bluuebunny/crossref_metadata_2025_split huggingface dataset:
211-OR: Dual Amylin and Calcitonin Receptor Agonists Increase Mitochondrial Respiratory Capacity in Adipose Tissues of Obese Rat
Authors: PETERSEN EMILIE A. , BLOM IDA , MELANDER SIMONE A. , KARSDAL MORTEN A. , LARSEN STEEN , HENRIKSEN KIM , LARSEN ANNA T. 
Published: June 2023

Dual amylin and calcitonin receptor agonists (DACRAs) are potential therapeutic candidates for treatment of obesity. Preclinical studies have shown favorable effects of DACRAs on appetite regulation contributing to a reduction in body weight. Interestingly, the DACRA-induced effects on weight loss are superior to the effects of a suppressed food intake, suggesting an effect on energy expenditure potentially by targeting the mitochondria.
We investigated the effects of long-term treatment with a class of DACRAs, namely KBPs, on body weight, food intake and mitochondrial respiratory capacity (MRC) in Sprague-Dawley rats fed a high-fat diet and treated s.c. with KBPs for 8 weeks. Moreover, a pair-fed (PF) group was used to examine food intake-independent effects of KBPs on MRC. At study end, MRC was analyzed in perirenal (pAT) and inguinal (iAT) adipose tissue using high resolution respirometry.
Expectedly, KBP treatment significantly reduced body weight compared to PF and vehicle. PF was successfully KBP-matched in terms of accumulated food intake and the food intake was significantly lower than that of vehicle-treated rats. Coupled and uncoupled MRC supported by complex I+II substrates and fatty acids were significantly greater in iAT and pAT after KBP treatment indicating effects on both carbohydrate and lipid metabolism. Additionally, an increased oligomycin-induced leak-respiration was found to be independent of food intake in iAT. Further analysis will shed light on whether these changes in MRC are a result of an increased mitochondrial content or of the respiratory capacity of each mitochondrion.
In conclusion, treatment with KBPs in obese rats is associated with an increased MRC in pAT and iAT and elicits effects additional to those obtained by diet-induced weight loss. This highlights DACRAs’ potential as anti-obesity agents with possible benefits on energy expenditure as a contributing cause to the DACRA-induced weight loss.

Disclosure
E.A.Petersen: Employee; Nordic Bioscience A/S. I.Blom: None. S.A.Melander: None. M.A.Karsdal: Speaker's Bureau; Pfizer Inc. S.Larsen: None. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S. A.T.Larsen: Employee; Nordic Bioscience A/S.

Funding
Innovation Fund Denmark
213-LB: Impact of Alpha- and Beta-Cell Dysfunction on the Longitudinal Progression to Type 2 Diabetes
Authors: SUBRAMANIAN VIJAYA , SHERMAN ARTHUR 
Published: June 2023

T2D results from glucotoxicity-driven impairment of insulin secretion which limits compensation for increased insulin demand. Increased demand results from insulin resistance and elevated hepatic glucose production (HGP). Increased HGP can result either from insulin resistance or alpha-cell dysregulation leading to hyperglucagonemia.
Objectives: To investigate with a mathematical model whether increased HGP and progression to T2D could result from impaired glucagon secretion in addition to insulin resistance. Toward this end, we developed a realistic model of beta-cell growth, death and function and interfaced it with a previously validated model of glucose-insulin-glucagon dynamics.
Methods: A previously published model of longitudinal progression to T2D over years was extended to include glucagon dynamics. The beta cell mass/function equation was parametrized by interfacing with results from a previously published paper on modeling isoglycemic, intravenous glucose infusion tests to obtain snapshots of the metabolic state. The range of parameters observed in the cohort studied cover the gamut from normal, insulin sensitive to normal, insulin resistant to T2D patients, and was used to calibrate the model. The influence of insulin resistance and impaired glucagon secretion as they develop over time was included in the combined model to see how they impact the balance between enhanced and impaired beta-cell function and mass.
Results and Conclusion: When only insulin sensitivity was allowed to decrease, the normal subjects did not transition to T2D. This was because the glucose levels were not elevated sufficiently to upset the balance between enhancement and impairment and lead to a catastrophic decline in insulin secretion. Including time-dependent impairment of glucagon suppression, in addition to declining insulin sensitivity, was sufficient to lead to the significant imbalance required to progress to T2D diabetes. Thus, both appear to be required.

Disclosure
V. Subramanian: None. A. Sherman: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK131328)
216-LB: Genetic Influences on Beta-Cell Function before Type 1 Diabetes Diagnosis
Authors: TRIOLO TAYLOR M. , PARIKH HEMANG M. , TOSUR MUSTAFA , FERRAT LAURIC A. , YOU LU , GOTTLIEB PETER , ORAM RICHARD A. , ONENGUT-GUMUSCU SUNA , KRISCHER JEFFREY , RICH STEPHEN S. , STECK ANDREA , REDONDO MARIA J. 
Published: June 2023

Autoimmune loss of beta-cell function (measured by C-peptide) is the hallmark of type 1 diabetes (T1D) targeted by interventions that aim to prevent T1D or its progression after onset. We sought to determine whether T1D genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms (SNPs) that have been previously associated with C-peptide preservation after T1D diagnosis (e.g., SNPs in CLEC16A, G6CP2, INS, JAZF1, PTPN22, SLC30A8 and TCF7L2) influence C-peptide levels before diagnosis.
We studied islet autoantibody (Ab)-positive participants in the TrialNet Pathway to Prevention Study who had T1DExomeChip data and assessed the influence of these 12 SNPs and the T1D-GRS2 on area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted between 0-9 months prior to the diagnosis of T1D. Participants (n=702) had a mean age of 13.5±10.3 years, 47% were female, mean BMI was 20.7±6.0 kg/m2, and mean HbA1c 5.4±0.4%. The T1D high-risk HLA-DR3-DQ2 haplotype was present in 47% and the high-risk HLA-DR4-DQ8 haplotype was present in 67% of participants. We performed univariate and multivariate analyses adjusting for BMI, age, sex, number of positive Ab, and the first 3 principal components of ancestry.
A higher T1D-GRS2 was associated with lower C-peptide AUC 0-9 months prior to T1D diagnosis in univariate (β=-0.06, P&lt;0.0001) and multivariate (β=-0.03, p=0.008) analyses. Participants with the JAZF1 rs864745 G allele had lower C-peptide AUC 0-9 months prior to T1D diagnosis in univariate (β=-0.10, p=0.003) and multivariate (β=-0.05, p=0.047) analysis.
In conclusion, the JAZF1 rs864745 G allele (which has also been associated with type 2 diabetes risk) and higher T1D-GRS2 predict lower C-peptide AUC prior to the diagnosis of T1D. Studies on their effect on response to trials to prevent or delay T1D onset are warranted.

Disclosure
T. M. Triolo: None. S. S. Rich: None. A. Steck: None. M. J. Redondo: None. H. M. Parikh: None. M. Tosur: Advisory Panel; Provention Bio, Inc. L. A. Ferrat: Consultant; Johnson & Johnson. L. You: None. P. Gottlieb: Advisory Panel; ViaCyte, Inc., Board Member; ImmunoMolecular Therapeutics, Research Support; Imcyse, Hemsley Charitable Trust, Novartis, National Institute of Diabetes and Digestive and Kidney Diseases, Precigen, Inc., Dompé, Nova Pharmaceuticals, Provention Bio, Inc. R. A. Oram: Consultant; Janssen Research & Development, LLC, Research Support; Randox R & D. S. Onengut-gumuscu: None. J. Krischer: None.

Funding
National Institutes of Health (R01DK121843, R01DK124395)
217-OR: The Supporting Emerging Adults with Diabetes (SEAD) Program—An Adult-Based Clinical Model That Improves Glycemic Control and Diabetes Technology Uptake in Underserved Young Adults (YA) with Type 1 Diabetes (T1D)
Authors: AGARWAL SHIVANI , MATHIAS PRIYANKA M. , SCHECHTER CLYDE , GREENBERG MICHAEL , FINNAN MOLLY , LONG JUDITH A. 
Published: June 2023

Background: Underserved YA with T1D transitioning from pediatric to adult care experience adverse outcomes, which stem from simultaneously unmet social, glycemic, and health system navigation needs. We developed a multidisciplinary clinical program called SEAD to address these challenges. In this analysis, we compared outcomes in YA with TID who were enrolled in SEAD to comparable YA in non-SEAD usual care.
Methods: The SEAD model was integrated into routine adult diabetes care at Montefiore in 2019, offering equal access to all YA with T1D aged 18-35 years old. SEAD provides YA-centered care, ongoing T1D education, diabetes technology support, psychological focus, and equity-based social need screening and referrals. We collected data prospectively on YA receiving care in SEAD vs. non-SEAD at Montefiore from 2019-2022 for a priori program evaluation, using multivariate linear regression to compare primary glycemic outcomes and Kaplan-Meier analysis for secondary technology outcomes, adjusted for age, sex, race/ethnicity, DKA, and complications.
Results: We included 416 YA with T1D (SEAD n=244, non-SEAD n=172): mean age 23 ± 4y, 49% F, 35% Black, 47% Hispanic, 73% Medicaid-insured (no baseline differences, p&gt;0.05). Compared to non-SEAD care, YA in SEAD care experienced double the HbA1c improvement with a cumulative effect size of -0.9% vs. -0.45% over the 3-year study period [SEAD: -0.30%/yr (-0.43, -0.18); non-SEAD: -0.15%/yr (-0.27, 0.04)], and had higher likelihood of accepting insulin pump (HR 1.96, [1.24, 3.12]) and CGM therapy (HR 1.63, [0.97, 2.72]).
Conclusion: Integration of the SEAD model into adult diabetes care to offer YA-centered T1D and social needs support improved glycemic control and diabetes technology uptake for underserved YA with T1D, compared to usual care. Cumulative effects over time could change YA trajectories into adulthood.

Disclosure
S.Agarwal: Advisory Panel; Medtronic, Consultant; Beta Bionics, Inc., Research Support; Abbott Diabetes, Dexcom, Inc. P.M.Mathias: None. C.Schechter: None. M.Greenberg: None. M.Finnan: None. J.A.Long: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K23DK115896-05)
218-OR: Predictors of Young Adults’ (YAs) Engagement in a Type 1 Diabetes (T1D) Self-Management Intervention—The Resilient, Empowered, Active Living–Telehealth (REAL-T) Diabetes Study
Authors: PYATAK ELIZABETH , SIDERIS JOHN , STEVEN FOX D. , GRANADOS GABRIELLE , DIAZ JESUS , BLANCHARD JEANINE , KHURANA ANYA R. , SALCEDO-RODRIGUEZ ELIZABETH , RAYMOND JENNIFER 
Published: June 2023

Background: YAs with T1D have more complications and mental health challenges, and are less engaged in care, than other age groups. Few studies have examined factors predicting engagement in self-management interventions, which may support YAs’ T1D care and overall well-being.
Methods: Using data from a T1D self-management RCT, we analyzed predictors of engagement among those randomized to the intervention who had reached the 6 month endpoint. Engagement was defined as the number of completed intervention sessions. Control variables were measured at baseline. Ordinary least-squares regression was used, entering categories of predictors in separate steps: 1) demographics: age, gender, race/ethnicity, insurance status, parental education; 2) clinical: A1c, duration of T1D, device use; 3) behavioral: medication adherence, diabetes self-management (DSMQ); 4) psychosocial: diabetes distress (DDS), self-efficacy (DES-SF), and autonomous motivation (TSRQ).
Results: Participants (n=87) were 24 (±4) yrs old, 60% female, 49% Hispanic/Latinx and 43% White, and completed a mean of 9.5 intervention sessions (range: 0-24). In the final model (p=0.0003), engagement was associated with low parental education (parameter estimate -4.1 visits), being uninsured (+3.6 visits), and higher glucose monitoring (-1.1 visits) and physical activity (-0.6 visits) on the DSMQ.
Discussion: Clinical and psychosocial variables were unrelated to OT visits; to an extent, poorer self-management predicted more visits. Indicators of SES were most predictive: low parental education decreased, and uninsured status increased, number of OT visits. Given that the factors most associated with engagement were indicators of SES, clinicians are encouraged to assess barriers and external factors that may impact access and participation as soon as possible in the therapeutic process, to facilitate engagement in services.

Disclosure
E.Pyatak: Research Support; Abbott Diabetes. J.Sideris: None. D.Fox: None. G.Granados: None. J.Diaz: None. J.Blanchard: None. A.R.Khurana: None. E.Salcedo-rodriguez: None. J.Raymond: None.
220-LB: Characterizing the Role of 99 Cardiometabolic Candidate Genes Using CRISPR/Cas9, In Vivo Imaging, and Deep Learning in Zebrafish Larvae
Authors: MUJICA ENDRINA , ZHANG HANQING , EMMANOUILIDOU ANASTASIA , MAZZAFERRO EUGENIA , COOK NAOMI , METZENDORF CHRISTOPH , ALAVIOON GHAZAL , BANDARU MANOJ , ROTTNER ANTJE , SUN HAN , NYBERG MICHAEL , DJORDJEVIC DJORDJE , GRY VIENBERG SARA , GLOYN ANNA L. , LARSSON ANDERS , ALLALOU AMIN , DEN HOED MARCEL 
Published: June 2023

Introduction: Genome-wide association studies identified 100s of loci that are associated with the risk of common cardio-metabolic diseases (T2D and CVD). Here we functionally characterise 99 candidate genes for a role in relevant traits using zebrafish larvae.
Methods: Fifty-six T2D and 46 CVD candidate genes (three overlap) were functionally characterised by targeting their zebrafish orthologs using CRISPR/Cas9. On day 9-11 post-fertilisation, we acquired optical sections of the pancreatic islet, liver and vasculature using semi-automated fluorescence microscopy, in 16,141 CRISPR/Cas9-edited zebrafish larvae, followed by image analysis using deep learning.
Results: Perturbing all nine T2D genes with at least moderate prior evidence affects ≥1 T2D trait (i.e., beta cell mass, beta cell insulin expression, liver fat, and/or glucose content), while no consequence is observed for 22 genes without prior evidence of a role in T2D. For 12 genes with at most modest prior evidence, perturbation also affects at least 1 T2D trait. Perturbation of 23 genes prioritised for a role in CVD affects at least one vascular trait, while no consequence is observed for 15 non-prioritised genes. Effects of mutations in mice and/or humans are published for 14 of 23 genes, 78% of which show directionally consistent effects across zebrafish larvae and mammals. Of the 15 genes influencing liver fat upon CRISPR/Cas9 editing, mutations in 12 previously showed an effect on liver fat in mice and/or humans, with 75% congruence in direction of effect across species.
Conclusion: Systematically characterising candidate genes for a role in image-based T2D, liver fat and CVD traits in CRISPR/Cas9-edited zebrafish larvae shows highly congruent results with mice and humans, and prioritises promising genes for further in-depth characterisation.

Disclosure
E. Mujica: None. H. Sun: None. M. Nyberg: Employee; Novo Nordisk A/S. D. Djordjevic: Employee; Novo Nordisk. S. Vienberg: Employee; Novo Nordisk A/S. A. L. Gloyn: Other Relationship; Genentech, Inc., Roche Pharmaceuticals. A. Larsson: None. A. Allalou: None. M. Den hoed: None. H. Zhang: None. A. Emmanouilidou: None. E. Mazzaferro: None. N. Cook: None. C. Metzendorf: None. G. Alavioon: None. M. Bandaru: None. A. Rottner: Employee; AstraZeneca.

Funding
Swedish Research Council (201901417); Swedish Heart and Lung Foundation (20200602, 20200781)
222-LB: Global Equity in Precision Medicine in Diabetes Research—A Scientometric Review
Authors: SONIWALA AAMNA , KIM SOPHIA , VENKAT NARAYAN K M , SAM VARGHESE JITHIN 
Published: June 2023

Objective: While non-Europid populations contribute to nearly 80% of the global diabetes burdens, they are grossly underrepresented in research. Given the growing interest in precision diabetes research, we investigated the proportion of such research in these populations.
Methods: We undertook an electronic search of literature in PubMed from 2010 to 2023 to identify studies in precision medicine in diabetes in populations from East Asia (EA), Latin America & Caribbean (LAC), Middle East & North Africa (MENA), South Asia (SA) and South East Asia & Pacific Islands (SEAP). We did not include Central Asia, Eastern Europe, and Sub-Saharan Africa in the current analysis. Two reviewers independently screened titles and abstracts selected by region-stratified sampling to identify articles relevant to precision diabetes. A third reviewer resolved any differences. We estimated the proportion of relevant research using probability sampling weights, and key themes using computational text abstraction.
Results: Of the 197,570 studies identified from PubMed, only 15,756 (8.0%) were in populations from EA (4.8%), LAC (1.0%), MENA (0.8%), SA (1.4%) and SEAP (&lt;0.1%) regions. After screening titles and abstracts of 1,686 studies, we estimate only 39.1% [95%CI: 36.1, 42.1] were research relevant to precision medicine in diabetes. Among research relevant to precision diabetes, only 5.9% [5.0, 6.9] of studies are from non-Europid populations (EA: 3.5% [2.7, 4.3], LAC: 0.9% [0.7, 1.2], MENA: &lt;0.1%, SA: 1.5% [1.2, 1.8], SEAP: &lt;0.1%). Nearly 48.9% [46.8, 51.2] of the relevant research used genomics technologies for precision medicine in diabetes.
Conclusions: While the vast majority of the global diabetes burden stem from non-Europid populations, only 6% of precision diabetes research are from these populations. This knowledge asymmetry should be addressed to maximize scientific advances and health equity.

Disclosure
A. Soniwala: None. S. Kim: None. K. Narayan: None. J. Varghese: None.

Funding
National Institutes of Health (1P30DK111024-01, 1P01HL154996-01A1 to K.M.V.N.)
223-LB: Associations between Genetic Risk for Insulin Resistance and Measured Insulin Sensitivity Are Impacted by Race and BMI Status
Authors: YURCHISHIN MARIAN L. , FOWLER LAUREN A. , PARCHA VIBHU , ARORA PANKAJ , GARVEY W. TIMOTHY , GOWER BARBARA 
Published: June 2023

African Americans (AA) are at greater risk for type 2 Diabetes (T2D) compared to European Americans (EA). This greater risk may derive in part from genetic factors. The genetic risk for insulin resistance (IR) has been linked to the failure to expand adipose tissue and is reflected in a genetic risk score (GRS) that is inversely associated with adiposity. In this study, we investigated whether associations between the GRS and measured insulin sensitivity (IS) differ by BMI status and/or race in a sample of 107 EA and AA adults without diabetes. IS was measured with the euglycemic clamp with an insulin dose of 120 µU/m²/min/kg lean body mass. In addition, surrogate indices of IS were calculated using glucose and insulin values obtained from an oral glucose tolerance test. Participants were classified as “high” or “low” BMI using the sample median (25.9 kg/m^2) as the cut-point. GRS were derived from imputed genotypes and weighted for clamp-derived IS. Multiple linear regression models were used to assess interactions between BMI status and GRS on measures of IS. Models were stratified by race and adjusted for percent body fat, sex, and age. In EA, associations of GRS with HOMA-IR and Matsuda differed by BMI status (pint=0.024 and pint=0.007, respectively), where GRS was inversely associated with IS in the high BMI group only (p=0.027 and p=0.010, respectively), suggesting that genetic risk for IR in EA is driven by greater adiposity. Conversely in AA, associations of GRS with IS from the clamp differed by BMI status (pint=0.083), but an inverse association was observed only in the low BMI group (p=0.035), suggesting that in AA, genetic risk for IR is associated with lower adiposity. Our results indicate that obesity status may differentially impact the link between genetic risk for IR and measured IS within and between races. Further, these results suggest that with a larger sample, a distinct phenotype may exist in AA where higher adiposity permits greater IS.

Disclosure
M. L. Yurchishin: None. L. A. Fowler: None. V. Parcha: None. P. Arora: None. W. Garvey: Advisory Panel; Boehringer-Ingelheim, Novo Nordisk, Eli Lilly and Company, Merck & Co., Inc., Alnylam Pharmaceuticals, Inc., Fractyl Health, Inc. Research Support; Novo Nordisk, Eli Lilly and Company, Epitomee, Pfizer Inc. Advisory Panel; Inogen. Research Support; Neurovalens. B. Gower: Consultant; Abbott.
226-LB: Repurposing a Cancer Drug, AZD6738 (ATRi), for the Prevention of Type 1 Diabetes
Authors: SUGITANI NORIE , MASON HANNAH R. , ROY SAPTARSHI , PIGANELLI JON D. 
Published: June 2023

Type 1 diabetes (T1D) is a chronic, incurable autoimmune disorder caused by the destruction of pancreatic β cells by diabetogenic T cells, leading to insulin deficiency and hyperglycemia. It affects 3 million Americans and 80 new people are diagnosed daily. Despite treatment with insulin, patients have a significantly reduced life expectancy. This study proposes a new approach to prevent T1D by specifically targeting diabetogenic T cells undergoing the Warburg effect, a metabolic process similar to cancer cells, with a cancer drug approved by the FDA. The use of FDA-approved drugs accelerates the development of new therapies as these agents have already undergone initial efficacy and toxicity tests in humans. One promising drug for this purpose is AZD6738 (ATRi), a cancer drug that is currently in clinical trials. ATRi is a small molecule inhibitor that targets ATR, a central DNA damage response kinase, whose inhibition blocks DNA replication. We demonstrate that ATRi treatment significantly delays T1D onset in an adoptive transfer mouse model by reducing the survival of diabetogenic CD4+ T cells by inhibiting their proliferation. Furthermore, an FDA-approved glycolysis inhibitor PFK158 potentiates inhibition of diabetogenic CD4+ T cells by ATRi. These agents target different properties of the Warburg effect. While ATRi inhibits rapid proliferation, PFK158 blocks glycolysis. Combination therapy allows for increased efficacy while reducing potential toxicity by allowing the use of lower doses of each agent. These data show promise in the rapid establishment of novel T1D prevention methods by repurposing FDA-approved cancer drugs.

Disclosure
N. Sugitani: None. H. R. Mason: None. S. Roy: None. J. D. Piganelli: None.

Funding
National Institutes of Health (R01DK132583); JDRF (2-SRA2020-910-S-B)