bluuebunny/crossref_metadata_2025_split huggingface dataset:
449-P: Liraglutide Rapid Effects on Glucose and Adipose Tissue during and after CABG
Authors: IACOBELLIS GIANLUCA , FRASCA DANIELA 
Published: June 2024

Introduction: Optimization of glucose control during coronary artery by-pass grafting (CABG) is a major goal to reduce intra and post-op morbidity and mortality in subjects with coronary artery disease (CAD) and type 2 diabetes (T2DM). Glucagon like peptide-1 receptor analogs (GLP-1RAs) reduce cardiovascular risk. However, the short-term effects of GLP1RA on intra and post CABG metabolic control is unknown.
Objective: was to evaluate if pre-operative treatment with liraglutide can improve intra and post CABG glucose and metabolic control
Methods: This was a 12-week randomized, double-blind, placebo-controlled interventional study in 38 patients with T2DM and CAD with an acceptable glycemic control (HbA1c &lt;8%) who required elective CABG. Subjects were started on either liraglutide or placebo in addition to current treatment for a minimum of 4 up to 12 weeks prior to CABG. Fat samples were collected during CABG; blood and clinical data were obtained before starting either liraglutide or placebo, intra-op and 1-month post-op.
Results: The two groups were very homogenous prior to the CABG. Patients who were randomized to liraglutide had significantly better intra-op glucose control during the CABG than those on placebo (146±21 vs 160±21 mg/dl, p&lt;0.01). BMI and body weight significantly decreased at 1-month post-op when compared to baseline in patients who were randomized to liraglutide (from 32.7±6 to 30.5±5 kg/m2; from 214±39 to 208±38 lbs p&lt; 0.05 for both), whereas placebo had no significant BMI or body weight changes. Post-op HbA1c improved in both liraglutide and placebo group (from 6.9 to 5.9% and from 7.2 to 6.1% respectively, p&lt;0.01). Coronary epicardial fat (EAT) inflammatory transcriptome was significantly different than subcutaneous fat (p&lt;0.01).
Conclusions: This RCT shows for the first time that short-term pre-CABG liraglutide induces significant beneficial cardio-metabolic effects, such as better intra- and post-operative glucose control, EAT changes and post-operative weight loss.

Disclosure
G. Iacobellis: None. D. Frasca: None.

Funding
NCT03260881
451-P: Different Cardioprotective Efficacy of Metformin, Empagliflozin, and Semaglutide to Attenuate High Glucose–Oxidative Stress via Nrf2/Keap1 in Murine Cardiomyocytes
Authors: SENESI PAMELA , FERRULLI ANNA , GALLAZZI MATTEO , BASSANI BARBARA , BRUNO ANTONINO , LUZI LIVIO 
Published: June 2024

SGLT2 inhibitors (SGLT2is) and GLP-1R agonists (GLP-1RAs) represent the innovative drugs in the management of failure and ischemic heart disease. Moreover, new studies are evaluating metformin (M) action on heart. However, cardiac cellular mechanisms regulated by glucose-lowering drugs have yet to be adequately investigated. This study aimed to compare M, E and GLP-1RA semaglutide (S) impact on i) mitochondrial reactive oxygen species (mtROS) production, ii) Nrf2/Keap1 axis, and iii) cellular damages induced by high glucose in H9c2 rat cardiomyocytes. H9c2 were exposed to normal (NG, 5.5 mM) or high glucose (HG, 33 mM) for 48 h and treated with 400 uM M (MHG), 500 nM E (EHG) or 100 nM S (SHG) for 24 h. H9c2 cells were cultured in NG or HG as controls. E and S reduced HG-induced mtROS production whereas M action was ineffective. Consistent with these results, E and S significantly activated Nrf2/Keap1 axis promoting Nrf2 translocation into the nuclei and the anti-oxidant response. In MHG cells, Nrf2 translocation was limited. As known, Nrf2/Keap1 is modulated by AKT and AMPK pathways that are inhibited by HG. E significantly improved AMPK activation whereas S increased AKT signaling. M weakly rise AMPK activation. HG induced-mtROS is associated to ERKs up-activation and structural alterations. In HG medium, H9c2 became hypertrophic and acquired rounded morphology. Both E and S significantly downregulated ERKs activation and restored fusiform morphology and size. M only counteracted hypertrophic process. All drugs have a similar effect only on cellular viability rescuing the reduction of H9c2 proliferation caused by HG. Overall, our results suggest that i) E and S are more effective in mitigating HG-induced cardiac injury that M, ii) E and S seem act in similar manner, reducing mtROS via Nrf2/Keap1 axis, and restoring respectively AMPK and AKT signaling. This study suggests potential combined therapy in diabetic patients.

Disclosure
P. Senesi: None. A. Ferrulli: None. M. Gallazzi: None. B. Bassani: None. A. Bruno: None. L. Luzi: Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. Research Support; Boehringer-Ingelheim. Advisory Panel; Medtronic. Research Support; MOVI. Advisory Panel; SUNSTAR. Speaker's Bureau; SAVIO, Amgen Inc.
458-P: Whole Left Ventricular Cardiac MRI in High-Risk People with Type 1 Diabetes Reveals Pathological Extracellular Volume Fraction and T1 Relaxation Times
Authors: NOVODVORSKY PETER , DUBSKY MICHAL , MARHEFKOVÁ NATÁLIA , ADLA THEODOR , ROLAND ROBERT , PAZDERNIK MICHAL , HALUZIK MARTIN , GARG PANKAJ 
Published: June 2024

Introduction: Diffuse myocardial fibrosis is a negative CV prognostic marker. We employed advanced cardiac MRI (CMR) techniques for detailed left ventricular myocardial tissue characterization people with type 1 diabetes (PwT1D) and high CV risk.
Methods: Quantitative native T1 mapping (T1) and extracellular volume fraction (ECV) calculation of the whole left ventricular myocardial volume (LVMV) was done (1.5T Avanto Fit, Siemens) in PwT1D and high CV risk (CAC score &gt;400 and/or presence of ≥2 atherosclerotic plaques in the carotids) but without clinical diagnosis of CVD or heart failure. Percentage of LVMV above the normal values for T1 (&gt;1100 ms) and ECV (&gt;28 %) was calculated.
Results: Twelve PwT1D (8/12 women) with mean (SD) [range] age 65 (2) [60 - 67] years, diabetes duration 36 (12) [16 - 56] years, HbA1c 7.5 (0.9) [6.0 - 8.8] %, LV EF 66 (7) [54 - 77] % were analyzed. Mean (SD) [range] native T1 time was 1060 (41) [996 - 1138] ms and the % of LVMV &gt;1100 ms was 27 (11) [14 - 47] % (Fig. 1A). Mean (SD) [range] ECV was 28.6 (3.5) [23 - 33] % and the % of LVMV &gt;28 % was 47 (21) [7 - 78] % (Fig. 1B).
Conclusion: This is the first CMR study which has applied threshold values to native T1 and ECV data for the whole LVMV in PwT1D. We demonstrate large myocardial areas which are above the normal values. Clinical implications of our findings will require further evaluation on larger populations.

Disclosure
P. Novodvorsky: Speaker's Bureau; Sanofi, Boehringer-Ingelheim. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Novo Nordisk A/S. Research Support; Sanofi. Speaker's Bureau; Abbott, Medtronic, Berlin-Chemie AG, Viatris Inc., Novartis AG. M. Dubsky: None. N. Marhefková: None. T. Adla: None. R. Roland: None. M. Pazdernik: None. M. Haluzik: Advisory Panel; Sanofi, Novo Nordisk, Eli Lilly and Company, AstraZeneca, Bayer Inc., Johnson & Johnson Medical Devices Companies. Consultant; Merck & Co., Inc., Sanofi, Novo Nordisk, Eli Lilly and Company, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Johnson & Johnson Medical Devices Companies, Novatin. Research Support; Sanofi. Speaker's Bureau; Sanofi, Novo Nordisk. P. Garg: Consultant; Edwards Lifesciences, Anteris. Advisory Panel; Pie Medical, Medis.

Funding
National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, Project No. LX22NPO5104); Funded by the European Union; Next Generation EU
478-P: Preventing Peripheral Neuropathy in Adults with Type 2 Diabetes—A Meta-analysis of Randomized Clinical Trials
Authors: GUNAWAN SOPHIA , ANTONY THERESA , NICHOLSON ANDREW , NATARAJAN SUNDAR 
Published: June 2024

Background: Diabetic Peripheral Neuropathy (DPN) is a debilitating complication of diabetes. Current diabetes management guidelines recommend targeting modifiable risk factors like glycemia, blood pressure (BP), lipids, obesity, and smoking to prevent DPN, but their individual effectiveness is unclear.
Aim: To quantify the effectiveness of interventions targeting modifiable risk factors to prevent DPN in adults with Type 2 diabetes (T2D).
Methods: The PubMed database was searched for randomized clinical trials (RCTs) from 1980 to 2023 focused on DPN prevention in adults with T2D. Eligible studies evaluated glycemic control, BP control, lipid control, obesity, or smoking cessation interventions against placebo or usual care, and reported DPN incidence for intervention and control groups. Meta-analysis for each therapy was conducted using a random-effects model in R. Heterogeneity was assessed using the I2 statistic.
Results: Seven RCTs for glycemic control and three RCTs for BP control were identified for adults with T2D. There was no significant difference in the incidence of DPN between intervention and control groups for glycemic control (Odds Ratio [OR]=0.96, 95% Confidence Interval [CI] [0.88, 1.05], p=0.38, I2=0%) and BP control (OR=0.86, 95% CI [0.39, 1.88], p=0.70, I2=78%). We were unable to identify enough high-quality RCTs to conduct meta-analysis evaluating the effect of lipid control, smoking cessation, or obesity reduction on preventing DPN.
Conclusions: While glycemic and BP control are recommended in clinical guidelines to prevent DPN, they have not been definitively shown to prevent incident DPN in adults with T2D. Identifying high-risk DPN groups using genomics or other markers and conducting high-quality RCTs in these high-risk groups using the aforementioned therapies calibrated to reach clearly specified risk factor levels may be needed to develop personalized treatments that are effective in preventing DPN in T2D.

Disclosure
S. Gunawan: None. T. Antony: None. A. Nicholson: None. S. Natarajan: None.
48-PUB: Implementation of a Student-Tailored Version of the Diabetes Prevention Program
Authors: WISK LAUREN E. , SOETENGA SAMANTHA , DIAZ ROLDAN KATE , BHAGAT MEERA , KRYGER VALERIE , VU AMANDA V. , MOIN TANNAZ 
Published: June 2024

One-in-four young adults have prediabetes in the US so there is a need to adapt evidence-based programming, such as the National Diabetes Prevention Program (DPP). To address this important public health concern, we are testing a student-tailored DPP in a pilot RCT during the 2023-24 academic year.Undergraduates at a major university were recruited in the first three weeks of the academic year using a self-administered eligibility form assessing type 2 diabetes risk. Survey responses and feasibility outcomes are described.
Among 875 completed surveys, 315 students (36.0%) met DPP eligibility criteria. Of eligible students, 28 (8.9%) disclosed a diagnosis of prediabetes, 309 (98.1%) met BMI-based eligibility criteria, and 15 (4.8%) had a qualifying score on the CDC risk test; 29 (9.2%) students met more than one criteria. Compared to ineligible students, eligible students were statistically (p&lt;0.05) more likely to be Hispanic/Latinx (36.2% vs 23.9%), have a family history of diabetes (41.0% vs 27.9%), physically inactive (23.5% vs 15.4%), food insecure (35.2% vs 23.4%), financially vulnerable (30.8% vs 21.8%), and report high levels of personal stress (54.0% vs 43.4%); groups were similar with regard to sex (74.5% female overall). We successfully enrolled our target of 80 participants into the trial. Enrolled participants were similar to eligible participants except for being younger (mean age 19.7±1.4 vs 20.9±4.2) and more likely to be Hispanic/Latinx (48.8% vs 36.2%). Sixty invited students declined participation, the most commonly cited reason was the time commitment (29, 48.3%).
Both the demand and need for diabetes prevention among university students was high. We were successful in reaching socioeconomically vulnerable and diverse students, who stand to benefit the most from targeted diabetes prevention.

Disclosure
L.E. Wisk: None. S. Soetenga: None. K. Diaz Roldan: None. M. Bhagat: None. V. Kryger: None. A.V. Vu: None. T. Moin: None.

Funding
American Diabetes Association (7-23-ICTST2DY-11); NIDDK (5R01DK124503)
484-P: Patient-Reported Burden of Disease in Diabetic Peripheral Neuropathic Pain—Learnings from In-depth Patient Interviews—Substudy of RELIEF-DPN 1
Authors: GAUDIANI LINDA M. , SIKIRICA SLAVEN , HARDIN MARQUETTE B. , ERVIN CLAIRE M. , GOSS DIANA S. , KOSA KATHERINE M. , GOPINATHAN SUMA 
Published: June 2024

Background and Aims: Diabetic peripheral neuropathy often results in diabetic peripheral neuropathic pain (DPNP) which is difficult to manage effectively with the current standards of care. RELIEF-DPN 1, a Phase 2 study in adult patients with Type 1 or 2 diabetes and moderate to severe established DPNP, evaluated the safety and efficacy of LX9211, a potent non-opioid inhibitor of AP2-associated protein kinase 1 (AAK1). A sub-study of RELIEF-DPN 1, employed patient interviews with the objectives of characterizing pre-trial patient-reported disease burden and assessing unmet need in DPNP management.
Methods: Sixty-two telephone interviews were conducted across 31 US clinical sites following a semi-structured interview guide to ensure consistent data capture. Data were analyzed using thematic qualitative data analysis. Dominant trends were compared across interviews to describe themes and relative importance of symptoms observed. Demographic and clinical information were summarized with descriptive statistics.
Results: Of 62 patients interviewed, 39 (63%) were male. The average age was 59.7 years. Analyses revealed the most commonly reported symptoms were numbness (89%), tingling (84%), and burning (71%). The symptoms reported as “most bothersome” were burning (30%), numbness (26%), and tingling (26%). The aspects of daily living most impacted by patient’s DPNP were sleep (81%), mood (66%), and mobility (66%). Over 40% of patients were “not at all satisfied” with prior treatments for DPNP, while 18% reported being “very satisfied.” DPNP was at least “moderately difficult” to manage for 82% of patients; 37% reported it “very difficult.”
Conclusion: This sub-study demonstrates that, from patients’ perspectives, symptoms and aspects of daily living impacted by DPNP are considerably burdensome to patients. This study highlights a pressing need for improved therapy and innovation in DPNP management.

Disclosure
L.M. Gaudiani: Consultant; Biomea Fusion, Inc., Lexicon Pharmaceuticals, Inc. Employee; LifeScan Diabetes Institute. Advisory Panel; Lilly Diabetes. Stock/Shareholder; Dexcom, Inc., Lilly Diabetes, Insulet Corporation, Omnipod, Tandem Diabetes Care, Inc. Research Support; Lilly Diabetes. S. Sikirica: Employee; Lexicon Pharmaceuticals, Inc. M.B. Hardin: Employee; Lexicon Pharmaceuticals, Inc. C.M. Ervin: Other Relationship; Lexicon Pharmaceuticals, Inc. D.S. Goss: Other Relationship; RTI International. K.M. Kosa: None. S. Gopinathan: Employee; Lexicon Pharmaceuticals, Inc.

Funding
Lexicon Pharmaceuticals, Inc. The Woodlands, TX USA
49-OR: GPSM1 Regulates Atherosclerosis Progression by Controlling Macrophage Chemotaxis through PKA/KLF4/PMP22-MAPK Pathway
Authors: ZHANG YUEMEI , HU CHENG 
Published: June 2024

Introduction & Objective: The infiltration of macrophages into the vessel walls are the central part of atherosclerosis-one kind of macrovascular complication of diabetes. However, the detailed mechanisms remain unclear. We aim to determine whether myeloid cell G-protein-signaling modulator 1 (GPSM1) regulates atherosclerosis and macrophage chemotaxis.
Methods: We used myeloid-specific GPSM1 ablation mice on Apoe-/- background, and GPSM1 overexpression/deficient mice with an AAV-PCSK9 injection to explore function of GPSM1 in atherosclerosis. BMDMs and THP-1 cells were used to access mechanism of GPSM1 in regulating macrophage chemotaxis. Apoe-/- mice were injected with a small-molecule compound, AN-465 that countered GPSM1 function to evaluate potential therapeutic effects of GPSM1 on atherogenesis.
Results: Myeloid-specific GPSM1 ablation protects mice against atherosclerosis and reduces atherosclerotic plaque formation and aortic inflammation, both in Apoe-/- double knockout mice and an AAV-PCSK9 injection model. In contrast, myeloid-restricted overexpression of GPSM1 induces promotes atherosclerosis development in mice. Particularly, GPSM1 deficiency suppresses oxidized low-density lipoprotein (oxLDL)-burdened monocytes priming and macrophages chemotaxis and migration, thereby alleviating pro-inflammatory responses within atherosclerotic plaque. Mechanistically, GPSM1 loss inhibits P38/ERK MAPK pathway through cAMP/PKA/KLF4/PMP22 axis in macrophages, ultimately resulting in impaired macrophage chemotaxis and migration. Finally, pharmacological inhibition of GPSM1 with AN-465 reduces plaque formation and macrophage infiltration, suggesting that targeting GPSM1 would be an approach for the treatment of macrovascular complication of diabetes.
Conclusion: Our findings establish that GPSM1 is a new regulator of atherosclerosis and suggest GPSM1 as a potential therapeutic target for atherosclerosis.

Disclosure
Y. Zhang: None. C. Hu: None.
493-P: Cerebral Spinal Fluid Supports Calvaria Bone Marrow to Sustain Hematopoiesis and Protect the Retina following Acute Ischemia/Reperfusion Injury and in Diabetic Retinopathy
Authors: GRANT MARIA B. , ASARE-BEDIAKO BRIGHT , LI CALZI SERGIO , ROSENCRANS ROBERT F. , PRASAD RAM , BOULTON MICHAEL , BUSIK JULIA V. 
Published: June 2024

Introduction and Objectives: Hematopoietic cells emanate from multiple bone marrow (BM) compartments and support microvascular repair. Calvaria BM has a unique exposure to cerebrospinal fluid (CSF) which may modulate hematopoiesis, whereas this exposure does not occur for long bones. We asked if hematopoiesis differed between calvaria and long bones and if so, how this impacted diabetic retinopathy (DR) or the response to ischemia/reperfusion (I/R) injury. Because oxysterols and hematopoiesis have been linked, oxysterol content of paired plasma and CSF were compared.
Methods: In 12-month db/db mice, flow cytometry, micro CT, mass spectrometry (MS) and IHC were used to investigate the impact of type 2 diabetes (T2D) on distinct BM compartments and on DR. Recruitment of BM-derived cells into retina after I/R injury was assessed using in vivo cell labelling of each BM compartment in Kikume Green-Red photoconvertible fluorescent protein (KIKGR) reporter mice.
Results: In db/db mice, calvaria in contrast to tibia underwent slower bone deterioration and less vascular degeneration while sustaining physiological hematopoiesis as evident by elevated levels of myeloid angiogenic cells (MACs), a key vascular reparative BM population. Calvaria was the source of reparative MACs following I/R injury, whereas long bones provided pro-inflammatory monocytes to the retina. MS demonstrated that CSF of db/db mice, but not serum, contained high levels of the neurotropic and anti-inflammatory oxysterols, 22-hydroxycholesterol and 27-hydroxycholesterol.
Conclusion: CSF-derived oxysterols, selectively accessible to the calvaria BM compartment but not long bones, preserves physiological hematopoiesis despite chronic T2D. Calvaria provides a source of reparative cells to the retina following acute injury and retards DR, whereas the long bones primarily provide pro-inflammatory monocytes.

Disclosure
M.B. Grant: None. B. Asare-Bediako: None. S. Li Calzi: None. R.F. Rosencrans: None. R. Prasad: None. M. Boulton: None. J.V. Busik: Consultant; Ceramedix, Inc.

Funding
NEIR01EY012601
494-P: Plasma Metabolomic Profiling of Diabetic Macular Edema
Authors: ZHU XIAO-RONG , LU JING , ZHANG LIN 
Published: June 2024

Background: Diabetic macular edema (DME), a sight-threatening retinopathy, is a leading cause of vision loss in persons with diabetes mellitus. Despite strict control of systemic risk factors, a fraction of patients with diabetes develop DME, suggesting the existence of other potential pathogenic factors underlying DME. This study aimed to investigate the plasma metabotype of patients with DME and to identify novel metabolite markers for DME. Biomarkers identified from this study will provide scientific insight and new strategies for the early diagnosis and intervention of DME.
Methods: To match clinical parameters between case and control subjects, patients with DME (DME, n=30) or those with diabetes but without DME (Control, n=30) were assigned to the present case-control study. Distinct metabolite profiles of serum were examined using liquid chromatography-mass spectrometry (LC-MS).
Results: A total of 190 distinct metabolites between DME and Control groups were identified (VIP &gt; 1, Fold Change &gt; 1.5 or &lt; 0.667, and P &lt; 0.05). The distinct metabolites between DME and Control groups were enriched in 4 KEGG pathways, namely, Glutamate Metabolism, Carnitine Synthesis, Oxidation of Branched Chain Fatty Acids, and Phytanic Acid Peroxisomal Oxidation. Finally, 4 metabolites were selected as candidate biomarkers for DME, namely, 5-Phospho-beta-D-ribosylamine, Succinic acid, Ascorbyl glucoside, and Glutathione disulfide. The area under the curve for these biomarkers were 0.693, 0.772, 0.762, and 0.771, respectively.
Conclusions: This study suggested that impairment in the metabolism and 4 potential metabolites were identified as metabolic dysregulation associated with DME, which might provide insights into potential new pathogenic pathways for DME.

Disclosure
X. Zhu: None. J. Lu: None. L. Zhang: None.

Funding
This work was supported by the National Natural Science Foundation of China (No.82000733)
500-P: Disruption of REDD1 Protein Allostery as a Therapeutic for Diabetic Retinopathy
Authors: DENNIS MICHAEL D. , SUNILKUMAR SIDDHARTH , MILLER WILLIAM P. , SHA CONGZHOU M. , DOKHOLYAN NIKOLAY V. 
Published: June 2024

Introduction & Objective: Increased abundance of the protein Regulated in Development and DNA damage 1 (REDD1, also known as RTP801/DDIT4) in cells of the retina is required for retinal pathology and visual function deficits in diabetic mice. Indeed, an RNA-based therapeutic designed to reduce REDD1 modestly improved visual acuity in patients with diabetic macular edema. Studies here investigated the cause of REDD1 upregulation in the context of diabetes.
Methods: Mice were administered low dose streptozotocin (STZ) to model diabetes and treated with either the SGLT-2 inhibitor dapagliflozin or the antioxidant N-acetyl cysteine. Complementary studies were performed in human MIO-M1 cells exposed to hyperglycemic conditions. Discrete molecular dynamics (DMD) and an artificial intelligence (AI) neural network were used to examine REDD1 structure and ligand binding.
Results: Hyperglycemia and an increase in reactive oxygen species were required for increased REDD1 protein abundance in the retina of diabetic mice, which was observed without a change in REDD1 mRNA expression. Hyperglycemic conditions promoted formation of a cross-strand disulfide bond in REDD1 at C150/C157 that suppressed its normally rapid degradation. DMD revealed allosteric regulation of residues upon formation of the redox-sensitive disulfide bridge that controlled REDD1 proteolysis. Genetic disruption of REDD1 allostery prevented the suppressive effect of disulfide bond formation on REDD1 degradation. Ligands with high bioavailability and cell permeability that bind REDD1 at the site of allosteric regulation were identified.
Conclusions: The results reveal a new molecular switch in the REDD1 protein that is activated by diabetes and suggest that the prior clinical trials designed to reduce REDD1 synthesis were undermined by diabetes-induced blockade of REDD1 degradation. Genetic or small molecule inhibition of REDD1 protein allostery may represent a new clinically translatable therapeutic intervention.

Disclosure
M.D. Dennis: None. S. Sunilkumar: None. W.P. Miller: None. C.M. Sha: None. N.V. Dokholyan: None.

Funding
R01 EY032879