bluuebunny/crossref_metadata_2025_split huggingface dataset:
436-P: Characterization of Autoimmunity in the Acceleration of Atherosclerosis in Type 1 Diabetes
Authors: PARK KYOUNGMIN , LI QIAN , PARK HYUNSEOK , ST-LOUIS RONALD , FU JIALIN , RASK-MADSEN CHRISTIAN , MADDALONI ERNESTO , YOKOMIZO HISASHI , KISSLER STEPHAN , LICHTMAN ANDREW H. , KING GEORGE L. 
Published: June 2020

Hyperglycemia, hyperlipidemia and hypertension have been evaluated extensively as risk factors for cardiovascular disease (CVD) in people with type 1 diabetes (T1DM). However, the impact of autoimmunity in T1DM on CVD has not been determined. We have generated several mice models of atherosclerosis including ApoE-/-/NOD, ApoE-/-/NOD (congenic non diabetes and non-autoimmune), ApoE-/-/NOD (autoimmunity with insulitis, nondiabetes) and ApoE-/-/NOD autoimmune diabetic mice. All groups of mice have high plasma lipids but only ApoE-/-/NOD diabetic mice had hyperglycemia. However, ApoE-/-/NOD (insulitis and nondiabetes) and ApoE-/-/NOD (insulitis and diabetes) had high titers of autoantibodies to IA2 compared to control CongApoE-/-/NOD mice or nondiabetic ApoE-/-/NOD mice (P&lt;0.0001). For the the severity of atherosclerosis, the presence of hyperglycemia in ApoE-/-/NOD-DM mice showed greater levels of lipid deposition in the descending aorta (22%) by en face assessment as compared to nondiabetic ApoE-/-/NOD mice (P&lt;0.01). Similarly, we also observed in the macrophage content of the descending aorta, was greater in numbers in the ApoE-/-/NOD mice than in ApoE-/-/CongNOD mice (P&lt;0.05) but less than in ApoE-/-/NOD-DM mice. FACS of the descending aorta showed the elevated CD3+/CD28- T-cells (CD4 and CD8) by 4.5 folds and decreased CD3+/CD28+ Treg cells by 46% at the atherosclerotic plaques of ApoE-/-/NOD mice, compared to those of CongApoE-/-/NOD mice. To further confirm the elevated infiltrate and accumulated CD3+ T-cells in vivo, we will investigate the levels of macrophages and CD3+ T-cells in the arterial wall of the coronary artery from the Medalists group T1D and autoimmunity with positive HLA DR3/4 risk alleles and autoantibodies and lacking monogenic diabetic variants, as compared to the group lacking HLA DR3/4 risk alleles and autoantibodies. These studies suggest that autoimmunity exacerbates atherosclerosis in T1D, independently and synergically hyperglycemia.

Disclosure
K. Park: None. Q. Li: None. H. Park: None. R. St-Louis: None. J. Fu: None. C. Rask-Madsen: None. E. Maddaloni: Consultant; Self; Merck KGaA. Speaker’s Bureau; Self; Abbott, AstraZeneca, Pikdare. H. Yokomizo: None. S. Kissler: None. A.H. Lichtman: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.

Funding
National Institutes of Health (R01DK053105); Thomas J. Beatson, Jr. Foundation
437-P: Postprandial Hyperglycaemia Is Associated with Coronary Plaque Rupture in Diabetic Patients with Acute Coronary Syndrome
Authors: SU GONG , ZHANG TAO , ZHUANG SHAOWEI 
Published: June 2020

Postprandial hyperglycemia was reported to play a key role in established risk factors of coronary artery diseases (CAD) and cardiovascular events. Serum 1,5-anhydroglucitol (1,5-AG) levels are known to be a clinical marker of postprandial hyperglycemia and short-term glycemic excursions. Low serum 1,5-AG levels have been associated with occurrence of CAD; however, the relationship between 1,5-AG levels and coronary plaque rupture has not been fully elucidated. The aim of this study was to evaluate 1,5-AG as a predictor of coronary plaque rupture in diabetic patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS). A total of 132 diabetic patients with NSTE-ACS were included in this study. All patients underwent intravascular ultrasound examination, which revealed 38 patients with plaque rupture and 94 patients without plaque rupture in the culprit lesion. Fasting blood glucose (FBS), hemoglobin A1c (HbA1c) and 1,5-AG levels were measured before coronary angiography. Fasting urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) level was measured and corrected by creatinine clearance. Patients with ruptured plaque had significantly lower serum 1,5-AG levels and a tendency of higher hemoglobin A1c levels than patients without ruptured plaque. In multivariate analysis, low 1,5-AG levels were an independent predictor of plaque rupture (odds ratio 3.3; p = 0.006) in diabetic patients with NSTE-ACS, but HbA1c was not. The area under the receiver-operating characteristic curve for 1,5-AG (0.678, p = 0.001) to predict plaque rupture was superior to that for HbA1c (0.618, p = 0.034). Levels of 1,5-AG were significantly correlated with urinary 8-iso-PGF2α (r=-0.224, p = 0.010). Thus, postprandial hyperglycaemia appeared to be superior to long-term average blood glucose levels in predicting plaque rupture in culprit lesions, which may be useful to assess the cardiovascular outcomes in diabetic patients.

Disclosure
G. Su: None. T. Zhang: None. S. Zhuang: None.

Funding
Outstanding Clinical Discipline Project of Shanghai Pudong (PWYGY 2018-05); Beijing Health Special Foundation (JING 15-10)
443-P: Effect of 3-Month Therapy with Liraglutide on Ambulatory Blood Pressure in Patients with Type 2 Diabetes Mellitus
Authors: PAPAZAFIROPOULOU ATHANASIA , MPOUMI LOUIZA , RALLATOU MARIA , PAPANTONIOU STYLIANI S. , KAMARATOS ALEXANDROS , ANTONOPOULOS STAVROS , MELIDONIS ANDREAS 
Published: June 2020

Background and Aims: Liraglutide, has been found to reduce systolic (SBP) and to a lesser extent diastolic blood pressure (DBP). The purpose of this study is to evaluate the effect of liraglutide on ambulatory BP in patients with poorly controlled type 2 diabetes (T2D).
Materials and Methods: A total of 42 patients (20 men) with T2D, mean age (± standard deviation) 60.6 ± 9.4 years, HbA1c 8.5 ± 1.1%, body mass index 37.1 ± 5.3 Kg/m2, duration of T2D 10.1 ± 4.3 years, were included. All patients underwent a complete clinical examination, laboratory testing, and ambulatory BP recording both on entry into the study and three months after initiation of treatment with liraglutide (background antidiabetic therapy remained stable during the study period). Ambulatory BP was measured with the oscillometric Mobil-O-Graph NGW 24-hour ambulatory BP and PWA monitor (IEM; Stolberg, Germany).
Results: At baseline, mean daytime SBP and DBP were 128.0 ± 11.2 and 77.2 ± 11.0 mmHg, respectively. After 3-month liraglutide therapy, daytime SBP and DBP were: 124.0 ± 7.8 and 73.5 ± 7.8 mmHg, respectively. Daytime SBP and DBP, mean change from baseline was -4.0 mmHg (P=0.26) and -3.6 mmHg (P=0.05). Nighttime mean SBP and DBP at baseline, were127.5 ± 12.6 and 73.7 ± 14.2 mmHg. After 3-month therapy, the above values were as follows: 118.6 ± 11.1 and 68.1 ± 9.8 mmHg, respectively. Nighttime SBP and DBP, mean change from baseline was -8.9 mmHg (P=0.009) and -5.6 mmHg (P=0.009). In accordance, pulse pressure change was: 53.9 ± 8.6 (baseline) to 50.6 ± 11.2 mmHg (3 months) and for heart rate: 75.9 ± 10.1 (baseline) to 77.8 ± 14.3 bpm (3 months). Pulse pressure and heart rate change from baseline was -3.2 mmHg (P=0.14) and -1.9 bpm (P=0.36), respectively.
Conclusion: In accordance with the existing data, 3-month therapy with liraglutide had a favorable effect of ambulatory BP, in terms of daily DBP and SBP and DBP during the night. In contrast, no significant effect on heart rate was observed despite the existing data.

Disclosure
A. Papazafiropoulou: None. L. Mpoumi: None. M. Rallatou: None. S.S. Papantoniou: None. A. Kamaratos: None. S. Antonopoulos: None. A. Melidonis: None.
457-P: Quantification of Vascular Density by 3D Light Sheet Imaging in a Surgical Ligation of the Left Anterior Descending Artery (LAD) Model in Mouse
Authors: ZOIS NORA E. , ROOSTALU URMAS , THISTED LOUISE , PEDERSEN PHILIP J. , FOSGERAU KELD , JELSING JACOB , VRANG NIELS 
Published: June 2020

Introduction: Patients with diabetes have an increased risk of cardiovascular disease including myocardial infarction (MI). A major consequence of MI is left ventricular (LV) remodeling including compensatory hypertrophy without concomitant adaptation of the capillary vasculature. Targeting capillary density is thus a promising therapeutic strategy but methods for unbiased and direct quantification are lacking. In a surgical MI model, we used 3D light sheet imaging to visualize and quantify LV remodeling including capillary density.
Methods: Surgical ligation of the left anterior descending artery (LAD) was performed in male C57BL/6 mice. Infarct localization and LV function were evaluated by echocardiography, and LV remodeling and capillary density quantified by 3D light sheet imaging.
Results: Ejection fraction (EF) as measured by echocardiography was reduced in LAD-ligated mice with anterior wall MI compared to mice without MI (29.1±1.5 vs. 55.2±1.1 %, p&lt;0.001), while internal LV volume (as assessed by 3D imaging) was increased (16.6±0.7 vs. 22.7±1.3 mm3, p&lt;0.01) 10 days after LAD ligation. Furthermore, EF and LV volume correlated (R2: 0.59, p&lt;0.001, slope -0.32). The capillary density in the infarct zone was reduced in MI versus no MI mice (10.5±1.00 vs. 23.5±2.5 % of total tissue volume, p&lt;0.001). In a subsequent treatment study, EF was reduced by 43.2% in MI compared to no MI mice (p&lt;0.001) 7 days after LAD ligation. The effects of 4 weeks of treatment with captopril on LV function, remodeling and capillary density was investigated by echocardiography and 3D light sheet imaging.
Conclusions: The combination of echocardiography and 3D light sheet imaging offers a novel approach to visualize and quantify LV function, remodeling and capillary density in a mouse model of MI. This high-resolution 3D imaging technology thus allows for preclinical efficacy testing of novel therapeutics for heart disease including MI.

Disclosure
N.E. Zois: Employee; Self; Gubra. U. Roostalu: Employee; Self; Gubra. L. Thisted: Employee; Self; Gubra. P.J. Pedersen: Employee; Self; Gubra. K. Fosgerau: None. J. Jelsing: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra.
464-P: Linagliptin Directly Enhances Cardiac Contractile Recovery through Nitric Oxide Mediated Endothelial–Cardiomyocyte Communication
Authors: YERRA VEERA GANESH , BATCHU SRI NAGARJUN , LIU YOUAN , KLEIN THOMAS , ADVANI ANDREW 
Published: June 2020

Despite a similar mechanism of action underlying their glucose-lowering effects, dipeptidyl peptidase-4 (DPP-4) inhibitors have diverse molecular structures, raising the prospect of agent-specific, glucose-independent actions. This possibility is supported by heterogeneous heart failure outcomes in cardiovascular trials, although few head-to-head comparisons exist. To explore the possibility of DPP-4 inhibitor cardiac heterogeneity, we perfused mouse hearts with different DPP-4 inhibitors at concentrations equivalent to their peak plasma levels achieved in humans with standard dosing (Cmax). We studied male and female mice, young nondiabetic mice and aged diabetic high fat diet-fed mice and observed that linagliptin enhanced recovery after ischemia-reperfusion, whereas sitagliptin, alogliptin and saxagliptin did not. DPP-4 transcripts were not detected in adult mouse cardiomyocytes by RNA-sequencing and the addition of linagliptin caused ≤0.2% of cardiomyocyte genes to be differentially expressed. In contrast, incubation of C166 endothelial cells with linagliptin induced cell signaling characterized by phosphorylation of Akt and endothelial nitric oxide synthase, whereas the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine increased serine 16 phosphorylation of the calcium regulatory protein, phospholamban in cardiomyocytes. Thus, at concentrations achieved with standard dosing in humans, linagliptin has direct effects on the recovery of mouse cardiac contractility after ischemia-reperfusion, most likely through NO-mediated endothelial-cardiomyocyte communication. The complex cardiac actions of NO (that depend on comorbidity, concurrent medications and disease setting, for instance) may contribute to both the discordance in DPP-4 inhibitor outcomes between preclinical and clinical observations and the heterogeneous outcomes observed in clinical trials to date.

Disclosure
V. Yerra: None. S. Batchu: None. Y. Liu: None. T. Klein: Employee; Self; Boehringer Ingelheim International GmbH. A. Advani: Research Support; Self; Boehringer Ingelheim International GmbH.

Funding
Boehringer Ingelheim
47-LB: Impact of Activity Intensity on Glucose Variability among Adolescents with Type 1 Diabetes
Authors: JAGGERS JASON R. , KING KRISTI , MCKAY TIM E. , DYESS RYAN J. , WINTERGERST KUPPER A. 
Published: June 2020

Studies have consistently shown improvements in daily glucose and hemoglobin A1c (HbA1c) for both type 1 and type 2 diabetes with increased moderate and/or vigorous physical activity (PA). A limitation with prior investigations is that they only tested this relationship in adult populations and seldom looked at glucose variability (GV). Whether or not similar results would be observed in a pediatric population with type 1 diabetes (T1D) is unknown.
Purpose: The purpose of this investigation was to test the relationship between GV and intensity of PA, and if duration of activity is predictive of changes in GV in a sample of teenagers with T1D. Methods: Data for this investigation were used from an ongoing study at a local pediatric Diabetes Center. Participants who wore a continuous glucose monitor (CGM) and Fitbit consecutively for a period of two weeks or more were included in the data analysis. GV was determined using 2-weeks of CGM data and PA intensity time was retrieved through Fitabase. Pearson’s correlation and a simple linear regression were used for final analysis with a p-value of 0.05 to determine significance.
Results: Minutes of daily moderate intensity activity had a significant inverse relationship (r= -0.59; p = 0.04) with GV, whereas moderate and vigorous PA (MVPA) combined showed a stronger inverse relationship (r= -0.86; p = 0.03). When placed in a simple linear regression only MVPA significantly predicted changes in glucose variability (β= -0.12, p=0.03).
Conclusion: These data show that not only is duration of PA an important factor when it comes to managing diabetes, but that more attention should be paid to the time spent at various intensity levels. Although more research is needed to determine feasibility it could be of great benefit for individuals managing diabetes to incorporate an activity monitor into their daily routine to share with their diabetes care team to better understand how PA levels impact their blood glucose.

Disclosure
J.R. Jaggers: None. K. King: None. T.E. McKay: None. R.J. Dyess: None. K.A. Wintergerst: None.
470-P: SIK2 Protects against Renal Tubular Injury by Inhibiting Endoplasmic Reticulum Stress
Authors: LIAO XIAOYU , LIU BINGYAO , ZHENG HONGTING 
Published: June 2020

Background and Aims: Identification of new biomarkers and drug targets for diabetic nephropathy (DN) is required for the development of more effective therapy. In this study, we investigated the role of SIK2 in protecting against renal tubular injury.
Methods: Diabetes was induced in C57BL/6 mice by streptozotocin (STZ) injection. Inhibitor ARN-3236 was administered 4 weeks after STZ injection 6 weeks, and metabolic indices and renal function were assessed. The apoptosis of HK2 cells was detected by flow cytometric analysis. The transcriptome sequencing was performed after SIK2 overexpression.
Results: Salt inducible kinase 2 (SIK2) expression was obviously decreased in the diseased kidneys from humans and mice, especially in the tubules. In vivo, downregulation of SIK2 with specific inhibitor ARN3236 accelerates tubular mitochondrial dysfunction, endoplasmic reticulum (ER) stress and apoptosis in STZ mice. In tubular epithelial cells, SIK2 overexpression attenuates thapsigargin-induced ER stress and apoptosis, whereas SIK2 knockdown aggravates apoptosis. Mechanistically, SIK2 overexpression upregulates HSP70 expression by phosphorylating HSF1, and then inhibits ER stress.
Conclusions: The newly identified SIK2/HSF1/HSP70 axis clarified the molecular mechanism of tubular epithelial cells apoptosis, indicating that SIK2 might be a novel target for therapeutic prevention of renal tubular injury.

Disclosure
X. Liao: None. B. Liu: None. H. Zheng: None.
475-P: Renal Loss of mTORC2 Is Associated with Improved Diabetic Nephropathy in Type 1 Diabetes
Authors: CHANG CHENG , ZHANG ZHAO , XU KEXIN , BHAT MANZOOR , SHI QIAN 
Published: June 2020

One of the major pathological features of early stage diabetic nephropathy (DN) is tubulointerstitial fibrosis on renal proximal tubular cells (RPTCs), which eventually progresses to fibrosis without proper renal function. However, little is known about the factors regulating these processes. Here, we show that mTOR complex 1 and 2 specifically regulate metabolic control processes of type-1 diabetes in kidney. Using conditional mouse genetic approaches to disable subunits of mTORC1 (Rictor) and mTORC2 (Raptor), respectively or both in PRTCs (Pax8cre), we showed that mice lacking Rictor or Raptor/Rictor develop improved renal pathologies in STZ induced type-1 diabetic model, including low levels of proteinuria, reduced matrix protein accumulation/matrix expansion and tubulointerstitial inflammation. However, the mice lacking Raptor alone were still largely susceptible to STZ toxicity. Meanwhile, Nox4 and oxidative stress levels were significantly reduced in RictorcKO diabetic animal, but to a lesser extent in RaptorcKO diabetic mice. Transcriptome analysis of kidney cortex identified unique pathways that play roles in mTORC/Nox4 pathway during type-1 diabetic pathogenesis, including autophagy, metabolism of lipids and fatty acid regulation. These pathways were largely unchanged in RictorcKO mice when they were exposed to STZ induction. Functionally, losing mTORC2 complex resulted in reduced cellular death and oxidative stress levels, and a profound perturbation of the endocytic machinery. Finally, we found that the treatment with pp242, the mTORC1/2 dual inhibitor, greatly ameliorated the renal pathology in OVE26 mice, a spontaneous type-1 diabetic model. Collectively, our findings highlight a novel mTOR-dependent regulatory network for maintaining metabolic homeostasis in RPTCs during the pathogenesis of DN, and further validates the relevance of simultaneously targeting Nox4 and mTORC2 as a potential early therapeutic option for treating DN.

Disclosure
C. Chang: None. Z. Zhang: None. K. Xu: None. M. Bhat: None. Q. Shi: None.

Funding
JDRF (1-FAC-2019-858-A-N)
483-P: Key Biochemical and Histopathological Markers of Diabetic Nephropathy Correlate with Hypertension in the Renin-AAV Uninephrectomized db/db Mouse Model
Authors: ØSTERGAARD METTE V. , SØRENSEN IDA R. , PEDERSEN ANNEMARIE A. , SECHER THOMAS , SEMBACH FREDERIKKE E. , MADSEN MARTIN R. , FOSGERAU KELD , FINK LISBETH N. , VRANG NIELS 
Published: June 2020

Introduction: Diabetic nephropathy (DN) is a long-term complication that occurs in ∼40% of diabetes patients and is a leading cause of end-stage renal disease. In a newly established mouse model of progressive DN, we investigated the effects of hypertension on kidney injury.
Methods: Female db/db mice were uninephrectomized (UNx) at 8 weeks of age and injected i.v. with a Renin adeno-associated virus (AAV) construct at different doses to induce hypertension, while a LacZAAV construct was used as negative control. Sham-operated db/+ mice served as healthy controls. Blood pressure and glomerular filtration rate (GFR) was measured at 22 weeks of age, while urine albumin to creatinine ratio (ACR) was measured before termination and kidney tissue sampling 24 weeks of age.
Results: GFR measurements indicated hyperfiltration in all AAV-injected UNx db/db mice compared to db/+ mice, while ReninAAV tended to dose-dependently decrease GFR compared to LacZAAV in UNx db/db mice. Urine ACR was worsened by ReninAAV-induced hypertension compared to LacZAAV controls. 3D kidney imaging demonstrated increased glomerular volume in LacZAAV UNx db/db mice compared to db/+ mice with no further effect in ReninAAV groups. Automized AI-based glomerulosclerosis scoring showed ReninAAV dose-dependent increases in glomerulosclerosis compared to LacZAAV controls. RNA sequencing revealed upregulated gene expression markers of kidney fibrogenesis (Col1a1, Col4, Fn1) and tubular injury (Ngal and Kim-1), as well as downregulation of proximal tubular markers (Megalin, Aqp1) in ReninAAV UNx db/db mice compared to LacZAAV controls.
Conclusion: ReninAAV-induced hypertension in female UNx db/db mice aggravates albuminuria and glomerulosclerosis paralleled by increased expression of genes associated with tubular injury renal fibrosis, thus confirming that ReninAAV UNx db/db mice is a reliable model of DN with features of late stage human disease.

Disclosure
M.V. Østergaard: None. I.R. Sørensen: None. A.A. Pedersen: None. T. Secher: Employee; Self; Gubra. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Gubra. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. F.E. Sembach: Employee; Self; Gubra. M.R. Madsen: None. K. Fosgerau: None. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra.
488-P: Isoliquiritigenin Protects Renal Tubular Epithelial Cells from Inflammatory and Oxidative Injuries via Directly Activating SIRT1 in Type 1 Diabetic Nephropathy
Authors: CHEN XIONG , SHEN FEIXIA 
Published: June 2020

Emerging evidence shows that increasing fibrosis and apoptosis have been observed in the tubular epithelia in the progression of type 1 diabetic nephropathy (DN). Excessive inflammatory response and oxidative stress contribute to the pathogenesis of progression. Isoliquiritigenin (ISL), a natural chalcone compound, has been reported to exert anti-inflammatory and anti-oxidative properties. However, little is known about the effects of ISL on diabetic nephropathy and its mechanism. In this study, we investigated the potential protective effects and pharmacological mechanisms of ISL on DN in vivo and in vitro. We test beneficial activities of ISL on streptozotocin (STZ)-induced type 1 diabetes mellitus mice and renal tubular epithelial NRK-52E cells. The study showed that ISL attenuated diabetic nephropathy by decreasing both pro-fibrotic and pro-apoptotic biomarkers. Diabetes or high glucose (HG) induced inflammatory response and oxidative stress were eliminated by ISL administration. The molecular docking using the multiple ligand simultaneous docking (MLSD) software indicated that three molecules of ISL might bound to the binding site of SIRT1 and formation of a stable complex. We also found ISL could neutralize HG-mediated inactivation of SIRT1. Activation of SIRT1 could attenuate HG-induced inflammation, oxidative stress, fibrosis and apoptosis in NRK-52E cells, paralleled with the effects of ISL. While inhibition of SIRT1 could significantly abrogate the protective effects of ISL. Our study implicated that ISL might have great pharmacological actions on attenuating tubular damage of diabetic nephropathy. The beneficial effects of ISL are likely associated with inhibiting excessive inflammatory response and oxidative stress via directly activating SIRT1.

Disclosure
X. Chen: None. F. Shen: None.

Funding
Wenzhou Science and Technology Bureau (Y20190125); First Affiliated Hospital of Wenzhou Medical University (FHY2019015)