bluuebunny/crossref_metadata_2025_split huggingface dataset:
168-OR: Perilipin 2 Regulates Fatty Acid Trafficking to Mitochondria through Microlipophagy in Beta Cells
Authors: LIU SIMING , JOGLEKAR ADITYA , FRESHLY AIDAN , PEACHEE SPENCER , WIPF ISRAEL J. , BOVEE CORINNE , VIKRAM ANAMIKA , GIEDT MICHELLE , FINK BRIAN , SIVITZ WILLIAM , ANKRUM JAMES A. , TOOTLE TINA , IMAI YUMI 
Published: June 2024

Perilipin 2 (PLIN2) is the major structural protein of triglycerides (TG) storing lipid droplets (LD) and increased in lipid loaded and type 2 diabetic pancreatic beta cells. PLIN2 is protective for beta cells since its knockdown increases fatty acid (FA) flux to mitochondria and impairs mitochondrial function. Here, we addressed a pathway by which PLIN2 deficiency compromises mitochondrial integrity in beta cells. When the incorporation of Bodipy C12 (C12, a fluorescent long chain FA analog) into organelles was followed in INS1 cells over 8 h, C12 incorporation into LD was seen in both control and shPLIN2 cells during the first hour indicating that PLIN2 downregulation does not affect the initial triglycerides (TG) synthesis and its incorporation into LD. C12 started to accumulate into mitochondria after 4 to 8 h only in shPLIN2 cells indicating that FA transfer to mitochondria occurs after LD formation under PLIN2 deficiency. Treatment with a lysosomal lipase inhibitor Lali2 increased TG level and prevented C12 transfer into mitochondria in shPLIN2 cells, indicating that lysosomal degradation of LD precedes FA transfer to mitochondria. Microlipophagy appears to mediate LD degradation in shPLIN2 cells since a macroautophagy blocker 3MA did not prevent FA flux to mitochondria. Importantly, Lali2 rescued mitochondrial fragmentation (p&lt;0.05 vs DMSO control) and glucose-stimulated insulin secretion (p&lt;0.05) in shPLIN2 INS1 cells. Mitochondrial fragmentation and its rescue by Lali2 were also seen in shPLIN2 treated human beta cells (p&lt;0.05). As for a mechanism mediating FA transfer to mitochondria, the direct contact between lysosome and mitochondria was increased (p&lt;0.01) before FA flux to mitochondria occurs in shPLIN2 cells. Collectively, PLIN2 deficiency in beta cells impairs mitochondrial integrity through lysosomal TG degradation followed by FA delivery to mitochondria. These data highlight the importance of regulation of microlipophagy by PLIN2 for beta cell function.

Disclosure
S. Liu: None. A. Joglekar: None. A. Freshly: None. S. Peachee: None. I.J. Wipf: None. C. Bovee: None. A. Vikram: None. M. Giedt: None. B. Fink: None. W. Sivitz: None. J.A. Ankrum: None. T. Tootle: None. Y. Imai: None.

Funding
R01 DK090490 (NIH) I01 BX005107 (VA)
1683-P: Characteristics of Lifestyle, Dietary Nutrients, and Gut Microbiota Associated with Predisease State of Metabolic Syndrome in Japanese Adults
Authors: WATANABE YOSHIYUKI , FUJISAKA SHIHO , HONOKI HISAE , KADO TOMONOBU , NISHIMURA AYUMI , BILAL MUHAMMAD , RAHIL ASLAM MUHAMMAD , IGARASHI YOSHIKO , MORINAGA YOSHITOMO , TOBE KAZUYUKI 
Published: June 2024

Introduction/Objective: Environmental factors such as lifestyle, diet, and associated changes in the gut microbiota are the most important determinants of obesity. Recently, we investigated the relationship among metabolic parameters, lifestyle habits, and fecal 16S rRNA seq data of Japanese healthy adults. These parameters are intricately and closely related, and we identified two microbes that can prevent metabolic syndrome (ADA 83rd scientific sessions). In this study, we further expanded this cohort study to examine lifestyle habits, nutrient intake, and microbial species associated with visceral obesity (VO).
Methods: A total of 435 participants who underwent annual health check in 2019 were enrolled, provided data on metabolic parameters, and completed a lifestyle questionnaire including a dietary record of the previous three days. Fecal 16S rRNA seq data were obtained from 38 participants in 2022 and analyzed along with the changes in body weight from 2019.
Results: The average age, body mass index, and HbA1c were 40.5±9.7, 24.0±4.1 kg/m2 and 5.5±0.37%, respectively. VO was clearly associated with metabolic parameters. There was a significant positive correlation between VO and lifestyle habits such as smoking, eating speed, irregular meal time, and frequency of fried food intake. Regarding nutrient composition, intake of resistant starch, β-carotene, maltose, and sorbitol were negatively correlated with waist circumference, while intake of caffeine and tannins were positively correlated. Furthermore, significant differences depending on weight changes were observed in the microbial species such as increased Bifidobacterium adolescentis and Prevotella stercorea in subjects who lost weight compared to those who gained weight.
Conclusion: Lifestyle, diet intake, and characteristic changes in the microbiota are associated with VO in healthy adults prior to onset of metabolic syndrome.

Disclosure
Y. Watanabe: None. S. Fujisaka: None. H. Honoki: None. T. Kado: None. A. Nishimura: None. M. Bilal: None. M. Aslam: None. Y. Igarashi: None. Y. Morinaga: None. K. Tobe: None.

Funding
Japan Society for the Promotion of Science (JSPS) KAKENHI (20K08882, 21K20896 and 22K16424); AMED PRIME (JP18gm6010023h0001); Lotte Foundation; Yakult Bio-Science Foundation; First Bank of Toyama Scholarship Foundation; Japan Diabetes Foundation; Japan Society for the Study of Obesity (JASSO); Yamaguchi Endocrine Resarch Foundation and Hokugin Young Researcher Grant
1712-P: DOC2b Enrichment Mitigates Cytokine-Induced CXCL10 Expression via Attenuating IKK-NFkB and STAT-1 Signaling in Beta Cells
Authors: CHATTERJEE BHOWMICK DITI , AHN MIWON , BHATTACHARYA SUPRIYO , THURMOND DEBBIE C. 
Published: June 2024

Introduction & Objective: The reduction of beta-cell dysfunction, and demise hold promise for therapeutic intervention for type 1 diabetes. Previously, we have reported the beneficial role of SNARE-regulatory protein DOC2b in preventing cytokine-induced beta-cell stress and apoptosis. However, the underlying mechanism remains unknown. We hypothesize that DOC2b enrichment mitigates cytokine-induced beta-cell apoptosis via attenuating CXCL10 signaling.
Methods: To test the hypothesis, we have used RNA-seq, qPCR, proteomics, biochemical studies, and immuno-confocal microscopy using DOC2b-enriched or -depleted primary islets (human and mouse) and clonal beta-cells challenged with or without proinflammatory cytokines.
Results: Human islet RNAseq analysis revealed a significant decline in NFkB signaling pathway in islets with DOC2b enrichment vs control. Our proteomics and co-immunoprecipitation studies identified IKK, NFkB p65 and STAT-1 as binding partners of DOC2b in clonal beta-cells. Western blot studies demonstrated that DOC2b enrichment corresponds with a significant reduction in total and activated levels of IKK, NFkB p65 and STAT-1 proteins in cytokine-stressed human islets. Immunofluorescent confocal microscopy showed DOC2b enriched cytokine-stressed clonal beta-cells to harbor reduced levels of NFkB p65 in the nucleus. In beta-cells, cytokine-induced chemokine ligand CXCL10 expression is known to be regulated via upstream NFkB p65 and STAT-1 mediated signaling. Intriguingly, qPCR and western blot studies revealed marked attenuation of cytokine-induced CXCL10 levels in DOC2b-enriched human islets and clonal beta-cells; by contrast, CXCL10 is elevated in DOC2b-depleted beta cells and mouse islets.
Conclusion: These data support a model in which DOC2b protects beta-cells from cytokine stress and apoptosis via attenuation of IKK-NFkB and STAT-1 signaling, thereby reducing CXCL10 expression.

Disclosure
D. Chatterjee Bhowmick: None. M. Ahn: None. S. Bhattacharya: None. D.C. Thurmond: Consultant; Truebindings.

Funding
JDRF Postdoctoral fellowship (3-PDF-2020-934-A-N); Diabetes Research Connection grant National Institutes of Health (DK067912, DK112917, and DK102233)
1745-P: IPO13 Maintains Glucose Homeostasis by Regulating Insulin Secretion and α-Cell Expansion
Authors: ZHAO QINYING , YANG YING , JI SHUHUI , CHEN YUANSI , FENG WENLI , LIU MING 
Published: June 2024

Introduction & Objective: Importin 13 (IPO13) is a member of IPOβ family and is one of only three mammalian IPO proteins able to mediate both import and export of cargo proteins. IPO13 contributes to brain and eye development, however the role of IPO13 in β cell function and glucose homeostasis remains unknown. Herein, we performed a new β cell-specific IPO13 knockout (IPO13-βKO) mouse model to investigate the β cell function changes caused by IPO13 deficiency.
Methods: Body weight, fasting blood glucose, and plasma insulin levels was tested weekly to observe the glucose homeostasis of IPO13-βKO mice. Insulin or glucagon gene expression, proinsulin processing, and insulin or glucagon content were detected. Isolated islets insulin and glucagon secretion ability was measured by glucose-stimulated insulin secretion test. Transcriptome analysis of associated genes GO term were used to understand the related gene changes.
Results: IPO13 was downregulated in β cells of diabetic db/db mice and high-fat fed mice, revealing a possible role of IPO13 in β-cell function. IPO13-βKO caused severe early-onset, insulin-deficient diabetes. Functional studies revealed the decreased expression of prohormone convertase 1/3 and carboxypeptidase E, and increased abnormal insulin granules, resulting in the decreased insulin production. Islet transcriptome analysis showed decreased expression of genes associated with β-cell maturation. Multiple experiments confirmed that, although IPO13 deletion decreased insulin, the expansion of α cells and elevated glucagon levels, especially after glucose stimulation. Importantly, IPO13 deficiency decreased expression of β-cell function-related genes, including Glut2, Cask, and Syt7, contributing to impaired islet glucose-stimulated insulin secretion (GSIS).
Conclusion: Our study not only reveal a critical role of IPO13 in the regulation of insulin secretion and α cell expansion but also provide insight into the mechanism of diabetes caused by IPO13 deficiency.

Disclosure
Q. Zhao: None. Y. Yang: None. S. Ji: None. Y. Chen: None. W. Feng: None. M. Liu: None.

Funding
National Natural Science Foundation of China (82220108014,81830025); National Key R&D Program of China (2022YFE0131400, 2019YFA0802502); Key project of Tianjin Municipal Health Commission (TJWJ2021ZD001); Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-030A); Tianjin Medical University General Hospital Clinical Research Program (22ZYYLCZD02).
1777-LB: Time Below Range Is Correlated with Level 2 (L2) Hypoglycemia Event Rates in Type 1 Diabetes—Results from DCLP3, DIAMOND, and WISDM Trials
Authors: LIGGINS RICHARD , CALHOUN PETER , PEERS SUSAN , RIDDELL MICHAEL C. , BECK ROY W. 
Published: June 2024

Background: Minimizing CGM time below range (TBR; T&lt;70 and T&lt;54 mg/dL), is an important therapeutic goal with clinical targets in diabetes (≤4% and ≤1%, respectively). TBR is valuable for clinical management of hypoglycemia, but individual symptomatic episodes are also important to patients. Clinical trials report both TBR and hypoglycemia events (glucose &lt;54 mg/dL for ≥15 min), but associations between the two have not been quantified. The purpose of this work is to compare the associations of TBR with L2 hypoglycemia event rates.
Methods: The relationship between hypoglycemic events and T&lt;70 or T&lt;54 was assessed for cohorts using real-time CGM or SMBG with interval use blinded CGM in 3 trials: DCLP3, DIAMOND, and WISDM. CGM metrics and CGM-detected event rates were calculated over a 6-month period.
Results: There was a strong correlation between hypoglycemic event rates and T&lt;70 or T&lt;54 (R = 0.91-0.93 for CGM and SMBG users). 70 CGM users exceeding the T&lt;70 target (28%) had mean of 3.1 L2 events/week. 85 SMBG users exceeding the T&lt;70 target (59%) had mean 4.1 events/week. Similar trends were seen for the T&lt;54 target. Those meeting T&lt;70 target had on average &lt;1 L2 event/week (CGM: 0.9; SMBG: 0.8 events/week).
Conclusion: TBR was highly correlated with hypoglycemia event rates and participants not meeting hypoglycemic clinical targets had frequent L2 hypoglycemic events.

Disclosure
R. Liggins: Employee; Zucara Therapeutics. Stock/Shareholder; Zucara Therapeutics. P. Calhoun: None. S. Peers: Employee; Zucara Therapeutics. M.C. Riddell: Consultant; Eli Lilly and Company. Speaker's Bureau; Novo Nordisk. Advisory Panel; Supersapiens. Consultant; Dexcom, Inc. Speaker's Bureau; Sanofi. Advisory Panel; Zealand Pharma A/S. Speaker's Bureau; Dexcom, Inc. Stock/Shareholder; Zucara Therapeutics. R.W. Beck: Consultant; Insulet Corporation. Research Support; Insulet Corporation. Consultant; Tandem Diabetes Care, Inc. Research Support; Tandem Diabetes Care, Inc. Consultant; Beta Bionics, Inc. Research Support; Beta Bionics, Inc., Dexcom, Inc., Bigfoot Biomedical, Inc. Consultant; Novo Nordisk. Research Support; Novo Nordisk, Eli Lilly and Company. Consultant; embecta, Vertex Pharmaceuticals Incorporated, Hagar, Ypsomed AG, Sanofi, Zucara Therapeutics, Sequel.
1784-LB: LRP5 Promotes Fatty Acid Oxidation through Enhancement of PPAR/PGC-1 Signaling in DKD with Dyslipidemia
Authors: HE XUEMIN , ZHANG RUI , WEN SIYING , XIANG XIAOXIN , CAI MENGYIN , CHEN YANMING 
Published: June 2024

Dyslipidemia is an independent risk factor for diabetic kidney disease (DKD), but some lipid-lowering drugs are reported to exacerbate this disease, as they prohibit fatty acid oxidation (FAO) which is the primary energy source in renal proximal tubules. In this study, we demonstrated low-density lipoprotein receptor-related protein 5 (LRP5) as a novel regulator of both systemic lipid metabolism and FAO in the kidney. In Lrp5-deficient mice fed with a high-fat diet, the levels of serum lipids were significantly up-regulated, accompanied by worsened tubulointerstitial fibrosis and loss of renal tubular epithelial cells. By overexpression and knockdown of LRP5 in renal proximal epithelial cells, LRP5 was proven to be essential for maintaining the epithelial phenotype under the condition of lipotoxicity. RNA-sequencing suggested that Lrp5 deficiency greatly promoted lipid deposition but compromised the FAO in the DKD kidneys. Further analysis identified that LRP5 potentiated the activation of peroxisome proliferator-activated receptor (PPAR)/PPARgamma coactivator 1 signaling, restoring the compromised FAO in the renal proximal tubules of DKD. These results highlight a potential therapeutic role of LRP5 in promoting systemic lipid metabolism and FAO for treating DKD with dyslipidemia.

Disclosure
X. He: None. R. Zhang: None. S. Wen: None. X. Xiang: None. M. Cai: None. Y. Chen: None.

Funding
Grants from the Municipal Science and Technology Planning Projects of Guangzhou City (SL2023A03J00003), National Natural Science Foundation of China (82270886, 82000782), Sci-Tech Research Development Program of Guangzhou City (202201020589), Key Area R&D Program of Guangdong Province (2019B020227003)
1789-LB: Prevalence of Atherosclerotic Cardiovascular Disease in Adults with Type 2 Diabetes in Jordan—The PACT-MEA Study
Authors: ABBAS FIRAS O. , ABBASI HIBA , ABU ALSAMEN MUNEER A. , ALMOUSA EYAS N. , AMMARI FAWAZ L. , HADDAD JIHAD A. , HADDAD SUHAIR E. , JARADAT MUSTAFA , KHASSAWNEH ADI , KHATIB NIDAL , MAGABLEH ARABIEH , HADDAD FARES H. 
Published: June 2024

Introduction & Objective: Globally, nearly one-third of people with type 2 diabetes (T2D) has a type of cardiovascular (CV) disease, the majority of which is atherosclerotic cardiovascular disease (ASCVD). To address the lack of representative data regarding these conditions in Middle Eastern and African (MEA) countries, we aimed to assess the prevalence of established atherosclerotic cardiovascular disease (eASCVD) and ASCVD risk in patients with T2D in seven countries across the Middle East and Africa. Here we present the primary results for Jordan to identify opportunities for improving T2D management in this country.
Methods: PACT-MEA (PACT-MEA; NCT05317845) is a cross-sectional, observational study of adults (≥18 years) with T2D from primary and secondary care settings. During scheduled clinic visits in 2022, medical history, demographic, clinical, laboratory, and pharmacotherapy data were extracted from medical charts of patients. We report the prevalence (95% CI) of eASCVD and ASCVD risk using the risk category definitions of moderate, high, very high (latter includes eASCVD) from the 2021 European Society of Cardiology (ESC) Guidelines on CV Disease Prevention in Clinical Practice.
Results: A total of 576 patients with T2D in Jordan were enrolled across ten study sites. The mean patient age was 59.7 and included 52% males and 48% females. Patients were enrolled from primary and secondary care settings (28% and 72%, respectively). A total of 151 patients with T2D had eASCVD, corresponding to a prevalence of 26.2% (95% CI: 22.8-30.0). Per ESC guidelines, 0.8% of people with T2D in Jordan were at moderate risk for ASCVD, 66.0% were at high risk, and 33.3% were at very high risk.
Conclusion: Our findings indicate that eASCVD is prevalent in more than one-quarter of people with T2D in Jordan, and nearly all are at high/very high ASCVD risk. This suggests there is an opportunity for improved screening and management of T2D to reduce CV risk in this country.

Disclosure
F.O. Abbas: None. H. Abbasi: None. M.A. Abu Alsamen: None. E.N. Almousa: None. J.A. Haddad: None. S.E. Haddad: None. M. Jaradat: None. A. Khassawneh: None. N. Khatib: None. A. Magableh: None. F.H. Haddad: None.

Funding
Novo Nordisk, Inc.
1828-LB: A Correlational Study on Improving Patients’ Cognition of Diabetes and Long-Term Reversal of Diabetes
Authors: WANG YAO 
Published: June 2024

Objective: Type 2 diabetes can be reversed through lifestyle intervention, but the long-term reversal rate is low. This study aims to explore how to improve patients' cognition of diabetes and cultivate a healthy lifestyle, and investigate its correlation with long-term diabetes reversal.
Methods: A total of 200 patients with early type 2 diabetes mellitus complicated with obesity were randomly selected and reversed diabetes through weight loss. They were randomly divided into a control group (Group A with 100 patients, weight loss + routine health education) and an intervention group (Group B with 100 patients + cognitive training). Group A received routine health education, while Group B received offline training + examination + artificial intelligence online diabetes knowledge education once a week for 12 weeks, with a one-year follow-up. Blood glucose, HbA1c, pancreatic function, body weight, body fat rate, muscle mass, and other related indicators were monitored in both groups. The differences in long-term reversal rates and related indicators between the two groups were analyzed.
Results: The intervention reversal rate in Group A was 46% at 12 weeks and 28% at one year; while in Group B, it was 62% at 12 weeks and 36% at one year. There were significant differences in short-term and long-term reversal rates between the two groups (P&lt;0.05). There were differences in cognitive scores between the two groups, with a score of 60.1±2.9 in Group A and 66.0±1.8 in Group B. Cognitive scores were positively correlated with long-term diabetes reversal rates.
Conclusion: Improvement in cognitive behavior among patients with type 2 diabetes is associated with increased long-term diabetes reversal rates, increased muscle mass, and decreased body fat rates.

Disclosure
Y. Wang: None.
1847-LB: Fear of Hypoglycemia and Sleep among Parents of Young Children with Type 1 Diabetes
Authors: CAMPBELL MARYJANE , MONZON ALEXANDRA , CLEMENTS MARK A. , PATTON SUSANA R. 
Published: June 2024

Background: Parents’ fear of hypoglycemia (FH) is common and associated with increased parental anxiety and stress. We examined the associations among FH and parental sleep in a sample of parents of young children with type 1 diabetes (T1D). We additionally explored whether FH and parental sleep differed by insulin modality or associated with child age and T1D duration.
Methods: One hundred and eighty-four parents completed the Hypoglycemia Fear Survey-Parent (HFS-PYC), the PROMIS Sleep Disturbance Short Form, and reported on their child’s T1D, insulin pump usage, and frequency of hypoglycemia.
Results: Parents were 92% mothers (M age=36.43±6.11) and children were 45% female (M child age=4.40±1.23; M HbA1c=7.54%±1.15). Children included 49% on a hybrid closed loop pump (HCL), 29% on an open loop pump (OLP), and 23% on multiple daily injections (MDI). Parent-reported FH (M=76.66±16.58) was associated with greater parental sleep disturbance and greater frequency of hypoglycemic events (&gt;2/week). Parents of youth on HCL reported greater difficulty staying asleep compared to parents of youth on MDI (p&lt;.05), but not compared to parents of youth on OLP (p&gt;.05). FH did not differ based on insulin modality. FH and sleep disruption were not associated with T1D duration or child age.
Conclusions: FH may contribute to disrupted sleep among parents of young children with T1D regardless of insulin modality, tT1D duration, or child age. Parents who reported greater FH were more likely to report greater frequency of hypoglycemic events; however, it is unclear whether parent-reported hypoglycemic events occurred during the night, contributing to disrupted sleep. Further, HCL usage was associated with sleep disruption, but not FH. Future research that incorporates continuous glucose monitoring and assesses parental FH specifically at night will help identify factors that may contribute to disrupted parental sleep and thereby help inform future sleep-promoting interventions for these parents.

Disclosure
M. Campbell: None. A. Monzon: None. M.A. Clements: Research Support; Abbott. Consultant; Glooko, Inc. Research Support; Dexcom, Inc. S.R. Patton: None.

Funding
National Institutes of Health (R01DK118514)
1860-LB: Preliminary Study of Efficacy and Duration of an mRNA-Based GLP-1R Agonist in Diabetic Monkeys
Authors: XU FENGWEI , WU KANGZENG , ZHANG LEI , DAI YONGCHAO , XU YUHONG 
Published: June 2024

HFG1 is an mRNA based GLP-1R agonist encoding a fusion protein of a GLP-1 analogue and a pH sensitive binder of human FcRn. The mRNA is encapsulated inside lipid nano-structures (LNPs) designed for subcutaneous gene delivery and local transfection, and the proteins expressed would be secreted and distributed into systemic circulation. In order to characterize the HFG1 activities in vivo, five monkeys with naturally occurred diabetes (FPG≥9.69 mg/dl, HbA1c≥5.6%) were selected to receive one subcutaneous injection of LNPs of slightly variable compositions containing about 0.5-1.0mg mRNA. The monkeys were closely monitored for 60 days and no behavior changes were observed except that they all had greatly reduced food uptake on the first few days after injection. By D56 they lost an average of 0.22kg each. Blood samples were collected at various time points and assayed in a GLP-1R/CRE Luciferase Reporter Cell system for GLP-1 equivalent activities. Figure 1 plotted the individual measurements (solid dots) and average value changes (solid line). The HbA1c% levels were assayed by Suzhou Xihua Scientific Co. and shown as open squares. Even though some time points are missing (TBD), the trend of HbA1c% reduction after a single HFG1 injection is significant.

Disclosure
F. Xu: Employee; highfield. K. Wu: Employee; high field. L. Zhang: Employee; HighField Biopharmaceuticals Corporation. Y. Dai: Employee; HighField Biopharmaceuticals Corporation. Y. Xu: Employee; Hangzhou HighField Biopharm. Stock/Shareholder; Hangzhou HighField Biopharm.