None.
196-OR: A Scalable Application of Artificial Intelligence (AI) to Transform Type 2 Diabetes Management in Clinical Practice
Authors: WARREN MARK L. , BERGENSTAL RICHARD M. , HAGER MATTHEW , BASHAN ERAN , HODISH ISRAEL
Published: June 2024

Introduction: Despite new pharmacotherapy, most patients with long-term type 2 diabetes are still hyperglycemic. This could have been solved by insulin with its unlimited potential efficacy, but its dynamic physiology demands frequent titrations which are overdemanding. This report provides a real-life account for a scalable transformation of diabetes care in a community-based endocrinology center by harnessing AI-based autonomous insulin titration.

Methods: The center embedded the d-Nav® technology and its dedicated clinical support. Reported outcomes include treatment efficacy/safety in the first 600 patients and use of cardiorenal-risk reduction pharmacotherapy.

Results: Patients used d-Nav for 8.2±3.0 months with 82% retention. Age-67.1±11.5 years and duration of diabetes-19.8±11.0 years. See Figure for HbA1c dynamics during the 3-years prior d-Nav, and on d-Nav. In 21% of the patients, insulin doses initially decreased to prevent hypoglycemia. GLP1/GLP1+GIPag were prescribed in about a half of the patients and SGLT2i in a third. The frequency of hypoglycemia (<54mg/dl) was 0.4±0.6/month and severe hypoglycemia 1.7/100-patient-years.

Conclusions: The use of d-Nav allowed for scalable improvement in overall diabetes management with appropriate use of both insulin and non-insulin pharmacologic agents.

Disclosure

M.L. Warren: Research Support; Novo Nordisk, Insulet Corporation. Speaker's Bureau; Lilly Diabetes. Advisory Panel; Lilly Diabetes. Research Support; AstraZeneca, Bayer Inc. Speaker's Bureau; Bayer Inc. Research Support; AbbVie Inc., Medtronic, Ascendis Pharma A/S, Amolyt. Speaker's Bureau; Ascendis Pharma A/S, Amgen Inc. Research Support; AstraZeneca. Advisory Panel; Hygieia. R.M. Bergenstal: Other Relationship; Abbott. Research Support; Arkray Marketing. Consultant; Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur. Other Relationship; Dexcom, Inc., Eli Lilly and Company. Consultant; embecta, Hygieia. Research Support; Insulet Corporation. Consultant; MannKind Corporation. Other Relationship; Medtronic, Novo Nordisk. Consultant; Onduo LLC, Roche Diabetes Care. Other Relationship; Sanofi. Research Support; Tandem Diabetes Care, Inc. Other Relationship; UnitedHealth Group. Consultant; Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S. M. Hager: Other Relationship; Hygieia. E. Bashan: Board Member; Hygieia. Employee; Hygieia. Stock/Shareholder; Hygieia. I. Hodish: Stock/Shareholder; Hygieia.
1963-LB: Prenatal Treatment of Glucagon-Like Peptide 1 Agonist Mitigates Cognitive Deficits in Offspring of Mothers with Diabetes by Modulating Placental Development Mediated by ADGRL3
Authors: ITO MARIKO , SUGAI KEIJI , SASAKI JUNKO , SUZUKI RYO , ODAWARA MASATO , TORII MASAAKI , HASHIMOTO-TORII KAZUE
Published: June 2024

Hyperglycemia during pregnancy is associated with increased neurobehavioral risks in offspring, even with insulin control. We hypothesized that prenatal administration of Glucagon-like peptide 1 (GLP-1) agonist to diabetic mothers could alleviate cognitive deficits in offspring. A pregestational diabetes model was made with 8-week-old C57BL/6J female mice using streptozotocin (STZ). Offspring were used for behavior test and the tissues underwent immunohistochemistry, single-cell RNA sequencing, and qRT-PCR analyses. In vitro studies utilized HTR8/SVneo cells for mass spectrometry and cAMP assays by shRNA mediated knocking down, and HEK293 cells for the SRE assay by ADGRL3 overexpression. Offspring of the dam with diabetes showed learning deficits and prenatal treatment of GLP-1 agonist starting mid-gestation mitigated the deficits. Immunohistochemical analysis found GLP-1 agonist in placental trophoblasts, without distribution in fetal brain. In placenta from STZ model, trophoblast invasion was inhibited, but improved by GLP-1 agonist treatment. qRT-PCR of human placental tissue mirrored mouse findings; genes related to trophoblast inveation were altered in placenta from mother with pregestational diabetes. In HTR8/SVneo cells that lacks GLP-1 receptor, another class B GPCRs, ADGRL3, was determined as a GLP-1 binding receptor in immunoprecipitation-mass spec analysis. Functional assays showed that ADGRL3 mediates GLP-1 signaling via G alpha s and G alpha q proteins. Altogether, our study demonstrates that prenatal GLP-1 RA treatment mitigates cognitive deficits of offspring from STZ-exposed dams by affecting ADGRL3 mediated GLP-1 signaling in placental trophoblasts.

Disclosure

M. Ito: None. K. Sugai: None. J. Sasaki: None. R. Suzuki: Speaker's Bureau; Novo Nordisk Pharma, Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma Inc., Kowa Company, Ltd., MSD, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Teijin Pharma Limited. Research Support; Sumitomo Dainippon Pharma Co., Ltd. M. Odawara: Speaker's Bureau; Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Novartis Pharmaceuticals Corporation, Eli Lilly and Company, Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Daiichi Sankyo, Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Boehringer-Ingelheim, MSD Life Science Foundation, AstraZeneca, Kowa Company, Ltd. Research Support; Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company. Other Relationship; Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Daiichi Sankyo, Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Boehringer-Ingelheim. M. Torii: None. K. Hashimoto-Torii: None.

Funding

National Institutes of Health (A12BC345678)
1968-LB: Early Prediction of Gestational Diabetes Mellitus Using Electronic Health Records and Machine Learning
Authors: GERMAINE MARK A. , O'HIGGINS AMY C. , HEALY GRAHAM , EGAN BRENDAN
Published: June 2024

Introduction: The objective of this study is to assess the efficacy of machine learning models in gestational diabetes mellitus (GDM) prediction using electronic health record (EHR) data collected in the first trimester.

Methods: Data were extracted from The Coombe Hospital EHRs, Dublin, spanning from 2018-2022. The year 2020 was excluded due to COVID-19-related deviations from usual screening practices. We employed four machine learning models—Random Forest, XGBoost, Logistic Regression and Explainable Boosting Machine—evaluating them using receiver operating characteristic (ROC) curve and average precision (AP). Models were trained on data within the EHRs collected during the first prenatal visit (8-14 weeks).

Results: 27,500 pregnancies and 3,100 GDM cases were analyzed post-processing. Logistic Regression consistently showed high performance (full feature set ROC AUC = 0.821, AP = 0.39; top 13 features ROC AUC = 0.818, AP = 0.39; first pregnancy only ROC AUC = 0.826, AP = 0.38). Other models demonstrated varying degrees of performance, some slightly decreasing when reducing features or considering only the first pregnancy.

Conclusion: Logistic regression appears to match or better the performance of more sophisticated machine learning models when predicting GDM using data from EHRs. This has the added benefit of easily explainable models for healthcare practitioners and stakeholders.

Disclosure

M.A. Germaine: None. A.C. O'Higgins: None. G. Healy: None. B. Egan: None.

Funding

This work has emanated from research supported in part by a grant from Science Foundation Ireland (18/CRT/6183).
1991-LB: Triglyceride–Glucose Index Is an Effective Tool for Assessing Glycemic Control in Asian Indians with Type 2 Diabetes
Authors: PRADEEPA RAJENDRA , JHA VINITAA , THYPARAMBIL ARAVINDAKSHAN PRAMODKUMAR , WAGHDHARE SWATI , MOHAN VISWANATHAN , CHAMBERS JOHN , MOHAN ANJANA RANJIT
Published: June 2024

Introduction & Objective: Glycated hemoglobin (HbA1c) may not accurately reflect glycemic control in certain conditions like hemoglobinopathy, hemolytic anemia, or acute blood loss. There is a need for alternative tools for assessing glycemic control, particularly in India, where high costs and unavailability of standardized assays make widespread use of HbA1c challenging. We attempted to evaluate the efficacy of the Triglyceride-glucose (TyG) index, as a cost-effective alternative to HbA1c for assessment of glycemic control.

Methods: Cross-sectional data from the South Asia Biobank were analyzed. This included data of 8597 adults (aged ≥18 years) with type 2 diabetes (T2D) from Chennai and Delhi, India, surveyed during the period 2019-21. T2D was diagnosed if the fasting plasma glucose [FPG] ≥126 mg/dl and/or HbA1c ≥6.5%. TyG index was calculated using the formula Ln [fasting triglycerides (mg/dL) × FPG (mg/dL)/2]. Receiver Operating Curve (ROC) and multivariable logistic regression were used to quantify the association of TyG index with HbA1c.

Results: TyG index (Mean± SD: 5.1±0.3 vs.4.8±0.3, p<0.001) was significantly higher in those with suboptimal glycemic control (HbA1c ≥7%) compared to those with good control (HbA1c <7%), and showed significant correlation with HbA1c (r=0.501; p<0.001). After adjusting for age and sex, regression analysis showed that Tertile 2-TyG index ≥4.9-5.6 (Odds Ratio [OR] 2.7, 95% Confidence Interval [CI]: 2.5-3.1) and Tertile 3-TyG index ≥5.7 (OR 9.1, 95% CI:8.0-10.3) were associated with HbA1c ≥7%. The area under the curve (AUC) of the ROC curve of TyG index ≥5.03 for prediction of HbA1c ≥7% was 0.75 (95% CI,0.74-0.76) with a sensitivity of 63% and specificity of 74% (p<0.001).

Conclusion: The TyG index appears to be a cost-effective marker for assessing glycemic control, offering a valuable tool for monitoring diabetes in low-resource settings and situations where HbA1c cannot be reliably estimated.

Disclosure

R. Pradeepa: None. V. Jha: None. P. Thyparambil Aravindakshan: None. S. Waghdhare: None. V. Mohan: None. J. Chambers: None. R. Anjana: None.

Funding

National Institute for Health Care and Research (NIHR132960)
2003-LB: Dissecting Ancestry-Aware Molecular Causal Paths of Type 2 Diabetes
Authors: YOSHIJI SATOSHI , BOCHER OZVAN , LUIZA ARRUDA ANA , YIN XIANYONG , CAMMANN DAVIS B. , ZHAO CHI , TAYLOR HENRY J. , CHEN JINGCHUN , MANDLA RAVI , HUERTA ALICIA , YANG TA-YU , WOOD ALEXIS , LORENZ KIMBERLY , MATSUDA FUMIHIKO , FLANNICK JASON , MERCADER JOSEP M. , SPRACKLEN CASSANDRA N. , MEIGS JAMES B. , ROTTER JEROME I. , VUJKOVIC MARIJANA , VOIGHT BENJAMIN F. , MORRIS ANDREW , ZEGGINI ELEFTHERIA
Published: June 2024

Multiple molecular mechanisms are involved in the pathogenesis of type 2 diabetes (T2D), with potentially different effects across ancestries. Recent large-scale efforts by the Type 2 Diabetes Global Genomics Initiative (T2DGGI) have broadly described the genetic architecture of T2D, data that can be subsequently used to pinpoint causal molecular mechanisms leading to T2D in an ancestry-aware manner.

In this work, we sought to explore the causal effects of gene expression and proteins on T2D across ancestries by leveraging data from the latest T2DGGI multi-ancestry genome-wide association study (GWAS). We conducted two-sample Mendelian randomization (MR) using cis-expression and protein quantitative trait loci (eQTL/pQTL) data from various datasets of four different major ancestries. To corroborate our findings, we performed statistical colocalization using PWCoCo. We then performed meta-analyses across ancestries for molecular traits showing evidence of causality in at least one ancestry (5% FDR-adjusted MR p-value and PWCoCo posterior probability ≥ 0.5).

We found causal evidence for changes in the genetically regulated expression of 267 genes and 15 proteins with T2D risk in at least one ancestry. When meta-analyzing the results across ancestries, we found, for eQTLs, evidence of causality between 148 genes and T2D, including PABPC4, a high-confidence effector gene for T2D with evidence of ancestry-correlated heterogeneity (I2 = 85%). For pQTLs, NELL1, ANXA7, PCSK1, and CTRB2 were found to be causal to T2D risk in the cross-ancestry meta-analysis, with CTRB2 showing evidence of ancestral heterogeneity (I2 = 85%).

Our findings highlight the power of large-scale GWAS and multi-omics MR to identify causal pathways involved in T2D risk. Our results also show the existence of ancestry-correlated heterogeneity, which emphasizes the need for expanding investigations into non-European ancestry populations to better understand T2D etiology.

Disclosure

S. Yoshiji: None. O. Bocher: None. X. Yin: None. C. Zhao: None. J. Chen: None. R. Mandla: None. A. Huerta: None. T. Yang: None. A. Wood: Research Support; Beef Checkoff. Consultant; The Lundquist Institute. K. Lorenz: None. F. Matsuda: None. J. Flannick: None. J.M. Mercader: None. C.N. Spracklen: None. J.B. Meigs: None. J.I. Rotter: None. M. Vujkovic: None. B.F. Voight: None. A. Morris: None. E. Zeggini: None.
2011-LB: Patterns of Genetic Risk for Type 2 Diabetes Are Specific to Ancestry
Authors: YURCHISHIN MARIAN L. , FOWLER LAUREN A. , GOWER BARBARA , FERNANDEZ JOSE R. , O'NEIL PATRICK M.
Published: June 2024

Introduction & Objective. The heterogeneity of type 2 diabetes (T2D) risk has a genetic basis that can be reflected in genetic risk scores (GRS). It is currently unknown if the nature of genetic risk for T2D varies with ancestral backgrounds. The aim of this study was to determine if patterns of genetic risk for T2D exist, and if they differ by ancestry in a sample of 342 Non-Hispanic White (NHW), Non-Hispanic Black (NHB), and Hispanic (HIS) adults with obesity and T2D.

Methods: Participants were genotyped using the Infinium Global array with imputation. Six GRS representing distinct T2D pathophysiological pathways (beta-cell, proinsulin, obesity, lipodystrophy, liver/lipid, and insulin resistance (IR)) were calculated. Principal components analysis was performed on the GRS and genetic admixture values to identify ancestry-specific patterns for risk. Spearman correlations quantified strength and direction of associations of variables to each component. Participant self-reported ethnicity was used as a supplementary categorical variable.

Results: Two principal components (PC) were retained. PC1 was associated with greater African ancestry (r=0.92, p <0.001) and the beta-cell and proinsulin GRS (r=0.442, p <0.001 and r=0.453, p<0.001, respectively). PC2 was associated with higher Native American ancestry (r=0.4691, p<0.001) and the IR and lipodystrophy GRS (r=0.52, p <0.001 and r=0.66, p<0.001, respectively). NHB were distinctly different from NHW for all variables. NHB had the highest scores for PC1, suggesting that genetic susceptibility to T2D in this group arises from impaired insulin secretion and processing abilities. HIS had the highest scores for PC2, which suggests T2D risk in this group is characterized by lipodystrophy-driven IR.

Conclusion: Our results demonstrate that genetic risk for T2D manifests in patterns that are ancestry-specific. This may be useful in future research to help refine criteria for identifying at-risk individuals based on ancestral background.

Disclosure

L.A. Fowler: None. B. Gower: Advisory Panel; Cook Keto, Simply Good Foods, Abbott. J.R. Fernandez: None. P.M. O'Neil: Other Relationship; Novo Nordisk.

Funding

National Institutes of Health (T32HL105349); National Institutes of Health (T32DK062710)Clinical trial from which data were collected was sponsored by Weight Watchers International to the Medical University of South Carolina (NCT01601574)
2032-LB: In Vivo Chain Splitting of Human Insulin
Authors: STURIS JEPPE , CRAMER CHRISTIAN , BRAND CHRISTIAN L. , HELLEBERG HANS , KURTZHALS PETER , HUBALEK FRANTISEK
Published: June 2024

Non-insulin receptor-mediated insulin degradation via insulin degrading enzyme has been proposed to play a role in insulin resistance (IR). Recently, chain-splitting (CS) via a disulfide bond exchange process has been shown to occur for insulin icodec dosed to humans. As insulin icodec contains disulfide bond stabilizing substitutions, the present aim was to estimate the degree of CS of human insulin (HI) from A-chain (Ach) levels during infusion of HI to rats combined with kinetics of Ach in rats.

Ach was injected IV into male Sprague-Dawley (SprD) rats (1, 7 and 50 nmol/kg), and Ach in plasma sampled from the carotid artery was measured by LC/MS. Ach clearance (CL) and t½ (geometric mean) were estimated by regression analysis. A euglycemic clamp during IV HI infusion (2 nmol/kg/min) into SprD rats (n=2) allowed plasma HI and Ach from in vivo CS to be measured. The rate of CS was estimated as the 180 min clamp Ach level multiplied by Ach CL.

Ach was measured in all rats. The estimated CS rate in the clamp experiment was 0.37 nmol/kg/min or 19% of the HI infusion.

We have estimated that a substantial proportion of HI was degraded by CS in rats during HI infusion. Further studies are warranted to substantiate our findings and to investigate 1) if CS of HI during transport to the interstitial fluid may limit the access of HI to target tissues and 2) to what extent increased CS and reduced access of endogenous insulin may be a mechanism for compensatory insulin secretion, hyperinsulinemia and IR.

Disclosure

J. Sturis: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. C. Cramer: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. C.L. Brand: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. H. Helleberg: Stock/Shareholder; Novo Nordisk A/S. P. Kurtzhals: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. F. Hubalek: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S.
2041-LB: The Divergent Effects of Alternate Day Fasting on Body Weight, Glucose Homeostasis, Endothelial Function, and Adipose Inflammation in Control and Type 2 Diabetic Mice
Authors: ZHANG HANRUI
Published: June 2024

Introduction: There is growing interest in the benefits of intermittent fasting for weight loss, glucose control, vascular protection, and mitigating chronic inflammation. Nonetheless, it remains unclear whether the metabolic and endothelial protective benefits depend on weight loss or anti-inflammatory effects.

Objective: Using type 2 diabetic (db/db) mice and the respective heterozygote controls, we aimed to determine whether alternate day fasting (ADF) provides metabolic benefits and endothelial protection, partially independent of its effects on weight control and adipose inflammation.

Methods: Mice were either allowed to eat ad libitum or placed on an ADF diet regimen for 12 weeks.

Results: In control mice, ADF led to significant reductions in body weight and insulin levels. There was a modest, though not statistically significant, decrease in blood glucose and HOMA-IR. In db/db mice, ADF significantly reduced blood glucose and HOMA-IR while not affecting body weight or insulin levels. This underscores the effects of ADF on improving glucose metabolism despite the absence of weight loss in diabetic mice. ADF improved endothelium-dependent vasorelaxation in small mesenteric arteries of db/db mice without altering endothelium-independent vasorelaxation or phenylephrine-induced vasoconstriction. In control mice, ADF exhibited a trend toward enhancing the maximal relaxation at 10-7 mol/L acetylcholine while not affecting endothelium-independent vasorelaxation or vasoconstriction. Despite the significant metabolic and endothelial protective benefits, ADF did not mitigate adipose inflammation in either control or db/db mice.

Conclusions: ADF's weight control, metabolic, endothelial protective, and anti-inflammatory benefits can manifest independently in diabetic and control mice. The results also imply the potential to explore ADF benefits in non-obese, healthy individuals.

Disclosure

H. Zhang: None.
2048-LB: Activation of Connexin Hemichannels and PGE2 Release in Osteocytes Reduce Global Adiposity and Improve Metabolic Homeostasis while Preserving Lean Mass
Authors: ACOSTA FRANCISCA M. , ZHANG JINGRUO , MOTA LINDA , MAKONAHALLI AMULYA , WANG XUEWEI , HERNANDEZ ELIZABETH , RIQUELME MANUEL A. , BREY ERIC , JIANG JEAN X.
Published: June 2024

Background: Research into signaling molecules for obesity therapies has largely overlooked the role of bone, particularly osteocytes (Ocy), which play crucial roles in biomechanical, inflammatory, & metabolic signaling. Connexin 43 (Cx43) hemichannels (HCs), abundant in Ocy, facilitate cellular communication. Research has shown these HCs, sensitive to mechanical cues, exchange molecules, such as prostaglandin E2 (PGE2), influencing bone quality and differentiation of adipose tissue (AT) & skeletal muscle (SkM).

Objective: Investigate the role of Ocy Cx43 HCs in mediating cross-organ regulation between AT & SkM in obesity.

Methods: In vivo we used transgenic mice with overexpression of Cx43 dominant negative mutants in Ocy: R76W (inhibited gap junctions (GJs), enhanced HCs) & Δ130-136 (inhibited HCs & GJs), or a monoclonal Cx43(M2) antibody that opens Cx43 HCs, ±high-fat diet, and in vitro, conditioned media (CM) collected from fluid flow-stimulated Ocy.

Results: Impaired HCs (Δ130-136) contributed to increased AT, while enhanced HC activity (R76W/M2) reduced it, resulting in improved energy expenditure and preservation of SkM/lean mass. This association was linked to Cx43 HC-mediated elevation in global PGE2 levels. Specifically, Δ130-136 mice exhibited up to an 8% increase in %fat and decrease in lean mass. Conversely, augmentation of HCs (R76W/M2) increased activity, food intake, & calorie expenditure, while mitigating up to a 4-fold increase in %fat & reducing weight (p=0.01), glucose, triglycerides, AT hypertrophy/whitening, & liver AT. Treatment with Ocy CM inhibited adipogenic differentiation of AT-derived stem cells, which was undone by CM from Ocy treated with a HC-blocking antibody.

Conclusion: These studies provide new insight into the role of Ocy Cx43 HC in metabolic health, through the regulation of AT/lean mass, and present it as a unique target for combatting obesity, with PGE2 being a major regulator.

Disclosure

J. Zhang: None. L. Mota: None. A. Makonahalli: None. X. Wang: None. E. Hernandez: None. E. Brey: None.

Funding

National Institutes of Health (F32DK134051), National Institutes of Health (AR072020), Welch Foundation (AQ-1507), and Clinical & Translational Research Pilot Grant Award from the Institute for Integration of Medicine & Science (IIMS) at UT Health San Antonio
2055-LB: Temporal Resolution of Single-Cell Transcriptomics and Epigenomics of Murine Pancreatic Islet in Diet-Induced Obesity
Authors: SINGH SIMRAN , PAVAN MUSALE KRUSHNA , BARELLA LUIZ F. , SHREE AJITA , ZAFAR HAMIM , WESS JÜRGEN , PRASAD PYDI SAI
Published: June 2024

Introduction: The escalating global prevalence of obesity has contributed significantly to the burgeoning incidence of type 2 diabetes (T2D). Despite major advancements in modern medicine, more effective therapies for treating obesity and T2D are needed. Pancreatic islets are the most dynamic endocrine organ with remarkable abilities to adapt to the dietary status. However, the transcriptional, epigenetic, metabolic, and cellular events that occur in pancreatic islets during the progression from a healthy state to insulin resistance and T2D are poorly characterized.

Objective: To address this issue, we took the advantage of single-cell omics and challenged mice with either regular and/or high-fat diet for different time intervals, to decipher the different molecular events associated with the progression of insulin resistance and diabetes. Method: To assess changes in gene expression in murine pancreatic islet cells, we used single-cell RNA and ATAC seq techniques during different degrees of obesity and insulin resistance.

Result: We identified subpopulations of alpha, beta, delta, gamma, endothelial, and immune cells and demonstrated commonalities and differences across murine and human species and dietary conditions. We found that different stages of obesity are associated with the trans-differentiation of endocrine cell types. Obesity led to dysregulated gene expression networks, including several metabolic and inflammatory pathways in a cell subtype-specific manner. Our findings also highlight the underappreciated role of endothelial islet cell in obesity across human and mouse population.

Conclusion: Our study provides a powerful resource for identification of heterogeneity across islet endocrine and non-endocrine populations during different states of obesity.

Disclosure

S. Singh: None. L.F. Barella: Employee; Kallyope. A. Shree: None. H. Zafar: None. J. Wess: None. S. Pydi: None.
2061-LB: Secreted EMC10 (scEMC10) Suppresses Thermogenesis in Brown Adipose Tissue via the Inhibition of PKA-CREB/p42 MAPK Signaling
Authors: WANG XUANCHUN , WANG YAHAO , LIU SHAN , ZHAN CHONGWEN , MIAO QING
Published: June 2024

Brown adipose tissue (BAT) plays a significant role in regulating energy metabolism, contributing to improved glucose homeostasis and reduced weight gain. We have shown Emc10 gene knockout or antibody neutralization of circulating scEMC10 prevent diet-induced obesity and its associated metabolic disorders in mouse via activation of BAT thermogenesis. In this study, we observed serum scEMC10 levels were significantly elevated by thermoneutrality, concomitant with suppression of active BAT in BAT-positive humans. Overexpression of scEMC10 promoted mouse diet-induced obesity via suppression of BAT thermogenesis, evidenced by reduced expression of UCP1 and PGC1α in BAT. scEMC10 overexpression also resulted in cold intolerance of HFD-fed mouse due to decreased levels of UCP1 and PGC1α in both epididymal adipose tissue and BAT, suggesting the involvement of scEMC10 in the sympathetic nervous system/norepinephrine-modulated BAT thermogenesis. Recombinant scEMC10 protein significantly suppressed CL 316243, a β3-adrenoceptor agonist, -induced expression of thermogenic (Ucp1, Pgc 1 ɑ, and Dio2) and lipolytic (Hsl and Atgl) genes via inhibiting PKA-CREB/p42 MAPK signaling in both cultured brown adipocyte in vitro and BAT in vivo. In conclusion, this work identifies scEMC10 exerts an inhibitory role in BAT thermogenesis via suppression of PKA-CREB/p42 MAPK signaling, and also suggests the inhibition of circulating scEMC10 will be a promising way to treat obesity and its related cardiometabolic diseases.

Disclosure

X. Wang: None. Y. Wang: None. S. Liu: None. C. Zhan: None. Q. Miao: None.

Funding

National Natural Science Foundation of China (81800691), Science and Technology Commission of Shanghai Municipality (22140902700).
2065-LB: Slug Regulates Adipogenesis and Adipose Tissue Growth
Authors: JU LIPING , KANG QIANQIAN , ZHOU RUOYU , ZHENG QIANTAO , RUI LIANGYOU
Published: June 2024

Adipose stem cell commitment, proliferation, and differentiation critically regulate adipose tissue development and homeostasis. Transcription factor Slug, also known as Snai2, is well known to promote epithelial-mesenchymal transition and cell motility. Slug also emerges as an important regulator of body weight and metabolism. In the hypothalamus, Slug promotes leptin resistance, leading to obesity. In the liver, hepatic Slug promotes de novo lipogenesis and fatty liver disease. In this study, we observed that Slug is expressed in adipose stromal vascular fraction cells (SVFs). SVFs contains adipose stem cells/preadipocytes. To determine the fate of Slug-expressing SVFs, we generated Slug-Cre and Slug-CreERT (tamoxifen-dependent) drivers. The drivers were crossed with Rosa26-mTmG or Rosa26-tdTomato reporter mice to generate Slug-expressing cell lineage-tracing models. The Slug-Cre based tracing paradigm revealed that Slug-expressing stem cells generate the majority of white adipocytes and brown adipocytes in mice. The Slug-CreERT models demonstrated that in adult mice, Slug-expressing SVFs play an important role in regulating adipose tissue regeneration and maintenance. To examine Slug function, we generated adipose stem cell-specific Slug knockout mice by crossing Slugf/f mice with PDGFRα-Cre drivers. Body weight was lower in Slug mutant mice relative to Slugf/f mice on a high fat diet (HFD). Likewise, whole body deletion of Slug also protected against HFD-induced obesity and insulin resistance. In conclusion, our results suggest that Slug directly regulates adipose stem cell behavior, adipogenesis, adipose growth, and adipose function.

Disclosure

L. Ju: None. Q. Kang: None. R. Zhou: None. Q. Zheng: None. L. Rui: None.
2078-LB: Effects of Obesity on Bladder Cancer and the Intervention Effect of Semaglutide
Authors: LIU YANHUI , CHEN SHUCHUN , BAN JIANGLI , LI ZELIN
Published: June 2024

Objective: Limited research has been conducted on the impact of semaglutide on bladder cancer in individuals with obesity. Hence, this study employed proteomics in conjunction with bioinformatics technology to demonstrate that semaglutide potentially operates through a mechanism that reduces the likelihood of bladder cancer among obese patients.

Methods: Thirty-six healthy male C57BL/6J mice were randomly divided into normal diet group (NCD group), high fat diet group (HFD group) and high fat diet group (Sema group). Serum indexes and SOD levels were measured, and tandem mass spectrometry combined with liquid chromatography-tandem mass spectrometry analysis was used to identify differentially expressed proteins. Bioinformatics technology was used to further analyze differentially expressed proteins, so as to explore the potential mechanism of semaglutide in reducing bladder cancer risk.

Result: In the obesity model induced by a high-fat diet, semaglutide administration resulted in decreased body weight, improved lipid profile, blood glucose levels, and enhanced antioxidant stress capacity in mice. Differential expression proteins (DEPs) were found in various cellular components such as cytoplasm, cell membrane, and nucleus. Biological processes (BPs) were enriched in fatty acid metabolism and regulation of response to external stimuli. Comparative analysis of gene expression revealed that Lama2, Lama4, Lamc1, and Thbs2 primarily participated in the extracellular matrix (ECM) pathway. Their expression was up-regulated in the high-fat group but down-regulated after treatment with semaglutide.

Conclusion: Semaglutide exhibits potential in ameliorating high-fat diet-induced obesity and delaying the onset and progression of bladder cancer. The involvement of Lama2, Lama4, Lamc1, Thbs2 in the extracellular matrix pathway may underlie semaglutide's mechanism of action against bladder cancer.

Disclosure

Y. Liu: None. S. Chen: None. J. Ban: None. Z. Li: None.
2082-LB: Heterogeneity in Adipose Progenitor (AP) Populations from Subcutaneous Abdominal and Thigh Adipose Tissues of Women
Authors: SUN YIFEI , SMITH GREGORY , ALBU JEANINE , WALSH MARTIN , FRIED SUSAN K.
Published: June 2024

Introduction & Objective: Lower body fat distribution decreases risk for T2D, but the mechanisms involved are poorly understood. The objective of this study was to compare AP populations of paired samples of upper body abdominal (A) vs lower body thigh (T) adipose tissues that may contribute to this association.

Methods: Single nuclei RNA sequencing (snRNASeq) identified AP subclusters (Seurat); bioinformatic and within subject statistical comparisons used pseudobulk analyses and paired ttest. Cell-Cell communication analysis (CellChat) addressed depot-dependent mechanisms tissue homeostasis.

Results: Healthy, premenopausal women in this study were n=7, BMI (28.7+/- 6.3 kg/m2), age 30 +/-5.5 y, waist to hip ratio 0.79 +/- 0.02 (mean ± SD). APs (6489 (A), 7194 (T)) in 9 subclusters varied in their degree of adipogenic commitment. An early AP population expressed higher levels of CD55 in A than T, and low MGP and AREG/F3. Two other ‘early’ AP clusters expressed the highest levels of anti-adipogenic factors, AREG/F3 AP were more abundant in T (9% vs 6%, p<0.007; 5.4 vs 3.7%, p=0.025). A small population (5%) of committed ‘preadipocytes’ was in both depots. Additional clusters had high expression of secreted adipokines and extracellular matrix factors and secretory pathways (Collagens, Lumicans). We found evidence for higher cell-cell communication in T (FGF-FGFR, IGF-IGFR1, PDGF-PDGFR).

Conclusion: Our results suggest that higher expression of anti-adipogenic factors in TSAT maintain a larger pool of APs that can respond to pro-adipogenic signals, as needed, to better preserve tissue and systemic metabolic homeostasis in response to a stress (e.g. obesity).

Disclosure

Y. Sun: None. G. Smith: None. J. Albu: None. M. Walsh: None. S.K. Fried: None.

Funding

National Institutes of Health (R01DK121547)
2083-LB: Effect of 8-Hour Time-Restricted Eating vs. Daily Calorie Restriction on Sleep in Adults with Type 2 Diabetes
Authors: PAVLOU VASILIKI , CIENFUEGOS SOFIA , LIN SHUHAO , CLAIRE RUNCHEY MARY , VARADY KRISTA
Published: June 2024

Objective: This study compared the effect of 8-h time-restricted eating (TRE) versus calorie restriction (CR) and a no-intervention control (CON) group on body weight and sleep in adults with obesity and type 2 diabetes (T2D).

Methods: Adults with obesity and type 2 diabetes (n = 75) were randomized to 1 of 3 interventions for 6 months: 8-h TRE (ad libitum eating between 12:00 to 8:00 pm, water fasting between 8:00 to 12:00 pm); CR (25% energy restriction daily); or control (ad libitum food intake with no meal timing restrictions).

Results: Seventy-five participants were enrolled (mean [SD] body mass index, 39 [7]; age, 55 [12] years; 53 [71%] female; HbA1c level 8.1% [1.6%]). By month 6, body weight decreased significantly (P < 0.003) in the TRE group (−3.56% [95% CI, −5.92% to −1.20%]; P = .004) but not the CR group (−1.78% [95% CI, −3.67% to 0.11%]; P = .06), relative to controls. Levels of HbA1c decreased in the TRE (−0.91% [95% CI, −1.61% to −0.20%]) and CR (−0.94% [95% CI, −1.59% to −0.30%]) groups, relative to controls, with no differences between the TRE and CR groups. The morning eveningness questionnaire (MEQ) was used to assess the participants’ chronotypes. The MEQ scores were 58 ± 7 for TRE, 55 ± 9 for CR and 54 ± 10 for the control group at baseline, which corresponds to an intermediate chronotype for all groups. Sleep quality, measured by the Pittsburgh Sleep Quality Inventory (PSQI), did not change in the TRE group (baseline: 7.6 ± 3.2; month 6: 7.4 ± 3.2), CR group (baseline: 8.2 ± 3.4; month 6: 7.0 ± 2.8), versus controls (baseline: 9.4 ± 3.8; month 6: 9.0 ± 4.4). Wake time, bedtime, sleep duration, and insomnia severity did not change (no group x time interaction) over the course of the study in any group.

Conclusions: These findings suggest that the weight loss induced by TRE and CR has no effect on sleep quality, duration, or insomnia severity in adults with obesity and type 2 diabetes.

Disclosure

V. Pavlou: None. S. Cienfuegos: None. S. Lin: None. M. Runchey: None. K. Varady: None.

Funding

Department of Kinesiology and Nutrition, University of Illinois Chicago, and National Institutes of Health (R01DK128180 and T32DK128782).
2093-LB: Aging and Beta-Cell Function
Authors: JANKAUSKAS STANISLOVAS , NIEVES GARCIA CRYSTAL , KANSAKAR URNA , GAMBARDELLA JESSICA , MONE PASQUALE , TOMER YARON , SANTULLI GAETANO , LOMBARDI ANGELA
Published: June 2024

Introduction and Objective: Alterations of glucose homeostasis and insulin secretory capacity increase with age and represent leading causes of morbidity and mortality. In order to prevent and/or improve diabetes-associated ailments of the pancreatic beta cell during aging we propose to leverage the therapeutic properties of ketone bodies. Specifically, a functional role as key signaling molecule is increasingly acknowledged for beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body.

Methods: The effects of BHB on metabolic fitness have been tested: 1) in vivo in 18-month-old C57BL/6J mice fed with a standard or BHB-enriched diet for 6 months; 2) ex vivo in murine islets isolated from aging mice fed with standard or BHB diet 3) ex vivo in islets isolated from brain-dead aging donors treated or not with BHB.

Results: In our preliminary studies, we found that 18-month-old C57BL/6J mice fed with a BHB-enriched diet for 6 months displayed a significantly ameliorated response to GTT compared to sex and age-matched mice fed with standard diet. Furthermore, BHB treatment increased islet yield protecting pancreatic islets from apoptosis and oxidative stress. We also observed an impaired glucose stimulated insulin secretion in islets isolated from old mice fed with standard diet and from aging donors that was significantly reduced by BHB in both systems. Moreover, BHB preserved mitochondrial membrane potential, attenuated the impaired mitochondrial respiration and mitochondrial fragmentation and rescued mitochondrial biogenesis during aging. Finally, BHB significantly increased mitophagy in aging murine and human islets after treatment with BHB, compared with control islets; confirming its pivotal role in the modulation of mitochondrial fitness.

Conclusion: In this study we produced compelling evidence that mitochondrial alterations represent a targetable molecular signature in aging beta cells and that ketone bodies are potentially useful to address age-related beta cell dysfunction.

Disclosure

S. Jankauskas: None. C. Nieves Garcia: None. U. Kansakar: None. J. Gambardella: None. P. Mone: None. Y. Tomer: None. G. Santulli: None. A. Lombardi: None.