bluuebunny/crossref_metadata_2025_split huggingface dataset:
251-OR: COIN2DOSE—Proof of Concept That a Behavioral Economics Intervention Can Increase Mealtime Insulin Use in Adolescents with Type 1 Diabetes
Authors: PATTON SUSANA R. , LOCKEE BRENT , MORGA KRISTEN , MCDONOUGH RYAN , FOX LARRY A. , CLEMENTS MARK A. 
Published: June 2024

Many adolescents with type 1 diabetes (T1D) miss or skip mealtime insulin boluses, contributing to higher glycated hemoglobin (HbA1c). We designed a novel mHealth intervention, called COIN2DOSE, that uses behavioral economics theories to promote mealtime insulin use among adolescents. Here, we present preliminary data evaluating COIN2DOSE. We enrolled 10 adolescents with T1D in a 12-week mHealth intervention that included weekly data sharing and automated remote patient monitoring via a digital dashboard. Adolescents earned money (up to $1.50/day or $15.50/week) based on their daily mealtime BOLUS score, a valid measure of insulin use during predetermined meal windows. Parents and adolescents completed surveys assessing diabetes distress and diabetes family conflict and adolescents completed a valid HbA1c home kit pre- and post-treatment. We measured treatment satisfaction post-treatment. Adolescents were [mean±SD] 13.4±1.01 years old, 50% boys, 80% Non-Hispanic White, 100% using a personal continuous glucose monitor (CGM), 60% using hybrid closed loop (HCL), and 40% using standard open pump therapy (open pump). Daily BOLUS scores increased from 1.50±1.10 to 2.14±0.72 (p=0.053) pre- to post-treatment. Mean HbA1c decreased from 8.8±2.8% to 8.2±1.6% for adolescents on HCL and increased slightly for adolescents on open pump (7.1±1.6 and 7.3±1.6%). We found no changes in parent- and adolescent-reported diabetes distress and parent-reported diabetes family conflict, though adolescent-reported diabetes family conflict decreased (p&lt;0.01). Parent- and adolescent-reported satisfaction with COIN2DOSE was moderately high. We provide proof of concept that COIN2DOSE and its supporting technology can promote mealtime insulin use, achieve reductions in adolescent-reported diabetes family conflict, and clinically reduce HbA1c in adolescents with T1D.

Disclosure
S.R. Patton: None. B. Lockee: None. K. Morga: None. R. McDonough: Speaker's Bureau; Provention Bio, Inc. L.A. Fox: Advisory Panel; Ki Health. Research Support; Dexcom, Inc. M.A. Clements: Research Support; Abbott. Consultant; Glooko, Inc. Research Support; Dexcom, Inc.

Funding
National Institutes of Health (R01DK128862)
254-OR: Sleep Disturbance and Diabetes Symptom Burden in Young Adults with Type 1 Diabetes
Authors: GRIGGS STEPHANIE , HOWARD QUIANA , HICKMAN RONALD 
Published: June 2024

Introduction: Sleep disturbance including difficulty initiating or maintaining sleep (insomnia symptoms) are associated with diabetes symptoms, precursors to micro-and macrovascular complications, among young adults with type 1 diabetes (T1D). About 50% of young adults develop vascular complications; however, modifiable contributors of diabetes symptoms are understudied in this population. Therefore, the purpose of this quantitative descriptive study was to determine the associations between sleep disturbance and diabetes symptom burden in young adults with T1D.
Methods: Baseline data from two longitudinal cohorts of young adults aged 18 to 26 years with T1D (61.3% female, 81.2% Non-Hispanic White) were analyzed. Sleep disturbance was measured with the 19-item Pittsburgh Sleep Quality Index, insomnia symptoms with the 7-item Insomnia Severity Index, and diabetes symptom burden with the 34-item Diabetes Symptom Checklist Revised. Associations were analyzed using multivariable linear and logistic regression models adjusted for age, race, sex at birth, T1D duration, and insulin pump use.
Results: Higher sleep disturbance and higher insomnia symptom severity were associated with a higher diabetes symptom burden even after considering covariates in the linear regression models. In logistic regression models, those with significant insomnia symptoms had 4 times higher odds of a high diabetes symptom burden in the unadjusted and adjusted models. Those with high sleep disturbance had 2.6 times higher odds of a high diabetes symptom burden; however, the association was no longer significant after adjusting for covariates.
Conclusion: Reducing sleep disturbance including difficulty initiating or maintaining sleep may alleviate the burden of diabetes symptoms among young adults with T1D.

Disclosure
S. Griggs: None. Q. Howard: None. R. Hickman: None.

Funding
National Institutes of Health (R00NR018886)
272-OR: Effect of 48 Months of Closed-Loop Insulin Delivery on Residual C-Peptide Secretion and Glycemic Control in Newly Diagnosed Youth with Type 1 Diabetes
Authors: WARE JULIA , BOUGHTON CHARLOTTE K. , ALLEN JANET M. , WILINSKA MALGORZATA E. , HARTNELL SARA , THANKAMONY AJAY , RANDELL TABITHA , BESSER RACHEL , GHATAK ATRAYEE , ELLERI DANIELA , TREVELYAN NICOLA , CAMPBELL FIONA , SIBAYAN JUDY , BAILEY RYAN , CALHOUN PETER , DUNSEATH GARETH J. , HOVORKA ROMAN , CONSORTIUM CLOUD 
Published: June 2024

Background: We evaluated the effect of long-term intensive metabolic control with hybrid closed loop on residual C-peptide secretion and glucose control compared to standard insulin therapy in youth with type 1 diabetes over 48 months.
Methods: Following the 24 month primary phase of a multicentre, randomised, parallel trial of 96 newly diagnosed youth aged 10-16.9 years, participants entered an extension phase using either hybrid closed-loop with Cambridge algorithm (CL) or standard insulin therapy (control) until 48 months post diagnosis. Analysis was intention-to-treat.
Results: At 24 months after diagnosis, 81 participants (mean±SD age 12±2 years) continued in the extension (47 CL). There was no difference in fasting C-peptide corrected for fasting glucose at 48 months between groups (CL: 0.3±0.5 vs control: 0.3±0.8pmol/L per mg/dL; mean adjusted difference ‑0.1 [95% CI ‑0.4, 0.2; p=0.54]). Central lab HbA1c remained lower in CL group by 10mmol/mol [0.9%] (95% CI 3, 17 [0.2, 1.5%]; p=0.01) at 48 months. Eleven severe hypoglycaemic events (6 CL, 5 control) and seven DKA occurred (3 CL, 4 control).
Conclusions: Improved glycaemic control was sustained over 48 months after diagnosis with closed loop insulin delivery compared to standard therapy in youth with type 1 diabetes. This did not appear to confer a protective effect on residual C-peptide secretion.

Disclosure
J. Ware: Other Relationship; Novo Nordisk, Ypsomed AG. C.K. Boughton: Consultant; CamDiab. Speaker's Bureau; Ypsomed AG. J.M. Allen: None. M.E. Wilinska: Consultant; CamDiab. S. Hartnell: Speaker's Bureau; Ypsomed AG. Employee; CamDiab. A. Thankamony: None. T. Randell: Consultant; Abbott. Speaker's Bureau; Novo Nordisk. R. Besser: Advisory Panel; Provention Bio, Inc. Speaker's Bureau; Medscape, Health Partners Institute. A. Ghatak: None. D. Elleri: None. N. Trevelyan: None. F. Campbell: None. J. Sibayan: None. R. Bailey: None. P. Calhoun: None. G.J. Dunseath: None. R. Hovorka: Other Relationship; CamDiab. Research Support; Abbott, Dexcom, Inc., Ypsomed AG. Speaker's Bureau; Ypsomed AG, Abbott, Novo Nordisk, Novartis Pharmaceuticals Corporation.

Funding
NIHR EME (14/23/09); Helmsley Trust (2016PG-T1D045 and 2016PG-T1D046); JDRF (22-2013-266 and 2-RSC-2019-828-M-N); National Institute for Health Research Cambridge Biomedical Research Centre
274-OR: Population-Scale Single-Nucleus Skeletal Muscle Chromatin Dynamics and Nucleosome Positioning in the Context of Type 2 Diabetes
Authors: WANG XIAOOU , ROBERTSON CASSIE , VARSHNEY ARUSHI , MANICKAM NANDINI , ORCHARD PETER , LAAKSO MARKKU , TUOMILEHTO JAAKKO , LAKKA TIMO A. , MOHLKE KAREN L. , BOEHNKE MICHAEL , SCOTT LAURA , KOISTINEN HEIKKI A. , COLLINS FRANCIS S. , PARKER STEPHEN 
Published: June 2024

Motivation: Insulin resistance in skeletal muscle plays a central role in the development of type 2 diabetes (T2D). T2D genome-wide association studies (GWAS) have nominated &gt; 600 signals potentially linked to cell type-specific regulatory processes, with most lying in the non-coding region. Studying the genetic regulation of local chromatin patterns in muscle fibers can provide mechanistic insights into T2D GWAS hits. Here, we employ population-scale single-nucleus ATAC-sequencing (snATAC) to better understand T2D mechanisms.
Methods: Leveraging snATAC profiles from 281 individuals, we used statistical models to infer nucleosome positioning and nucleosome-free regions (NFR). We then combined genetic variation with chromatin accessibility patterns to identify cis-quantitative trait loci (QTL) for both NFR (nfrQTL) and nucleosome positioning (nucQTL) globally and at T2D-related trait GWAS signals.
Results: We identified 14,417 nfrQTLs and 19,265 nucQTLs (5% FDR) in type 1 muscle fibers. NfrQTLs were significantly enriched to overlap T2D and fasting insulin signals (P &lt; 0.005). Colocalization analyses revealed that 5,890 pairs of nfr- and nucQTLs contained shared causal variants. Furthermore, mediation analyses revealed that at 765 pairs of colocalized nfr&nucQTLs, genetic variant(s) regulated the nucleosome positioning through NFRs and 65 pairs with the reverse direction (5% FDR). Notably, 25 nfrQTLs colocalized with T2D GWAS signals. Interestingly, signals at FARSA and PLEKHA1 colocalized with both nfr- and nucQTLs, and the nfrQTLs were causal on the nucQTLs. These findings imply that genetic variants in these GWAS signals regulate the NFR's position, which subsequently influences nucleosome positioning.
Conclusion: These results provide single-nucleus resolution mechanistic hypotheses for local chromatin dynamics in skeletal muscle, providing significant insights into T2D therapeutic strategies involving NFRs.

Disclosure
X. Wang: None. C. Robertson: None. A. Varshney: None. N. Manickam: Employee; 10x Genomics. P. Orchard: None. M. Laakso: None. J. Tuomilehto: Stock/Shareholder; Orion Pharma, Aktivolabs, Digostics. T.A. Lakka: None. K.L. Mohlke: None. M. Boehnke: None. L. Scott: None. H.A. Koistinen: Other Relationship; AstraZeneca, Novo Nordisk. F.S. Collins: None. S. Parker: Research Support; Pfizer Inc.
28-OR: Posttranslational Modifications in Skeletal Muscle Direct Divergent Metabolic Responses to Different Exercise Training Modes
Authors: PATAKY MARK W. , HEPPELMANN CARRIE J. , SEVITS KYLE , ASOKAN ANEESH K. , KLAUS KATHERINE , SREEKUMARAN NAIR K. 
Published: June 2024

Different exercise modes yield distinct metabolic outcomes, yet the underlying molecular mechanisms driving these exercise responses remain unclear. Here, we investigated the impact of post-translational modifications (PTM) to skeletal muscle proteins in response to 3 months of high intensity aerobic interval training (HIIT) and resistance exercise training (RT). Frozen muscle biopsy tissue was obtained from a sub-cohort of our previously published study which showed significantly enhanced insulin sensitivity following either HIIT (n=7) or RET (n=7). After digestion, peptides were isobarically labeled and either acetyl- or phospho-enriched and fractionated by high-performance liquid chromatography (HPLC). Mass spectra were measured using a Thermo Fusion Tribrid coupled to Ultimate 3000 HPCL, revealing global-, phospho-, and acetyl-proteomic responses in muscle to HIIT or RT. Reactome analysis was used to determine exercise-regulated PTM pathways. HIIT significantly (p-value &lt;0.05, fold-change ≥ 0.3) increased the abundance of ~9% of the global proteome (444 proteins) and ~22% of the acetylproteome (504 peptides), with primarily global and acetyl modifications occurring on mitochondrial pathways. HIIT also significantly (P &lt; 0.05) increased the abundance of the deacetylase, SIRT3, which was positively associated with mitochondrial respiration. RT significantly (p-value &lt;0.05, fold-change ≥ 0.3) altered the abundance of ~3% of the global proteome (144 proteins) and ~7% of the phosphoproteome (817 peptides), with minimal effect on the acetylproteome (~1%). RT primarily regulated contractile function and muscle structure pathways. These results indicate that the divergent metabolic responses to HIIT or RT are related to differential PTM mechanisms that contribute to cardiometabolic outcomes.

Disclosure
M.W. Pataky: None. C.J. Heppelmann: None. K. Sevits: None. A.K. Asokan: None. K. Klaus: None. K. Nair: None.

Funding
NIH (R01AG062859); NIH (T32DK007352)
293-OR: Improvement of Tissue-Specific Insulin Sensitivity after Bariatric Surgery Does Not Restore Hepatic OXPHOS Capacity
Authors: KAHL SABINE , PUETZER-FURMANCZAK JENNIFER , TRINKS NINA , DEWIDAR BEDAIR , PAFILI KALLIOPI , TRENKAMP SANDRA , ESPOSITO IRENE , SCHLENSAK MATTHIAS , GRANDERATH FRANK A. , RODEN MICHAEL 
Published: June 2024

Common insulin resistance relates to positive energy balance and is central to obesity, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). In early MASLD, the liver adapts to increased energy supply by upregulating its oxidative phosphorylation (OXPHOS) capacity (mitochondrial plasticity), which is lost during MASLD progression and in type 2 diabetes. This study examined whether improvements in insulin sensitivity after bariatric surgery restore hepatic mitochondrial plasticity and thereby ameliorate liver histology. Persons with insulin resistance and obesity (n=16, BMI 52±8 kg/m2; HbA1c 5.5±0.1%) underwent bariatric and follow-up surgeries, at which liver biopsies were taken. MASLD was assessed histologically. Hepatic maximal ADP-stimulated respiration, reflecting OXPHOS capacity, was measured by high-resolution respirometry, tissue-specific insulin sensitivity by hyperinsulinemic-euglycemic clamps with 2H2-glucose. Mean body weight loss (-48.5 kg over 0.5-5 years) increased whole-body (stimulated glucose disposal) as well as hepatic (suppressed endogenous glucose production) insulin sensitivity by 57 and 32% (both p&lt;0.05), respectively. Fasting adipose tissue insulin resistance (Adipo-IR) decreased by 61% (p=0.005). Steatosis grade decreased in all participants, whereas lobular inflammation and ballooning did not uniformly change after surgery. Hepatic mitochondrial DNA (mtDNA) content slightly rose (p=0.02), whereas OXPHOS capacity remained unchanged for TCA cycle- and β-oxidation-linked respiration upon normalization for both tissue wet weight and mtDNA.
In conclusion, bariatric surgery led to robust improvements in whole-body, hepatic and adipose tissue insulin sensitivity as well as hepatic steatosis. However, the failure to restore hepatic mitochondrial plasticity and to reverse inflammation indicates the need for novel mitochondria-targeted concepts for MASLD treatment.

Disclosure
S. Kahl: None. J. Puetzer-Furmanczak: None. N. Trinks: None. B. Dewidar: None. K. Pafili: None. S. Trenkamp: None. I. Esposito: None. M. Schlensak: None. F.A. Granderath: None. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; TARGET PharmaSolutions, Inc. Speaker's Bureau; AstraZeneca.

Funding
German Federal Ministry of Health (BMG); Ministry of Culture and Science of the State North Rhine-Westphalia (MKW NRW) to DDZGerman Federal Ministry of Education and Research (BMBF) to German Center for Diabetes Research (DZD e. V.). HORIZON-HLTH-2022-STAYHLTH-02-01: Panel A to the INTERCEPT-T2D consortium EUREKA Eurostars-2 (E!-113230-DIA-PEP)German Science Foundation (DFG; SFB/CRC1116, RTG/GRK 2576) Schmutzler-Stiftung "Profilbildung 2020"
298-OR: Precision-Engineered Activin and GDF Ligand Trap HS235—A Novel Lean Mass–Preserving Treatment for Obesity
Authors: SCHANG GAUTHIER , DE MOLLIENS MATHILDE , BRÛLÉ EMILIE , SOURS ARIANE , DENIS JEAN-FRANCOIS , CHAUVET CRISTINA , GANESH VANN , TREMBLAY GILLES , SCHOELERMANN JULIA , O'CONNOR MAUREEN 
Published: June 2024

Introduction: Incretin mimetics have revolutionized the pharmacotherapy of obesity leading to unprecedented weight loss and improvement of cardiometabolic health. However, incretins reduce body mass in a non-selective manner. In obese patients treated with incretins, undesirable loss of lean body mass (LBM) can account for up to 40% of overall weight loss. Loss of LBM negatively impacts resting metabolic rate, leading to a weight loss plateau and often unsustainable results. LBM preservation is a desirable treatment goal for obesity pharmacotherapy and overall cardiometabolic health. Activins and growth differentiation factors (GDFs), members of the TGF-beta superfamily, are validated targets controlling body composition and metabolism. Specific and selective blockade of activins and GDFs represents a novel anti-obesity treatment strategy which can act orthogonally to incretins. HS235 is an activin receptor ectodomain-based Fc-fusion protein that has been rationally designed to attain optimal inhibition of ligands controlling body composition in obesity.
Methods: To validate the anti-obesogenic potential of HS235, diet-induced obese (DIO) mice were injected with HS235, an incretin mimetic, or a combination of both. Fat mass, LBM, muscle weights, and biomarker readouts were assessed at the end of study.
Results: In DIO mice, HS235 and the incretin mimetic significantly improved metabolic parameters and decreased fat mass, but only HS235 increased LBM, while incretin-based treatment led to LBM loss. Importantly, the addition of HS235 to the incretin mimetic lead to a synergistic fat mass loss and prevented loss of LBM.
Conclusion: Potent and selective inhibition of activins and GDFs by HS235 represents a novel LBM preserving weight loss strategy orthogonal to incretin mimetics. This data supports the development of HS235 as a novel anti-obesity agent to complement currently approved incretin-based medications to improve quality of weight loss.

Disclosure
G. Schang: Employee; 35Pharma. M. De Molliens: Employee; 35Pharma. E. Brûlé: Employee; 35Pharma. A. Sours: Employee; 35Pharma. J. Denis: Employee; 35Pharma. C. Chauvet: Employee; 35Pharma. V. Ganesh: Employee; 35Pharma. G. Tremblay: Employee; 35Pharma. J. Schoelermann: Employee; 35Pharma. M. O'Connor: Employee; 35Pharma.
31-PUB: Efficacy and Safety of Sodium–Glucose Cotransporter 2 Inhibitors (SGLT2i) vs. Dipeptidyl Peptidase 4 Inhibitor (DPP4i) as Initiator Therapy with Type 2 Diabetes on Cardiovascular Outcomes—A Systematic Review and Meta-analysis
Authors: SHRESTHA ABHIGAN B. , RAJAK KRIPA , TUMMALA NAYANIKA , RESEARCH HUB MEDICAL , MADDINENI GAUTAM 
Published: June 2024

Introduction & Objective: SGLT2i are recommended for the treatment of heart failure due to their cardioprotective effects, despite primarily being used as antidiabetic medications. However, the comparative profile of SGLT2i with DPP4i remains unclear. This study aims to compare the efficacy and safety of SGLT2is versus DPP4is as initial therapy in older adults with type 2 diabetes.
Methods: A comprehensive search was conducted in PubMed, EMBASE, ScienceDirect, Google Scholar, and Cochrane Central using appropriate Mesh terms from inception until February 23, 2023. The outcomes were pooled using a random-effects model for Hazard ratio (HR) with a 95% confidence interval. A p-value of &lt;0.05 was considered statistically significant.
Results: 12 studies were included after systematic screening, with a sample size of 745,688 for SGLT2is and 769,386 for DPP4is. The mean age in each group was 61.1 (8.52) and 61.28 (9.25) years, respectively. Upon pooling the included articles with SGLT2i versus DPP4i, the primary outcome of all-cause death demonstrated an HR of 0.64 [0.57, 0.70], I2: 65.54%, p&lt;0.001, and major adverse cardiovascular events (MACE) yielded an HR of 0.76 [0.65, 0.86], I2: 87.83%, p&lt;0.001. The secondary outcomes included myocardial infarction with an HR of 0.84 [0.78, 0.90], I2: 47.64%, p&lt;0.001, stroke with an HR of 0.81 [0.75, 0.87], I2: 36.78%, p&lt;0.001, and Hospitalization with an HR of 0.62 [0.53, 0.70], I2: 83.32%, p&lt;0.001.
Conclusion: Our findings suggest that compared to DPP4is, initiating treatment with SGLT2is provides cardiovascular disease protection and can be considered for use in patients with type 2 diabetes.

Disclosure
A.B. Shrestha: None. K. Rajak: None. N. Tummala: None. G. Maddineni: None.
317-OR: Identification of Genetic Regulators of Circulating Biomarkers of Kidney Decline in Diabetes
Authors: STUCKI DEVORAH , SATAKE EIICHIRO , KROLEWSKI ANDRZEJ , PEZZOLESI MARCUS G. 
Published: June 2024

Background: Over the past decade, major progress has been made in identifying predictors of kidney disease progression in patients with diabetes mellitus (DM). Despite this progress, however, a key feature that has yet to be considered in current prognostic models, and one that is critical toward implementing Precision Medicine and Precision Diagnostics in diabetic kidney disease (DKD), is the contribution of genetic factors on the levels of these biomarkers. To advance this area, we set out to define the genetic drivers of circulating biomarkers of kidney disease progression in individuals with diabetes.
Methods: Leveraging genetic and proteomic data from 3,267 participants with diabetes from the UK Biobank Pharma Proteomics Project (UKB-PPP), we performed genome-wide association study (GWAS) analyses using REGENIE, adjusting for age, gender, BMI, and principal components, and biomarker data for 21 Joslin Kidney Panel (JKP) biomarkers measured on the OLINK Explore 3072 platform.
Results: We identified genome-wide significant (p-value &lt; 5x10-8) cis-protein quantitative trait loci (pQTLs) at 12 of the 21 JKP biomarkers (57%). In total, 1,855 SNPs achieved genome-wide significance across these 12 cis-pQTLs. The strongest association was observed at rs13278062 (p-value = 1.25x10-54) with TNFRSF10A protein levels. In addition to cis-pQTLs, we also identified genome-wide significant trans-pQTLs for 4 JKP biomarkers. Colocalization of transcriptomic and epigenomic data nominate 237 putative regulatory SNPs across the 12 cis-pQTLs.
Conclusion: Our results indicate that genetic variation (both cis and trans) is associated with circulating levels of the majority of JKP biomarkers (14/21, 67%) and suggest that incorporating information on genetic regulators (i.e., genetic-biomarkers) of protein-biomarkers of kidney disease progression in prognostic models may further improve risk stratification in DKD.

Disclosure
D. Stucki: None. E. Satake: None. A. Krolewski: None. M.G. Pezzolesi: None.

Funding
American Diabetes Association (11-22-ICTSPM-09)