bluuebunny/crossref_metadata_2025_split huggingface dataset:
362-OR: Divergent Roles of METTL14-Mediated m6A in Regulating Brown and White Adipose Tissue Transcriptomes and Systemic Metabolism
Authors: XIAO LING , DE JESUS DARIO F. , JU CHENG-WEI , HU JIANG , WEI JIANGBO , DISTEFANO-FORTI AVA , SALERNO GONZALES VALERIA R. , TSUJI TADATAKA , WEI SIYING , BLÜHER MATTHIAS , TSENG YU-HUA , HE CHUAN , KULKARNI ROHIT 
Published: June 2024

N6-methyladenosine (m6A) is among the most abundant post-transcriptional modifications in mRNA, yet its precise cell-type-specific roles in orchestrating gene expression programs remain elusive. Although brown and white adipocytes are both considered fat cells, their unique properties underscore the importance of context-specific post-transcriptional regulation for whole-body metabolism. Here, we provide the first evidence that m6A methyltransferase-like 14 (METTL14) differentially regulates transcriptomes in brown and white adipose tissue (BAT and WAT), leading to divergent metabolic outcomes. We found that human brown and white adipocytes (hBAT and hWAT) display markedly distinct m6A landscapes; besides, in insulin-resistant humans and mice, METTL14 expression differs significantly between the fat depots in the context of correlation with insulin sensitivity. Mettl14-knockout in BAT via Ucp1-cre promotes secretion of specific prostaglandins and improved peripheral insulin sensitivity in mice. Conversely, Mettl14-deficiency in WAT via Adipoq-cre triggers white adipocyte apoptosis, lipodystrophy, and systemic insulin resistance. Integration of m6A-seq and RNA-seq profiling revealed strikingly distinct transcriptomes and m6A methylomes in Mettl14-deficient BAT versus Mettl14-deficient WAT. More specifically, upregulated prostaglandin biosynthesis pathways were enriched in Mettl14-deficient BAT, and TNF-associated and apoptotic pathways were activated in Mettl14-deficient WAT. Using stable METTL14-knockout hBAT or hWAT cell lines, we report that METTL14-mediated m6A negatively regulates gene expression of PTGES2, CBR1, and PGC1a in hBAT, and TRAIL, TNFR1, RIP, and DFFA in hWAT by promoting mRNA decay. These data shed light on the ability of m6A to impact metabolism in a cell-type-specific manner with implications for influencing the pathophysiology of metabolic diseases.

Disclosure
L. Xiao: None. D.F. De Jesus: None. C. Ju: None. J. Hu: None. J. Wei: None. A. DiStefano-Forti: None. V.R. Salerno Gonzales: None. T. Tsuji: None. S. Wei: None. M. Blüher: Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Speaker's Bureau; Pfizer Inc., Sanofi. Y. Tseng: Other Relationship; Biohaven. Consultant; LyGenesis. C. He: None. R. Kulkarni: Advisory Panel; Novo Nordisk, Biomea Fusion, Inc. Consultant; Inversago Pharma. Advisory Panel; REDD Pharmaceutical.

Funding
This work is supported by NIH grants R01 DK67536 (R.N.K.), UC4 DK116278 (R.N.K. and C.H.), and RM1 HG008935 (C.H.).
371-P: Different Definition Wording of Severe Hypoglycemia (SH) Yields Variable Prevalence and Incidence Rates
Authors: KUEI LIN YU , YE WEN , HEPWORTH EMILY , ANG LYNN , DE ZOYSA NICOLE , AMIEL STEPHANIE A. , FISHER SIMON J. 
Published: June 2024

Introduction & Objective: To determine if different SH definition wording result in different measured SH prevalence and incidence.
Methods: T1D Exchange registrants were surveyed cross-sectionally to collect 6-month SH history with definitions worded from (1) the International Hypoglycemia Study Group (IHSG) 2013 consensus; (2) a large diabetes community website (diabetes.co.uk); (3) a hypoglycemia awareness assessing instrument (HypoA-Q); and (4) the IHSG 2017 consensus. Analyses included McNemar test, kappa statistic, pair-wise Wilcoxon signed-rank test and Spearman correlation coefficient calculation.
Results: 1,580 participants (52% women, median[IQR] age 43[33—58]y, diabetes duration 24[12—37]y, 87% non-Hispanic Caucasian) completed the survey. SH prevalence with the 2013 IHSG definition wording was higher than the website, HypoA-Q and 2017 IHSG definition wording (Figure), with pairwise kappas ranging from fair to good (website definition .75; HypoA-Q .72; the 2017 IHSG definition .69). Compared to the 2013 IHSG definition wording, the website, HypoA-Q and 2017 IHSG definition wording yielded lower incidence. The 2013 IHSG definition wording correlated strongly with the website (rs=.73), HypoA-Q (rs=.72) and moderately with the 2017 IHSG definition wording (rs=.61) (P&lt;.001 for all).
Conclusion: Reported SH prevalence and incidence vary based on definition wording.

Disclosure
Y. Lin: None. W. Ye: None. E. Hepworth: None. L. Ang: None. N. de Zoysa: None. S.A. Amiel: Advisory Panel; Vertex Pharmaceuticals Incorporated. Other Relationship; Sanofi. S.J. Fisher: None.

Funding
National Institutes of Health (U01DK135111, K23DK129724)
38-PUB: Tunable Glucose Limiting Membranes for CGMs
Authors: MARTINEZ ANDRE 
Published: June 2024

Introduction & Objective: Glucose limiting membranes (GLM) are essential components of continuous glucose monitors (CGM), often generated as blends of hydrophobic and hydrophilic polymers. Blending may complicate processing steps for manufacturers with issues including a need for multiple solvents and strict control of casting conditions to avoid inhomogeneities and macrophase separation. DSM Biomedical has developed new amphiphilic thermoplastic polyurethanes (TPUs) called the Sparsa platform to serve as single component GLMs that achieve required properties without blending.
Methods: Sparsa TPUs were synthesized via a two-step, prepolymer and chain extension method. The formulation was varied to evaluate impact of polymer hardness and hydrophilicity. Permeability of glucose and oxygen through the membranes were analyzed utilizing a Franz cell experiment and oxygen transmission rate instrument respectively. Microphase architecture was evaluated using AFM and SAXS. Fouling behavior was investigated using a quartz crystal microbalance technique and bovine serum albumin. Biocompatibility was evaluated using the L929 MEM elution test and histology following implantation in a porcine model.
Results: Sparsa TPUs were tunable to desired glucose permeability levels and cast from a single solvent. Microstructure and performance were minimally sensitive to fluctuation in ambient humidity during casting. Protein fouling was substantially reduced compared to conventional TPUs. Sparsa TPUs did not cause cytotoxicity and tissue response was similar or less pronounced than for a commercial CGM sensor.
Conclusion: Sparsa TPUs demonstrate tunability in glucose permeability and simplify production of CGMs. Technical properties and biocompatibility indicate Sparsa TPUs can replace current GLMs with improved or equivalent performance.

Disclosure
A. Martinez: None.
391-P: Targeted Deletion of Rho-Associated Coiled-Coil–Containing Protein Kinase 2 in Kidney Tubules Suppresses Expression and Function of Mineralocorticoid Receptor in Mice
Authors: SEKIGUCHI KENSUKE , MATOBA KEIICHIRO , OHASHI SHINJI , MITSUYOSHI ETSUKO , NAGAI YOSUKE , NISHIMURA RIMEI 
Published: June 2024

The mineralocorticoid receptor (MR) is a steroid receptor responsible for fluid and electrolyte reabsorption in kidney tubules. Traditionally, MR has been considered a ligand-activated nuclear transcription factor primarily transactivated by aldosterone. Recent studies have indicated that MR is stimulated in an aldosterone-independent manner by Rac1, a member of the Rho small GTPase family. Rho and its effector Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) plays important roles in various cellular functions such as cell adhesion and cytoskeletal rearrangement. However, the tissue-specific role of ROCK2 in kidney tubules is not fully understood. To investigate the role of ROCK2 signaling in tubules, we generated tubule-specific ROCK2 knockout mice (TR2KO) by crossing Ksp-Cre mice with mice containing loxP sites flanking in Exon 3 of ROCK2. These mice displayed no significant differences in body appearance or blood pressure compared to wild-type mice (WT). However, when sodium reabsorption was activated by low dietary potassium, the urinary excretion of sodium and chloride in TR2KO was significantly higher than that in WT. MR and its downstream target, epithelial sodium channel (EnaC), were significantly downregulated in TR2KO compared with WT at mRNA and protein levels. To identify factors related to the regulation of MR by ROCK2, we obtained several candidates from the Chip Atlas. Among these, the expression of STAT3 protein was significantly reduced in TR2KO. Using HEK293-MR cells, which stably expressed human MR, we found that siRNA-mediated STAT3 deletion led to the downregulation of MR at the mRNA level. These findings provide novel insights into the ROCK2 signaling in kidney tubules and establish a hitherto unidentified regulatory mechanism of MR in modulating electrolyte homeostasis.

Disclosure
K. Sekiguchi: None. K. Matoba: None. S. Ohashi: None. E. Mitsuyoshi: None. Y. Nagai: None. R. Nishimura: Speaker's Bureau; Abbott. Advisory Panel; Abbott Japan Co., Ltd. Speaker's Bureau; Boehringer-Ingelheim, Mitsubishi Tanabe Pharma Corporation, Kowa Company, Ltd., Medtronic, Sanofi, Taiho Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Teijin Pharma Limited, Eli Lilly and Company, Novo Nordisk A/S. Consultant; Terumo Corporation.
393-P: SZ-A Ameliorates the Nondiabetic Chronic Kidney Disease by Modulating Fatty Acid Metabolism and Restoring Mitochondrial Homeostasis in Rats
Authors: SONG JIAWE , YE JUN , TANG YAN , XIAO XINHUA , LIU YULING 
Published: June 2024

Introduction: Current treatment strategies for chronic kidney disease ( CKD ) focus on controlling risk factors, and diabetes is the main cause of CKD progression to end-stage renal disease. SZ-A, a natural medicine for type 2 diabetes approved by the China National Products Administration in 2020, exerts protective effects against the development of diabetic nephropathy. However, the mechanism and whether SZ-A has an effect on kidney damage independent of its glucose-lowering effect have not been thoroughly elucidated. This study aims to evaluate the efficacy of SZ-A in slowing the progression of nondiabetic CKD.
Methods: A rat model of chronic kidney disease induced by adenine was established, and treated with SZ-A or control medication: acarbose or dapagliflozin, daily oral gavage for four weeks. Kidneys from all groups of rats were functionally evaluated and harvested for transcriptome sequencing analysis at the end of the experiment.
Results: Chronic adenine dosing resulted in severe CKD in vehicle-treated rats, as evidenced by significant increases in serum creatinine and UACR. SZ-A dose-dependently attenuated renal injury independent of glucose-lowering effects. This effect of the highest dose of SZ-A was comparable to that of dapagliflozin, whereas acarbose had no effect. In addition, renal fibrosis and inflammation were improved in the SZ-A treatment group compared to the model group. Transcriptomic analysis showed that the renoprotective effect of SZ-A was associated with the upregulation of PPAR signaling pathway and the inhibition of inflammation; in addition, the PPAR signaling pathway was closely related to FAO and mitochondrial homeostasis, and the ameliorative effect of SZ-A on both was verified at both tissue and cellular levels of rat kidney.
Conclusions: The fact that SZ-A is able to attenuate CKD progression in the adenine-induced model corroborates its potential as a therapeutic renoprotector.

Disclosure
J. Song: None. J. Ye: None. Y. Tang: None. X. Xiao: None. Y. Liu: None.

Funding
CAMS Innovation Fund for Medical Sciences (CIFMS, no. 2021-I2M-1-028)
395-P: QingReYiQiHuoXue Formula Attenuates Dyslipidemia and Ferroptosis in DKD HFD/STZ Mice
Authors: WEI YU , ZHANG LILI 
Published: June 2024

Background: Diabetic kidney disease (DKD), a common complication of diabetes, increasingly threatens patients. Approximately 20%-40% of diabetic patients develop DKD, with 30%-50% progressing to end-stage renal disease. QingReYiQiHuoXue Formula (QRF) has demonstrated clinical efficacy in treating DKD, yet its underlying mechanisms remain unclear. Purpose: This study aimed to explore the mechanisms of QRF in treating DKD and to validate its effects on lipid abnormalities and ferroptosis in a DKD mouse model.
Methods: An integrated approach, encompassing network pharmacology, molecular biology, pharmacodynamics, and lipidomics, was employed to elucidate the mechanisms of QRF in treating DKD. Network pharmacology was initially used to predict potential pathways and targets of QRF in treating DKD, along with potential targets for ferroptosis from the ferroptosis database. The efficacy was then validated in a DKD mouse model induced by HFD and STZ injection, including blood and urine tests, histopathological analysis, ferroptosis level measurement, and lipidomic analysis.
Results: Through network pharmacology, we discovered that QRF may regulate both the PI3K/AKT/GSK3β signaling pathway and ferroptosis. In vivo experiments confirmed QRF's renal protective effects in HFD/STZ-induced DKD mice, significantly reducing blood glucose levels, ameliorating blood lipid abnormalities, and reducing renal tissue damage. Lipidomic analysis revealed QRF's regulatory effects on renal lipid metabolism, particularly in reducing levels of polyunsaturated fatty acids (PUFAs) associated with ferroptosis. Further validation showed QRF's potential in modulating ferroptosis and the PI3K/AKT/GSK3β signaling pathway.
Conclusion: QRF alleviates renal damage in a diabetic mouse model by modulating the PI3K/AKT/GSK3β signaling pathway, improving lipid metabolism disorders, and suppressing ferroptosis. This study offers preliminary insights into the mechanisms of QRF in treating DKD.

Disclosure
Y. Wei: None. L. Zhang: None.
429-P: The Correlation Analysis between Trajectory Patterns of Triglyceride–Glucose Index and Diabetic Kidney Disease
Authors: YU SHANSHAN , MEN LILI , DU JIANLING 
Published: June 2024

Introduction & Objective: The triglyceride-glucose (TyG) index, an effective marker of insulin resistance (IR), has been confirmed to be associated with the risk of cardiovascular events in T2DM patients. However, studies related to the correlation between TyG index and diabetic kidney disease (DKD) is still limited.
Methods: 678 T2DM patients were selected from Metabolic Management Center of the First Affiliated Hospital of Dalian Medical University from October 2016 to October 2022. The patients were divided into groups according to the different change trajectories of TyG index, eGFR, and urinary albumin according to latent class growth model (Figure A-C), and multiple unordered logistic regression was used to analyze the correlation between TyG trajectory, eGFR trajectory and urinary albumin trajectory.
Results: Compared with the middle stable trajectory group of eGFR, the TyG index of patients in the low decline trajectory group and the high stable trajectory group was higher (P&lt;0.001). Compared with the low trajectory group of urinary albumin, the TyG index of patients in the middle trajectory group and high trajectory group was higher (P&lt;0.05). Trajectories of TyG index in T2DM patients were related to trajectories of eGFR and urinary albumin (Table 1).
Conclusion: TyG index is related to DKD in T2DM patients.

Disclosure
S. Yu: None. L. Men: None. J. Du: None.
45-PUB: Persistent Performance Improvement Using Interdisciplinary Resources and Continuous Glucose Monitoring in Patients with Poorly Controlled Type 2 Diabetes
Authors: BEHNKE ANDREW , REDDY VARSHA , LUCAS KARA , ORLOWSKI MICHELLE 
Published: June 2024

Aims: The purpose of this study was to examine the effects of a pharmacist managed monitoring and interaction program using continuous glucose monitoring in a population of poorly controlled (A1C &gt;10 %) patients with type 2 diabetes.
Methods: This study was conducted in the outpatient clinical setting and examined levels of Time in Range and A1C for 12 patients with poorly controlled type 2 diabetes as indicated by an A1C level of greater than 10%. The intervention included use of a continuous glucose monitor (CGM) and weekly interactions either virtually or by telephone by one of the team members.
Results: After 13 weeks, the average A1C levels reduced from 11.47% to 7.7% (p&lt;001). Over 90% of the subjects achieved an A1C of less than 10%. After 26 weeks, the average A1C was 8.18% (p =0.01). Time in Range increased from 36.5 % initially to 60% at three months and 56% at six months. There were no significant changes in the amount of insulin dose.
Conclusions: The combination of continuous glucose monitoring and frequent interaction in a brief (three months) time frame may be a significant tool to improve glucose control up to 6 months in this high-risk population.

Disclosure
A. Behnke: Research Support; Abbott. V. Reddy: None. K. Lucas: None. M. Orlowski: None.

Funding
Abbott (15130167v1)
452-P: Folic Acid on Homocysteine Levels in Type 2 Diabetes Patients—Systematic Review and Meta-analysis of Randomized Controlled Trials
Authors: MOKGALABONI KABELO O.S. , PHOSWA WENDY N. , MASHABA RENEILWE G. 
Published: June 2024

Introduction and objectives: The beneficial effect of folate has been observed in various conditions; however, the available evidence on homocysteine and reduction of cardiovascular disease (CVD) in type 2 diabetes (T2D) is limited. This study aims to quantitatively assess the effects of folate on homocysteine levels and the risk of CVDs in individuals with T2D.
Methods: We comprehensively searched clinical trials from PubMed, Cochrane, and Scopus. The trials that focused on adult T2D using folate were included, while those with different interventions, T1D, and animal models of T2D were excluded. A random effect model was used due to heterogeneity. The data was analyzed using Jamovi 2.4.8. Results were presented as standardized mean differences (SMD) and 95% confidence intervals using forest plot.
Results: Evidence retrieved from 9 studies with a sample size of 426 T2D patients was analyzed. Folate supplementation led to a significant reduction in homocysteine (SMD = -1.26 µmol/L, 95% CI: -1.74 to -0.78, p &lt; 0.05) (Figure 1). The subgroup of the sample below 50 revealed no heterogeneity compared to a sample over 50.
Conclusion: Our findings suggest that folate in T2D patients may reduce homocysteine and consequently mitigate CVD. Future trials should explore the effects of folate on homocysteine, especially using a large enough sample size.

Disclosure
K.O.S. Mokgalaboni: None. W.N. Phoswa: None. R.G. Mashaba: None.
519-P: Association of Circulating Sphingolipids with Glycemia in People without Diabetes
Authors: ASUZU PEACE , ALIYE FETO NASER , STENTZ FRANKIE B. , WAN JIM Y. , MANDAL NAWAJES , DAGOGO-JACK SAMUEL 
Published: June 2024

Objective: Sphingolipids (SPL) are involved in the pathogenesis of diabetes. We examined plasma SPL levels in relation to glycemic markers in people without diabetes.
Methods: Plasma SPL levels{ceramides (Cer), monohexosylceramides (MHC), sphingomyelin (SM) and sphingosine (So)} were assayed using LC-MS/MS in healthy adults free of diabetes. Using OGTT, subjects were classified into those with normal fasting (FPG) and 2hPG (NFG-NGT), IFG, IGT, and IFG-IGT.
Results: The participants (N=520, 63% female; 48% Black, 52% White) had a mean age of 45.5 + 9.84 yr, BMI 32.4 + 7.24 kg/m2 and waist 101 + 17.0 cm; FPG was 99.8 + 10.5 mg/dl mg/dl, 2hPG 145+ 29.4 mg/dl, and HbA1c 5.80 + 0.53%. FPG and 2hPG correlated inversely with MHC and positively with other circulating SPL levels (Fig. 1), adjusted for age, sex, race, BMI and waist. Weaker correlations were seen with HbA1c (r 0.04-0.19, P=0.43-&lt;0.001). Compared with NFG-NGT, subjects with IFG-IGT had lower MHC and 4-fold higher Cer C16:0/C18:0 (P&lt;0.0001).
Conclusion: Higher levels of major SPL species, and lower MHC, are associated with upward glycemic drift within the nondiabetic range, suggesting a link between SPL metabolism and glucoregulation.

Disclosure
P. Asuzu: None. N. Feto: None. F.B. Stentz: None. J.Y. Wan: None. N. Mandal: None. S. Dagogo-Jack: Consultant; Merck Sharp & Dohme Corp., Medtronic, Bayer Inc. Stock/Shareholder; Aerami.

Funding
National Institute of Health (DK128129)
545-P: Ethnic Variations in Willingness to Participate in Diabetes-Related Health Research
Authors: ROMERO RYAN L. , CRIST SHAUN M. , VACCARO JOAN A. , WEBB FERN , NEFF DONNA F. , GAILLARD TRUDY R. 
Published: June 2024

Introduction & Objective: In the US, there is a clear disparity in ethnically diverse participation in health research due to historical and social contexts. Our objective was to analyze the willingness of ethnically diverse adults to participate in health research within the Florida Statewide Register for Aging Studies (FSRAS).
Methods: A structured survey of 164 ethnically diverse adults who listed diabetes as a top three health concern, drawn from the FSRAS, captured the degree of willingness to engage in various health research modalities. The survey stratified responses by ethnicity, including Black Hispanic, Black Non-Hispanic, Caribbean, and White Hispanic groups. Statistical measures of central tendency and dispersion characterized the level of interest in participation.
Results: The study uncovered a complex landscape of willingness to participate in diabetes-related research. Caribbean adults demonstrated the most robust engagement, with nearly 59% indicating "Definitely" or "Maybe" to participating (n=197 for both responses). White Hispanic individuals showed a similar trend (n=187 for "Definitely" or "Maybe"). In contrast, Black Non-Hispanic adults exhibited the highest levels of reluctance, with 63% choosing "Maybe Not" or "Definitely Not" (n=199 for both responses). Black Hispanics mirrored this hesitancy (n=198 for "Maybe Not" or "Definitely Not").
Conclusion: Willingness to participate in diabetes-related research varied by ethnicity within the Black race with Caribbean adults being most willing and Black non-Hispanic adults the least willing. White Hispanics were more likely than Black Hispanics to participate. The study underscores the necessity for multifaceted, culturally competent engagement strategies that are grounded in the understanding of ethnicity-specific concerns and historical contexts. Enhancing trust and participation through such tailored approaches could lead to more inclusive health research engagement.

Disclosure
R.L. Romero: None. S.M. Crist: None. J.A. Vaccaro: None. F. Webb: None. D.F. Neff: None. T.R. Gaillard: None.

Funding
NIAR24AG067951