bluuebunny/crossref_metadata_2025_split huggingface dataset:
1452-P: Financial Toxicity and Cost-Related Nonadherence (CRN) in Adults with Type 1 Diabetes (T1D)—Prevalence and Associations with Social Determinants of Health
Authors: WENTZELL KATHERINE , SMITH ALYSSA N. , PATEL MINAL R. 
Published: June 2024

Introduction: Financial toxicity with healthcare needs and CRN, such as insulin rationing, are increasingly recognized as challenges to optimal T1D self-care in the US. This study examined prevalence of financial toxicity, CRN, and associations with SDOH.
Methods: This study included 130 adults with T1D with A1c ≥7.5% and unmet social needs. Sociodemographic and clinical variables, as well as the COST-FACIT modified for diabetes (lower score=more financial toxicity; cut-point ≤20) were collected. CRN was defined as endorsing at least 1 diabetes-specific behavior in the past year: took less medication, skipped medication, delayed/did not fill prescription, delayed/did not see healthcare provider because of cost. SDOH-related factors included income, employment, and insurance status. T-tests, ANOVAs, chi square, Fisher’s exact tests, and Pearson correlations determined the strength and direction of relationships.
Results: Mean age of the sample was 41 years (range 19-74), 65% female, 79% Non-Hispanic White, T1D duration was 24 years, A1c was 8.0±1.4%, 55% reported financial toxicity, and 32% reported CRN. Participants who endorsed CRN had significantly more financial toxicity (17±7 vs 21±8, p=.007). Financial toxicity and A1c were not correlated and A1c did not differ between those endorsing vs not endorsing CRN. Financial toxicity was substantial in those with lower income, not in the workforce, or with public health insurance (p&lt;.01) while CRN did not differ statistically by these SDOH. Financial toxicity and CRN did not differ by gender or race/ethnicity. While financial toxicity did not differ by age, adults over age 30 endorsed less CRN vs those ≤30 (p=.03).
Conclusion: More than half of this sample endorsed financial toxicity and nearly one third reported CRN. Multiple SDOH appear related to financial toxicity. Financial concerns should be further probed among patients with T1D to facilitate disease management.

Disclosure
K. Wentzell: None. A.N. Smith: None. M.R. Patel: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (R01 DK116715-01A1); (P30DK092926) (Michigan Center for Diabetes and Translational Research); Mary K. Iacocca Foundation
1505-P: Dipeptidyl Peptidase 6–Targeted Nanobody—A Precision Medicine Tool for Noninvasive Detection of Pancreatic Islets by PET
Authors: KHALIL AMINA , ROCA RIVADA ARTURO , VELIKYAN IRINA , BITZIOS ATHANASIOS , SERAFINI PAOLO , EIZIRIK DECIO L. , ERIKSSON OLOF 
Published: June 2024

Background: Nanobodies are single-domain antibodies that have gained popularity for various imaging techniques, including positron emission tomography (PET) due to their small size, high affinity and specificity to the target, and rapid blood clearance. A novel nanobody, NOTA-4hD29 with nanomolar affinity for human dipeptidyl peptidase 6 (DPP6) was developed as an alpha and beta cell-specific biomarker for the detection of pancreatic islets by PET. It enables non-invasive, longitudinal detection and quantification of islets of Langerhans, in the human pancreas or graft site post islet transplantation.
Method: The synthesis of [68Ga]NCS-NOTA-4hD29 was performed manually using a 68Ge/68Ga generator. Binding specificity was assessed via autoradiography with frozen sections of human islets (24%, 43%, and 90% purity) and islet-devoid exocrine pancreatic tissue. Specificity was validated by pre-blocking with excess unlabeled NOTA-4hD29. Stability of [68Ga]NCS-NOTA-4hD29 was tested in human plasma and in vivo in rats. In vivo biodistribution and plasma stability were evaluated in healthy rats and pig using PET/CT. Fluorescence labeling of 4hD29 evaluated its stability and internalization in EndoC-βH1 cells.
Results: [68Ga]NCS-NOTA-4hD29 radiosynthesis yielded 96.9% ± 1.47, with 99.6% ± 0.2 radiochemical purity. It demonstrated high affinity to human islets (r=0.98, p&lt;0.05), minimal binding to the exocrine pancreas, and complete signal abolition with blocking. In vitro stability in human plasma exceeded 90% after 60 min; in vivo rat plasma stability was ∼55% after 60 min. In vivo biodistribution in rats and pig showed renal excretion (kidney SUV &gt; 10) with low background. The 4hD29 nanobody underwent EndoC-βH1 cell endocytosis, remaining detectable in the cytosol for 6 h.
Conclusions: [68Ga]NCS-NOTA-4hD29 demonstrated excellent specificity and could differentiate between small differences in islet numbers.

Disclosure
A. Khalil: None. A. Roca Rivada: None. I. Velikyan: None. A. Bitzios: None. P. Serafini: None. D.L. Eizirik: None. O. Eriksson: Employee; Antaros Medical. Stock/Shareholder; Antaros Tracer AB.
1511-P: Fas Apoptosis Inhibitory Molecule (FAIM) Regulates Adipose Browning, Glucose Homeostasis, and Thermogenesis
Authors: NORIEGA LLOYD , WANG CHIH-HAO 
Published: June 2024

Brown/beige adipocyte activation triggers adipose thermogenesis, which is crucial for maintaining homeostasis in the body as it helps regulate glucose metabolism, reduce fat accumulation, and enhance insulin sensitivity. However, the underlying mechanisms remain unclear. Thus, our research aims to identify the master regulator for brown/beige activation and non-dependent UCP1 thermogenesis. Using engineered Cas9 activation complexes to explore the transcriptional activation of thermogenesis using single-guide RNA, we discovered Fas apoptosis inhibitory molecule (FAIM) as the top candidate. Previous studies have demonstrated that FAIM is negatively correlated with BMI and obesity and is highly expressed in brown adipocytes compared to white adipocytes. Interestingly, our further validation using ERthermAC dye showed that thermogenesis is highly activated in FAIM-overexpressed white adipocytes. Moreover, RT-qPCR showed that the thermogenic marker UCP1, browning marker CIDEA and glucose uptake marker Glut1 are increased in FAIM-overexpressed white adipocytes. Collectively, our study proves that FAIM is essential in the regulation of browning, glucose, and thermogenesis. Therefore, targeting FAIM poses a good strategy to combat obesity and type 1 and 2 diabetes.

Disclosure
L. Noriega: None. C. Wang: None.
1536-P: DEP-1 Is a Novel Modulator of Brain Energy Metabolism
Authors: CHOPRA SIMRAN , KADIRI OTSUWARE L.J. , ULKE JANNIS , HAUFFE ROBERT , JONAS WENKE , BISHOP CHRISTOPHER A. , CHESHMEH SAHAR , RATH MICHAELA , SCHELL MAREIKE , KAPPERT KAI , KLEINRIDDERS ANDRE 
Published: June 2024

Obesity's metabolic impact goes beyond peripheral insulin resistance, influencing the brain and thereby disrupting energy homeostasis by altering anabolic and catabolic reactions. Density-enhanced phosphatase-1 (DEP-1), a ubiquitously expressed receptor-like tyrosine phosphatase, has emerged as a novel regulator with a specific role in dephosphorylating the insulin receptor (IR). Strikingly, diet-induced obese mice exhibit elevated DEP-1 expression in metabolically sensitive tissues. In this study, we sought to elucidate the role of DEP-1 in brain insulin signaling and highlight its potential impact on the central regulation of metabolism in vitro and in vivo.
To explore DEP-1 deficiency in vitro, CRISPR/Cas9 was employed to create a DEP-1 knockout (KO) in mouse Neuro-2a cells. Given DEP-1’s high expression in the forebrain and the region's abundant IR expression, we examined the metabolic consequences of DEP-1 deficiency in the forebrain by deleting Dep-1 using CamKIIa Cre mice (DEFO KO).
DEP-1 KO cells exhibited an increase in IR phosphorylation and downstream signaling upon acute insulin stimulation, coupled with unexpected activation of AMP-activated protein kinase (AMPK) cascade. Similarly, male DEFO KO mice showed heightened insulin and AMPK signaling in the forebrain under random-fed conditions. A notable outcome manifested in the gonadal white adipose tissue of DEFO KO mice, where an ex vivo lipolysis assay revealed elevated basal lipolytic potential compared to control mice stimulated with isoproterenol, indicating enhanced sympathetic activation. Brown adipose tissue (BAT) of DEFO KO mice also demonstrated in a mitochondrial respiration assay, an upregulation of fatty acid oxidation, signifying increased BAT activity. Both tissues also revealed higher beta-adrenergic receptor gene expression, suggestive of sympathetic activity.
In conclusion, DEP-1 is a pivotal neuronal IR phosphatase, that prevents the establishment of futile cycles and emerges as a novel modulator of energy metabolism.

Disclosure
S. Chopra: None. O.L.J. Kadiri: None. J. Ulke: None. R. Hauffe: None. W. Jonas: None. C.A. Bishop: None. S. Cheshmeh: None. M. Rath: None. M. Schell: None. K. Kappert: None. A. Kleinridders: Speaker's Bureau; Novo Nordisk A/S, Daiichi Sankyo.

Funding
German Research Foundation (DFG)KL2399/6-1
1538-P: KCNQ2/3 Voltage Gated Potassium Channels Regulate the Activity of Intrapancreatic Neurons
Authors: LEVI NOAH , TAMAYO ALEJANDRO M. , MAKHMUTOVA MADINA , CAICEDO ALEJANDRO 
Published: June 2024

Introduction & Objective: Input from the parasympathetic nervous system is necessary to adapt pancreatic islet and acinar function to the internal and behavioral status of an organism. pancreancreatic neurons, which form a vast interconnected ganglionated plexus, serve as mandatory targets of the parasympathetic vagus nerve. However, the exact mechanisms by which this local neuronal network conveys parasympathetic signals to the endocrine and exocrine pancreas are not well understood.
Methods: To interrogate the physiology of local pancreatic neurons in response to cholinergic input, we generated living pancreas slices from transgenic mice expressing the genetically encoded calcium indicator GCaMP3 in cholinergic neurons.
Results: We found that pancreatic neurons exhibit differential intracellular Ca2+ dynamics in response to nicotinic (nAChR) and/or muscarinic acetylcholine receptor (mAChR) agonists. While the nAChR agonist nicotine produces a single transient of intracellular Ca2+, the mAChR agonist Oxotremorine-M produces a long lasting Ca2+ response consisting of several oscillations. Furthermore, we were able to show that the intracellular Ca2+ responses elicited by Oxotremorine-M could be suppressed by compounds that activate KCNQ2/3 channels—voltage gated potassium channels that regulate membrane excitability. Concomitant application of KCNQ2/3 channel activators retigabine or ICA-069673 with Oxotremorine-M resulted in a roughly 60% reduction in response duration and number of Ca2+ transients.
Conclusion: These data suggest that pancreatic neurons may not represent canonical postganglionic neurons of the parasympathetic nervous system since they respond to mAChR stimulation and that KCNQ2/3 channel function may be required for the delivery of cholinergic input to pancreatic tissues. These data aid in providing a more complete understanding of the autonomic control of pancreas physiology and provide insight for potential therapeutic targets.

Disclosure
N. Levi: None. A.M. Tamayo: None. M. Makhmutova: None. A. Caicedo: None.

Funding
R01DK30328
1546-P: Autonomic Intrapancreatic Neurons Alterations in Type 1 Diabetes
Authors: EWING SAM , HASELDEN SYDNEY , NAIR MALAVIKA , BUTTERWORTH ELIZABETH A. , CAMPBELL-THOMPSON MARTHA 
Published: June 2024

Introduction: Little is known about parasympathetic intrapancreatic neurons despite their important role in regulation of endocrine and exocrine functions. 3D imaging studies show innervation of these ganglia and islets in organ donors with type 1 diabetes (T1D). This study analyzed intrapancreatic ganglia from organ donors without and with T1D.
Methods: Paraffin sections from donors with no diabetes (ND, n=15) or T1D (n=9) were obtained from nPOD. Multiplex immunofluorescence was performed using antibodies to HuC/D, synapsin (SYN), and allograft inhibitory factor 1 (IBA1) to define neurons, synapses, and macrophages, respectively. Confocal images from 83 ganglia were analyzed using QuPATH software to quantify each ganglia area and immunopositive areas within ganglia. Ganglion sizes were binned into four groups. Neuron analyses included area (size) and numbers/ganglion (density). Statistical comparisons were made using non-parametric t-tests.
Results: A significant reduction in HuC/D+ area/ganglia was observed in T1D donors compared to ND (p &lt; 0.01). Neuron sizes were smallest in T1D donors in the smallest ganglia (&lt;3000 µm2). Comparisons of all neuron sizes, regardless of ganglia size, showed trends for smaller neurons and lower neuron density in T1D donors. No significant differences were found in synaptic or macrophage areas between groups.
Conclusions: Our results represent the first study analyzing human intrapancreatic ganglia for neurons, synapses, and macrophages. Our analysis indicates a significant reduction in neuronal HuC/D expression and trends for smaller and fewer neurons in T1D donor intrapancreatic ganglia. However, synapse loss or increased macrophage-mediated inflammation were not observed. Future studies will examine whether these findings are observed in at-risk autoantibody-positive donors. Understanding which neuron subtypes are affected by T1D is important for understanding altered islet compositions and dysregulated hormone secretion in the natural history of T1D.

Disclosure
S. Ewing: None. S. Haselden: None. M. Nair: None. E.A. Butterworth: None. M. Campbell-Thompson: None.

Funding
National Institutes of Health (OT2 OD023861, R01DK123329)
1572-P: Lipotoxicity-Induced TET1 Mediates CD36 DNA Demethylation in Liver Macrophages to Aggravate NAFLD Progression
Authors: YU PIAOJIAN , XIAN YINGXIN , CAO HUANYI , DENG XIAOJIE , CAI MENGYIN , XU FEN 
Published: June 2024

Aims: DNA methylation is dysregulated in nonalcoholic fatty liver disease (NAFLD), yet the dominant genes and regulatory mechanisms remain obscure. Here, whole-genome bisulfite (WGBS) and RNA-seq revealed significantly downregulated DNA methylation and upregulated mRNA expression of Cd36 in a high fat diet (HFD)-induced murine fatty liver, particularly in macrophages. Meanwhile, ten-eleven translocation-1 (TET1), a DNA demethylase, was upregulated. We investigated whether lipotoxicity-induced TET1 erases the methylation at Cd36 promoter in liver macrophages and aggravates NAFLD progression.
Methods: The livers of 16-week HFD-induced male C57BL/6J mice were subjected to WGBS, RNA-seq and pyrosequencing. Hydroxymethylated DNA immunoprecipitation- and chromatin immunoprecipitation-qPCR were conducted to detect the level of 5-hydroxymethylcytosine on DNA, and the binding efficiency to the Cd36 promoter, respectively. TET1 expression was knocked down by adeno-associated virus in HFD-induced NAFLD mice. In vitro, Palmitate acid was applied to simulate lipotoxicity in Kupffer cell- and THP-1 cell line. CRISPR/Cas9 sg-Tet1 knockout lentivirus and TETs enzyme inhibitor were applied, and CD36 expression was knocked down by siRNA.
Results: In macrophages of fatty liver, the expression of CD36 and TET1 is markedly increased. Lipotoxicity enhances TET1 localization and demethylase activity at the Cd36 promoter. RXRα is recruited to the Cd36 promoter following the DNA demethylation of Cd36 by TET1 and increases Cd36 expression. Moreover, lipotoxicity-induced CD36 promotes M1 macrophage polarization and exacerbates inflammation. And the deficient TET1 activity restores DNA methylation of the Cd36 promoter, reducing its expression and M1 polarization.
Conclusion: TET1-mediated DNA demethylation has a crucial role in lipotoxicity-driven CD36 transcription in liver macrophage that boosts steatosis-to-nonalcoholic steatohepatitis progression.

Disclosure
P. Yu: None. Y. Xian: None. H. Cao: None. X. Deng: None. M. Cai: None. F. Xu: None.

Funding
National Natural Science Foundation of China grants (81970741, 82270942); the Local Innovative and Research Teams Projects of Guangdong Pearl River Talents Program (2017BT01S131); and the Guangdong Basic and Applied Basic Research Foundation (2022A1515012633).
1596-P: Personalized Glycemic Response to Carbohydrates and Associated Physiological Signatures in Multiomics
Authors: WU YUE , EHLERT BENJAMIN W. , PERELMAN DALIA , PARK HEYJUN , METWALLY AHMED A. , LU YINGZHOU , CELLI ALESSANDRA , BEJIKIAN CAROLINE , MCLAUGHLIN TRACEY , SNYDER MICHAEL 
Published: June 2024

Introduction & Objective: Individuals with type 2 diabetes (T2D) exhibit heterogeneous metabolic dysfunction (e.g., muscle insulin resistance (IR), beta-cell dysfunction) and varying intervention needs. People also have different dynamic responses to daily activities (e.g., exercise and food), which are associated with their metabolic function. Understanding personalized glycemic control and specific metabolic dysfunctions is crucial for T2D subtyping and personal intervention.
Methods: Here, we incorporated real-life continuous glucose monitoring (CGM) to evaluate the personal responses to 7 different carbohydrate foods (each 50 grams of carbohydrate) and 3 different nutrients (fat, protein, and fiber) that tend to mitigate glycemic spikes in 50 participants (25 with prediabetes and 25 with normoglycemic levels). We built a computational workflow to extract 20 different metrics (e.g. peak height and time to peak) related to metabolic functions, subtype participants according to their relative response to different foods, and uncover physiological and pathological associations in multi-omics.
Results: We found that the average glycemic response depends on carbohydrate types and fiber contents. Worst metabolic control (e.g., IR) is also significantly associated with higher glycemic spikes. In addition, we discovered different CarbResponders, that different groups of people have different relative glycemic spikes to different foods. Some people spike more on rice and others on grapes. We found a higher proportion of rice spiking in Asians (p=0.007), better metabolic functions (e.g., IR) associated with lower spikes in starch food, and signature of diet habits in metabolomics and proteomics.
Conclusions: Food response profiles provide individualized food recommendations and indicate underlying metabolic functions for personalized interventions.

Disclosure
Y. Wu: None. B.W. Ehlert: None. D. Perelman: None. H. Park: None. A.A. Metwally: Employee; Google. Y. Lu: None. A. Celli: None. C. Bejikian: None. T. McLaughlin: Stock/Shareholder; Eiger BioPharmaceuticals. Board Member; January, Inc. Research Support; Eli Lilly and Company, Weight Watchers International, Merck & Co., Inc., Vogenyx. M. Snyder: Stock/Shareholder; January, Inc., Personalis, Inc, Iollo, Qbio, RTHM, Enovone, Marble Therpeutics, Fodsel, Mirvie. Advisory Panel; Applied Cognition.

Funding
American Diabetes Association (11-23-PDF-76); National Institutes of Health (NIDDK1R01 DK110186-01); Leona M & Harry B Helmsley Charitable Trust
1598-P: Transcriptional Profiling of the Intestinal Tract in Type 2 Diabetes—Unraveling Pathophysiological Pathways for Therapeutic Insights
Authors: GILLIAM-VIGH HANNAH , ELLEGAARD ANNE-MARIE , MADSEN MARTIN R. , JENSEN BENJAMIN A.H. , RIGBOLT KRISTOFFER , KNOP FILIP K. 
Published: June 2024

Introduction and Objective: Investigating the intestinal gene expression in type 2 Diabetes (T2D) may reveal novel insights into its pathophysiology. We conducted a comprehensive investigation to compare gene expression profiles along the entire human intestinal tract of individuals with T2D and healthy counterparts, aiming to identify unique gene expression patterns associated with T2D.
Methods: Mucosal biopsies from 16 intestinal sites were collected via anterograde and retrograde double-balloon endoscopy in 12 individuals with T2D and 12 matched individuals. Bulk transcriptome profiles were compared between T2D individuals and healthy individuals.
Results: Healthy participants (8M/4F, mean age: 50 years, BMI: 27.1 kg/m2, HbA1c: 5.3%) were compared to individuals of T2D (9M/3F, mean age: 51 years, BMI: 26.8 kg/m2, HbA1c: 6.5%, diabetes duration: 5 years). All were of European descent. Altered mitochondrial function and immune system activity were observed in the ileocecal segment and large intestine, respectively, in individuals with T2D compared to healthy individuals.
Conclusion: The notable changes in mitochondrial function and immune system activity in the ileocecal segment and the large intestine of individuals with T2D underscore the complex pathophysiology of the disease and its influence on intestinal function and health. The publicly and freely available database generated from this study provides a comprehensive reference for future research on intestinal gene expression in T2D and is a valuable resource for the exploration of the mucosal transcriptome along the human intestinal tract.

Disclosure
H. Gilliam-Vigh: Research Support; Zealand Pharma A/S. A. Ellegaard: None. M.R. Madsen: Employee; Gubra. B.A.H. Jensen: None. K. Rigbolt: None. F.K. Knop: Advisory Panel; AstraZeneca. Consultant; AstraZeneca. Speaker's Bureau; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company. Consultant; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Advisory Panel; Novo Nordisk A/S. Consultant; Novo Nordisk A/S. Employee; Novo Nordisk A/S. Research Support; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. Advisory Panel; Sanofi. Speaker's Bureau; Lundbeck. Advisory Panel; Zealand Pharma A/S. Consultant; Zealand Pharma A/S. Research Support; Zealand Pharma A/S. Speaker's Bureau; Zealand Pharma A/S. Stock/Shareholder; Zealand Pharma A/S.

Funding
This work was supported by a research grant from the Danish Diabetes and Endocrine Academy, which is funded by the Novo Nordisk Foundation, grant number NNF22SA0079901
1616-P: MENTSH—A Mitochondrial Microprotein and SNP-Associated with Diabetes in People with Native American Ancestry
Authors: YEN KELVIN , COHEN PINCHAS 
Published: June 2024

Introduction & Objective: The mitochondria has been implicated in the etiology of diabetes, but the role of mitochondrial microproteins in this process has not been thoroughly investigated. Furthermore, diabetes prevalence differs between races and ethnicities, and although social economic factors are a major cause, we wanted to examine if genetics also played a role. Our objective was to 1) determine if variations in the mitochondrial genome correlated with diabetes and 2) determine if mitochondrial microproteins played a role in diabetes.
Methods: We performed a mitochondrial genome focused GWAS on the Health and Retirement Study, which a study of over 15,000 individuals over the age of 50 years in the USA. In vivo studies were performed in mice on a high fat diet (60% fat) or ob/ob mice that lack leptin. Western blots and other molecular biology techniques were performed using standard procedures.
Results: While performing a mitochondrial focused GWAS (miWAS), we have discovered a common SNP in populations of Native American descent that is associated with an increased chance of diabetes and also interrupts the start codon of a novel mitochondrial microprotein that we call MENTSH. Supporting this finding, administration of this microprotein in different mouse models of diabetes (60% high fat diet and ob/ob mice that lack leptin) can attenuate the disease progression. Treatment with MENTSH and MENTSH analogues improved glucose tolerance as measured by GTT and reduced weight gain. Molecularly, we find that MENTSH differentially affects AKT phosphorylation in muscle and fat.
Conclusion: We have discovered a SNP and a previously unknown microprotein that are now implicated in diabetes. Administration of this microprotein to mouse models of diabetes improves their outcomes. This discovery opens up the possibility of using MENTSH or its analogues as a novel therapeutic approach for diabetes.

Disclosure
K. Yen: None. P. Cohen: None.