bluuebunny/crossref_metadata_2025_split huggingface dataset:
318-OR: Dapagliflozin Acutely Improves Renal Cortical Oxygenation in Individuals with Type 1 Diabetes and Albuminuria
Authors: LAURSEN JENS CHRISTIAN , HEINRICH NIELS S. , MELO JOANA , HADDOCK BRYAN , RASMUSSEN IDA B. , SAFAVIMANESH FARZANEH , HANSEN CHRISTIAN S. , STØRLING JOACHIM , LARSSON HENRIK B.W. , GROOP PER-HENRIK , FRIMODT-MOELLER MARIE , ANDERSEN ULRIK B. , ROSSING PETER 
Published: June 2021

Objective: Inhibitors of the sodium-glucose cotransporter 2 slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria.
Research Design and Methods: A randomized, double-blinded, crossover study with a single dose of 50 mg dapagliflozin and placebo separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal tissue oxygenation (R2*), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline and three and six hours from intervention. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation and peripheral blood mononuclear mitochondrial oxygen consumption rate, were evaluated at baseline and 12 hours from intervention.
Results: We included 15 individuals (33% females) with a mean (±SD) age 58±14 years, median [Q1;Q3] urinary albumin creatinine ratio of 46 [21;58] mg/g and eGFR of 73±32 ml/min/1.73m2. The mean changes (±SE) in renal cortical R2* from baseline to six hours were for dapagliflozin -1.3±0.7 s-1 and for placebo +1.4±0.7 s-1 respectively, resulting in a difference between interventions of -2.6 s-1 (95% CI, -4.5 to -0.7, p=0.001). No between-intervention differences were found in other MRI outcomes, physiological parameters or exploratory outcomes.
Conclusions: Dapagliflozin improved renal cortical R2* without changing renal perfusion and blood flow. This suggests an improved renal cortical oxygenation due to reduced tubular transport work in the proximal tubules.

Disclosure
J. Laursen: None. P. Groop: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Mundipharma International. M. Frimodt-moeller: None. U. B. Andersen: Other Relationship; Self; Bayer AG. P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd. N. S. Heinrich: Stock/Shareholder; Self; Akebia Therapeutics, Inc., Novo Nordisk A/S. J. Melo: None. B. Haddock: None. I. B. Rasmussen: None. F. Safavimanesh: None. C. S. Hansen: None. J. Størling: None. H. B. W. Larsson: None.
329-OR: Neural Networks in Examining the Association of Built Environment with Diabetes Prevalence
Authors: ZHENG KEVIN , LAWTON RALPH , ZHENG DANIEL Z. , HUANG ERICH 
Published: June 2021

Background: Diabetes is associated with factors such as physical activity, diet, and the environment. Previous studies have shown the use of deep learning and satellite imagery to predict community-level health outcomes. However, no studies have assessed whether these deep learning tools can extract information distinct from demography and socioeconomic status, or can be integrated together for a more robust approach.
Objective: To utilize satellite-imagery based deep learning and traditional survey-based statistical methods to examine the relationship between built environment and diabetes prevalence.
Methods: A convolutional neural network (CNN), a deep learning approach, was used to extract features of built environment from 100,000+ satellite images of Seattle (SEA), Los Angeles (LA), San Antonio (SA), and Memphis (MEM). Diabetes prevalence and population data were retrieved from the CDC PLACES Project and American Community Surveys (ACS). Elastic net and ordinary least squares (OLS) regressions were used to quantify the associations of 1) environmental features and diabetes rates, 2) ACS covariates and diabetes rates, and 3) environmental features and the residuals of the ACS data model.
Results: The all-cities environment CNN model explained 68.2% of variation, while single-city models explained 90.3% (MEM), 81% (SA), 70.5% (SEA), and 46.2% (LA) of variation. ACS OLS models explained 81.2% (all-cities), 84.4% (MEM), 74.1% (SA), 78.1% (SEA), and 76.5% (LA) of variation. The integrated model explained 91.3% (all-cities), 91.5% (MEM), 90.1% (SA), 85.9% (SEA), and 85.9% (LA).
Conclusion: Superior performance of the multimodal analysis, conjoining environmental and population data, demonstrates the capability of CNNs in capturing features of built environment absent from ACS data. Such combined models may enable better understanding of the effects of built environment on diabetes, and guide policymakers in implementing community changes to reduce diabetes prevalence.

Disclosure
K. Zheng: None. R. Lawton: None. D. Z. Zheng: None. E. Huang: Other Relationship; Self; Stratus Medicine, kelaHealth, MedBlue Data.

Funding
National Center for Advancing Translational Sciences (UL1TR002553)
334-OR: Sex Differences in Protein Phosphorylation in Insulin Resistance in Humans at the Cellular Level
Authors: HAIDER NIDA , LEBASTCHI JASMIN , BATISTA THIAGO M. , PAN HUI , DREYFUSS JONATHAN , CARCAMO-ORIVE IVAN , KNOWLES JOSH , KAHN C. RONALD 
Published: June 2021

Insulin resistance in muscle precedes and predicts type 2 diabetes in offspring of diabetic parents and is also observed in ~25% of the general population. However, whether these changes represent cell autonomous defects or are secondary to changes in circulating factors is unclear. To define possible cell autonomous determinants of insulin resistance, we have utilized induced pluripotent stem cell (iPSC) differentiated into myoblasts from 20 nondiabetic individuals - 10 insulin sensitive (I-Sen) and 10 insulin resistant (I-Res) as assessed using the steady-state plasma glucose approach. While there was no difference in the ability of the iPSCs to differentiate into myoblasts (iMyos), cells from I-Res individuals show impaired insulin signaling, decreased insulin-stimulated glucose uptake, and glycogen synthase activity compared to iMyos from insulin sensitive individuals, indicating that these cells mirror in vitro the alterations seen in vivo. The global phosphoproteomic analysis using LC-MS/MS uncovered a large network of proteins whose phosphorylation was altered in association with insulin resistance, mostly outside the canonical insulin-signaling cascade. We also observed striking differences in the phosphoproteomic signature of iMyos derived from male versus female subjects. Analysis of the proteins involved reveals that male cells show enhanced phosphorylation of proteins associated with transcription, Rho GTPases, SUMOylation, mRNA splicing, and membrane trafficking, whereas females show a dominance of phosphorylation of proteins involved in the cell cycle, chromatin organization, gene expression, and protein ubiquitination. Taken together, these data demonstrate major alterations in cellular signaling underlying insulin resistance, even in the absence of diabetes, and provide evidence of a super-network of cell signaling differences in males and females that must be considered in understanding cellular regulation in health and disease.

Disclosure
N. Haider: None. J. Lebastchi: None. T. M. Batista: None. H. Pan: None. J. Dreyfuss: None. I. Carcamo-orive: None. J. Knowles: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences, Inc., Consultant; Self; Flagship Pioneering, Sana/Cobalt.
338-OR: Reversal of Insulin Resistance by Resveratrol and Hesperetin Combination in Overweight and Obese Subjects Correlates with Decrease in Expression of Thioredoxin Interacting Protein
Authors: XUE MINGZHAN , WEICKERT MARTIN , RABBANI NAILA , THORNALLEY PAUL 
Published: June 2021

Trans-Resveratrol and hesperetin combination (tRES-HESP) in randomized, double-blind, placebo-controlled crossover study in overweight and obese subjects corrected insulin resistance; healthy aging through functional food study (HATFF, Clinicaltrials.gov identifier NCT02095873). tRES-HESP is an optimized supplement for induction of expression of glyoxalase 1 (Glo1) via activation of transcription factor Nrf2. Increased Glo1 expression decreases reactive metabolite, methylglyoxal (MG), contributing to insulin resistance through glycation-linked unfolded protein formation and activation of the unfolded protein response (UPR). Herein, we report further analysis of study variables and follow-up reverse translational studies. With tRES-HESP treatment, plasma MG correlated negatively with peripheral blood mononuclear cell (PBMC) quinone reductase activity - a marker of Nrf2 activation (r = - 0.68, P&lt;0.01). For change from baseline of PBMC gene expression with tRES-HESP treatment (assessed by the Nanostring method), change in area-under-the-curve plasma glucose (ΔAUGg) during oral glucose tolerance tests correlated negatively with change in Glo1 expression (r = - 0.56, P&lt;0.05) and correlated positively with change in expression of thioredoxin interacting protein (TXNIP) (r = 0.59, P&lt;0.05). In reverse translational studies, we found tRES-HESP decreased TXNIP expression by 39 ± 1% (P&lt;0.001) in human hepatocyte-like HepG2 cells and 14 ± 3% in BJ fibroblasts in vitro (P&lt;0.01). tRES-HESP may decrease TXNIP expression by decreasing the MG-driven UPR and by direct Nrf2-driven down regulation. TXNIP is a mediator of insulin resistance in liver and skeletal muscle and impaired pancreatic beta-cell insulin secretion. tRES-HESP is suitable for further evaluation for prevention and treatment of type 2 diabetes where decreased TXNIP may contribute to the therapeutic response.

Disclosure
M. Xue: None. M. Weickert: None. N. Rabbani: None. P. Thornalley: None.

Funding
Qatar Foundation; Qatar University
34-OR: Role of Arid5b in Thermogenesis and Adipose Tissue Browning
Authors: SHUKARE MENGISTU LEMECHA , HUANG RUI , EHSANI ALI , ZHANG GUOXIANG , CHALISE JAYA PRAKASH , WHITSON ROBERT H. , ITAKURA KEIICHI 
Published: June 2021

Background: Adipose tissue considerably influence metabolic homeostasis and play a central role in regulating whole-body energy and glucose metabolism. Previously, we have reported that mice with the global deletion of Arid5b are lean and have less fat in white and brown adipose tissues. However, this role is unknown in adipocyte specific Arid5b knockout (5bFKO) mice.
Aim: We investigated the effects of adipose-specific deficiency of Arid5b on systemic glucose homeostasis and adipose tissue metabolism.
Result: Deletion of Arid5b in adipose tissue using adiponectin promoter-driven Cre recombinase significantly improved glucose tolerance with significant reduction of insulin level. Body weight of 5bFKO mice was significantly reduced at the later age. Core body temperature of 5bFKO mice was significantly higher compared to the control mice. Robust increase in the protein expression of uncoupling protein 1 (Ucp1) was observed in inguinal white adipose tissue (iWAT) of 5bFKO mice housed at ambient temperature. This phenotype was further confirmed by prolonged cold exposure where Ucp1 and mitochondrial proteins such as pyruvate dehydrogenase (PDH), mitochondrially encoded cytochrome c oxidase (MTCO1) and ATP5A were substantially increased in iWAT of adipocyte specific Arid5b deficient mice. Gene expression of beige adipogenesis markers such as cell death inducing DFFA like effector A (Cidea) and iodothyronine deiodinase 2 (Dio2) were also significantly increased indicating browning of iWAT. Furthermore, loss of Arid5B in fat led to significant reduction in macrophages and total immune cells in iWAT. All together these results show that the deletion of Arid5b could promote browning of iWAT.
Conclusion: These findings demonstrate that Arid5b regulates thermogenic genes expression to promote beige adipocytes formation and controls adipose inflammation. Inhibition of Arid5b may provide a novel therapeutic approach for obesity and diabetes.

Disclosure
M. Shukare: None. R. Huang: None. A. Ehsani: None. G. Zhang: None. J. Chalise: None. R. H. Whitson: None. K. Itakura: None.
340-P: Nocturnal Hypoglycemia Prediction in Hospitalized Patients with Type 1 Diabetes Using Combined Supervised and Unsupervised Ensemble Learning
Authors: BERIKOV VLADIMIR , SEMENOVA JULIA F. , KLIMONTOV VADIM 
Published: June 2021

The Aim: To assess the efficacy of combined supervised and unsupervised ensemble machine learning based on continuous glucose monitoring (CGM) data for short-term prediction of nocturnal hypoglycemia (NH) in hospitalized patients with type 1 diabetes (T1D).
Materials and Methods: We analyzed CGM records with a minimal duration of 72 hours obtained from 406 adult patients admitted to tertiary referral hospital. An episode of NH was defined as ≥3 consequent glucose values of &lt;3.9 mmol/L recorded between 0 and 6 am. Depending on predictor sequence length (30 min - 1 h) and horizon (H) of forecasting (5-30 min), we obtained 209-256 and near 4∙104 records with and without NH respectively. Twenty nine metrics, including mean, minimal and maximum glucose, range, gradient, linear, quadratic and cubic trend coefficients, dynamic time wrapping similarity-based indices, and a number of glucose variability indices, were evaluated. The ensemble clustering was used for extraction of representative samples. Random Forest ensemble model was applied for NH prediction. The obtained quality metrics were averaged over 100 random partitions of the dataset on training and testing subsets.
Results: The quality metrics did not depend significantly on predictor sequence length; we used 30 min as a baseline. Depending on H, values of sensitivity and specificity varied from 98% and 97% (H=5 min) to 85% and 87% (H=30 min). The false alarm ratio values were very high (&gt;90%) due to the unbalanced nature of data. Minimal glucose, low blood glucose index, and increment in the penultimate value of sequence were the most important predictors assessed with Random Forest algorithm.
Conclusions: The results demonstrate the usefulness of ensemble machine learning models based on CGM time series data for prediction of NH events in hospitalized patients with T1D. Additional studies are needed for improving false alarm ratio metrics of forecasting quality.

Disclosure
V. Berikov: None. J. F. Semenova: None. V. Klimontov: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Sanofi, Research Support; Self; Boehringer Ingelheim International GmbH, Speaker’s Bureau; Self; AstraZeneca, Medtronic.

Funding
Russian Science Foundation (20-15-00057)
359-P: Congestive Heart Failure and the Metabolic Syndrome Are Mutually Independent Predictors of Nonalcoholic Fatty Liver Disease
Authors: MAECHLER MAXIMILIAN , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , SPRENGER LUKAS , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2021

Nonalcoholic fatty liver disease (NAFLD) is associated with both the metabolic syndrome (MetS) and congestive heart failure (CHF). The MetS is highly prevalent in CHF patients; however, the single and joint associations of the MetS and CHF with NAFLD have not been investigated yet. This issue therefore is addressed in the present study.
We investigated 202 patients with CHF and 670 controls who did not have signs or symptoms of CHF and in whom significant coronary artery disease was ruled out angiographically. The presence of NAFLD was determined using the validated fatty liver index (FLI).
The prevalence of the MetS was 61.9% in CHF patients and 45.7% in controls (p&lt;0.001). FLI values and prevalence rates of NAFLD (FLI≥60) in non-CHF subjects without MetS were 40±25 and 25.0%, respectively. They were significantly higher in non-CHF, but MetS patients (71±22, p&lt;0.001 and 69.3%, p&lt;0.001, respectively), in CHF patients without MetS (54±24, p&lt;0.001 and 42.9%, p=0.002, respectively) and in CHF patients with MetS (76±20, p&lt;0.001 and 82.4%, p&lt;0.001, respectively). In multivariate analysis of covariance, the MetS and CHF proved to be mutually independent predictors of FLI after adjustment for age, sex, BMI, LDL-C, history of smoking and hypertension (F=296.94; p&lt;0.001 and F=21.68; p&lt;0.001, respectively); concordantly, the MetS and CHF independently predicted the presence of NAFLD in logistic regression analyses, with adjusted odds ratios of 6.67 [4.83-9.21]; p&lt;0.001 and 2.52 [1.67-3.79]; p&lt;0.001, respectively.
We conclude that CHF and the MetS are mutually independent predictors of NAFLD.

Disclosure
M. Maechler: None. C. H. Saely: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. L. Sprenger: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
365-P: Remnant Cholesterol in Patients with Established Cardiovascular Disease Predicts Cardiovascular Events Both among Patients with Type 2 Diabetes and among Nondiabetic Subjects
Authors: MADER ARTHUR , SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MAECHLER MAXIMILIAN , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2021

Remnant cholesterol, which is calculated as total cholesterol minus LDL cholesterol minus HDL cholesterol has attracted interest as a marker of cardiovascular event risk. The power of remnant cholesterol to predict cardiovascular events in patients with established cardiovascular disease is unclear and is addressed in the present study. We enrolled 1822 consecutive patients with angiographically proven stable CAD (n=1472) and sonographically proven peripheral artery disease (n=350). Prospectively, cardiovascular events were recorded over a mean follow-up period of 6.2±3.2 years. At baseline, remnant cholesterol was significantly higher in patients with T2DM (n=608) than in nondiabetic subjects (27±25 vs. 21±21 mg/dl; p&lt;0.001). During follow-up, 584 of our patients suffered cardiovascular events; the event rate was significantly higher in patients with T2DM than in nondiabetic subjects (45.4 vs. 32.2%; p&lt;0.001). Remnant cholesterol in Cox regression models adjusting for age, sex, hypertension, smoking, body mass index and LDL cholesterol independently predicted cardiovascular events in the total study population (standardized adjusted HR 1.15 [1.07-1.23]; p&lt;0.001), and in patients with T2DM as well as in nondiabetic subjects (standardized adjusted HRs 1.17 [1.03-1.34]; p=0.013 and 1.12 [1.01-1.23]; p=0.028, respectively). From our data we conclude that remnant cholesterol in patients with established Cardiovascular Disease predicts cardiovascular events both among patients with T2DM and among nondiabetic subjects.

Disclosure
A. Mader: None. C. H. Saely: None. L. Sprenger: None. A. Vonbank: None. B. Larcher: None. M. Maechler: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
368-P: Type 2 Diabetes Mellitus Increases Epicardial Adipose Tissue Senescence in Subjects with Coronary Artery Disease during Elective Cardiac Surgery
Authors: MRAZ MILOS , TRNOVSKA JAROSLAVA , KASPEROVA BARBORA JUDITA , DVORAKOVA IVETA , LACINOVA ZDENKA , HLAVACEK DANIEL , MAHRIK JAKUB , IVAK PETER , NETUKA IVAN , HALUZIK MARTIN 
Published: June 2021

Cellular senescence is a novel mechanism suggested to contribute to the development of type 2 diabetes mellitus (T2DM) and cardiovascular diseases. Here, we analyzed the expression of senescent markers in myocardium and adjacent adipose tissue of subjects with and without coronary artery disease (CAD) and T2DM undergoing elective cardiac surgery. Eleven subjects with CAD and T2DM (DM group), 13 subjects with CAD without T2DM (CAD group) and 8 subjects without both CAD and T2DM (C - control) group undergoing elective cardiac surgery (CABG and/or valvular surgery) were included into the study. Samples of subcutaneous (SAT) and epicardial (EAT) adipose tissue and myocardium form right atrial wall were taken along with standard biochemical and anthropometric parameters at the beginning and end of surgery. mRNA expression of senescent markers p21 and p16 was assessed using qRT PCR. All 3 groups did not differ with respect to age (65.2 ± 6.9 vs. 61.7 ± 9.8 vs. 57.9 ± 12.3 years for DM vs. CAD vs. C, n.s.) or BMI (30.8 ± 3.9 vs. 28.5 ± 3.9 vs. 30.2 ± 3.4 kg/m2, n.s.), while DM group showed higher levels of fasting glucose (8.4 ± 1.6 vs. 5.9 ± 1.1 vs. 5.9 ± 0.9 mmol/, p=0.005) and HbA1C (52.5 ± 8.9 vs. 38.9 ± 4.2 vs. 31.5 ± 8.9 mmol/mol, p&lt;0.001) relative to others. At the beginning of surgery no difference in mRNA expression of either factor could be seen in any of the examined tissues except of increased expression of p16 in the myocardium of CAD group (p=0.044 vs. C group). In DM subjects, cardiac surgery significantly increased mRNA expression of p21 in myocardium (p=0.15 vs. C and CAD group) and EAT (p=0.002 vs. C group), while not such change could be seen in the nondiabetic CAD and C group. To conclude, in CAD subjects T2DM is associated with increased cellular senescence in EAT and myocardium during elective cardiac surgery. This mechanism might at least partially explain the more detrimental outcomes of CAD patients with as compared to without T2DM.

Disclosure
M. Mraz: None. M. Haluzik: Advisory Panel; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk, Consultant; Self; Sanofi. J. Trnovska: None. B. Kasperova: None. I. Dvorakova: None. Z. Lacinova: None. D. Hlavacek: None. J. Mahrik: None. P. Ivak: None. I. Netuka: None.

Funding
Ministry of Health of the Czech Republic (RVO-VFN64165, NV19-0200118); IKEM (IN00023001)
369-P: Wound Repair by P53 Silenced Human Endothelial Cell-Derived Conditioned Media, In Vitro
Authors: RIVERA DAYNA K. , NANDULA SESHAGIRI RAO , SEN SABYASACHI 
Published: June 2021

Introduction: Diabetes is associated with impaired wound healing. Studies have demonstrated that endothelial progenitor cells (EPCs) and mature human endothelial cells (EC) are susceptible to apoptosis in hyperglycemic environment and p53 gene silencing prevents cellular senescence and helps vascular regeneration. Our goal was to test whether cell conditioned media obtained from p53 silenced human cells can also improve cellular regeneration.
Methods: Ad-human-P53 (TP53)-shRNA was used to silence P53 and Ad-scrambled-null-shRNA was used as control. To collect condition media, different human cells such as HEK, human CD14+ve cells and HUVEC (human umbilical vein endothelial cells) were cultured in exosome free FBS media for 5 days, following transduction with Ad-p53sh or Ad-null, as the case may be. After transduction, cells were grown in media containing 2% BSA (with no FBS and growth factors) for only 24 h and the collected supernatant was concentrated 10-fold to obtain the conditioned media (CM). Endothelial regeneration or wound healing was tested using endothelial wound healing assay kit (from Cell Biolabs # CBA-120-T).
Results: We compared CM obtained from null and p53sh in HEK, CD14+ve and HUVEC cells on human endothelial cells. Proliferation capacity of the endothelial cells was greater with p53sh CM compared to null and non-transduced CM. The CM obtained from the untreated and null samples did not show increased proliferation in any of the 3 kinds of cells tested. The CM from p53sh HUVEC was more effective than CM from other cells. We are analyzing the CM (exosome and non-exosome fraction) for identification of specific secretory proteins.
Conclusion: P53 silencing appears to improve HUVEC paracrine factors and this particular modality of cell free therapy may have therapeutic role in treating diabetes complications and even aging.

Disclosure
D. K. Rivera: None. S. Nandula: None. S. Sen: None.

Funding
American Heart Association