bluuebunny/crossref_metadata_2025_split huggingface dataset:
426-P: ROCK2 Regulates Monocytic Migration and Cell-to-Cell Adhesion in Vascular Endothelial Cells
Authors: TAKEDA YUSUKE , MATOBA KEIICHIRO , KAWANAMI DAIJI , NAGAI YOSUKE , UTSUNOMIYA KAZUNORI 
Published: June 2019

A pro-inflammatory lipid mediator, lysophosphatidic acid (LPA), is a potent activator of the RhoA/Rho-kinase signaling pathway and has been shown to induce the expression of chemokines and cell adhesion molecules (CAMs). LPA levels are elevated in the circulation of patients with acute coronary syndrome and have also been detected inside human atherosclerotic specimens. However, the involvement of Rho-kinase isoforms (i.e., ROCK1, ROCK2) in LPA-mediated expression of chemokines and CAMs in endothelial cells is not fully understood. In this study, we investigated isoform-specific roles of Rho-kinase in LPA-mediated MCP-1 and E-selectin expression using human aortic endothelial cells (HAEC). Exposure of HAEC to LPA resulted in an increase of MCP-1 and E-selectin expression at both mRNA and protein levels. Rho-kinase inhibitor abolished MCP-1 and E-selectin protein expression, indicating that LPA induces MCP-1 and E-selectin expression via Rho-kinase activation. From a mechanistic standpoint, phosphorylation of IκBα, a well-characterized initial step in NF-κB activation, was decreased by Rho-kinase inhibition in the LPA-stimulated cells. Furthermore, using isoform specific siRNAs, we found that Rho-kinase isoform ROCK2 is the key mediator of LPA-induced MCP-1 and E-selectin expression. Consistently, ROCK2 but not ROCK1 controlled LPA-induced monocytic migration and adhesion in functional assays using HAECs and human monocytic cells (THP-1). In the present study, we demonstrate that endothelial ROCK2 mediates monocyte migration and cell adhesion induced by lipid mediator. In order to further explore endothelial-specific role of ROCK2 in vivo, we generated endothelial ROCK2 knockout mouse (EC-ROCK2KO) by mating of ROCK2 flox mice with VE-cadherin-cre mice. Further investigation using HFD (high-fat diet) mouse model is ongoing. ROCK2 could be an important therapeutic target against atherosclerosis.

Disclosure
Y. Takeda: None. K. Matoba: Research Support; Self; Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Sanofi, Shionogi & Co., Ltd., Takeda Pharmaceutical Company Limited. D. Kawanami: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Y. Nagai: None. K. Utsunomiya: None.

Funding
Japan Society for the Promotion of Science; Uehara Memorial Foundation; MSD Life Science Foundation
429-P: Therapeutic Inertia: Gap between Goals and Achievement between the T1DX and DPV Registries
Authors: MAAHS DAVID M. , HERMANN JULIA , FOSTER NICOLE C. , KARGES WOLFGANG , MILLER KELLEE , DOST AXEL , WEINSTOCK RUTH S. , PAVEL MARIANNE , SHAH VIRAL N. , HOLL REINHARD W. 
Published: June 2019

Despite increased cardiovascular (CV) mortality in people with type 1 diabetes (T1D), treatment of CV risk factors may not be optimized. International registry comparisons highlight opportunities to improve clinical care and improve outcomes. We analyzed data from 28,494 patients from the German/Austrian DPV registry and 19,442 patients from the U.S. T1D Exchange (T1DX) Clinic registry with data between 01/2016 and 03/2018. Percent of patients by age category with HbA1c &lt;7.5%, hypertension (HTN) and its treatment, dyslipidemia and its treatment, urine albumin to creatinine ratio &gt;30 mg/g, BMI &gt;30 kg/m2, and current smoking are reported. Logistic regression models by age group adjusted for sex and diabetes duration were used to calculate whether registry differences existed. The prevalence of obesity is lower in the DPV than the T1DX registry (Table). In those age &lt;26 years more DPV than T1DX patients had A1c &lt;7.5%. Hypertension was more prevalent in the DPV for those &lt;26 years, but less prevalent for those &gt;50 years. Dyslipidemia was more prevalent in DPV for those &lt;50 years, but less for those &lt;50 years. Elevated ACR and smoking are higher and HTN and dyslipidemia treatment are lower in the DPV than in the T1DX. Vascular disease remains the leading cause of morbidity and mortality in T1D. Comparison of risk factors and their treatment in these registries highlights opportunities to improve care and outcomes.

Disclosure
D.M. Maahs: Advisory Panel; Self; Novo Nordisk Inc. Consultant; Self; Abbott, Sanofi. Research Support; Self; Dexcom, Inc., Tandem Diabetes Care. J. Hermann: None. N.C. Foster: None. W. Karges: None. K. Miller: None. A. Dost: None. R.S. Weinstock: Consultant; Self; Insulogic LLC. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Jaeb Center for Health Research, Kowa Pharmaceutical Europe Co. Ltd., Medtronic MiniMed, Inc., Oramed Pharmaceuticals. Other Relationship; Self; Unitio, Inc. M. Pavel: None. V.N. Shah: Advisory Panel; Self; Sanofi US. Consultant; Self; Dexcom, Inc. R.W. Holl: None.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust; German Center for Diabetes Research; German Diabetes Association; European Foundation for the Study of Diabetes; INNODIA
437-P: Association of Skeletal Muscle Mass and Grip Strength with Cardiovascular Disease in Korean Patients with Type 2 Diabetes
Authors: SHIN JANG YEL 
Published: June 2019

Sarcopenia is a progressive decline in muscle mass and strength with aging. Few studies have investigated that lower muscle mass or strength were associated with cardiovascular disease (CVD). We evaluated whether skeletal muscle mass and grip strength were associated with CVD in type 2 diabetic patients. A total of 1,038 subjects with type 2 diabetes were recruited. We measured appendicular skeletal muscle mass (ASM) using dual energy X-ray absorptiometry and used ASM/BMI for muscle mass quantity. Grip strength (GS) was assessed using a JAMA dynamometer. Patients were divided into sex-specific three groups of ASM/BMI and GS. CVD included coronary heart disease (CHD), cerebral infarction (CI), and peripheral artery disease (PAD) diagnosed by ICD-10. Patients with CVD, CHD, CI, and PAD were 232 (22.4%), 151 (14.5%), 68 (6.6%), and 38 (3.7%), respectively. Subjects with lowest tertile of ASM/BMI were more likely to be elderly and hypertensive, had higher values of systolic BP (SBP), waist circumference (WC), BMI, diabetes duration (DD), C-reactive protein (CRP), serum creatinine (Cr), urine albumin excretion (UAE), and HbA1c, and had lower values of diastolic BP (DBP) and HDL compared with those with highest. Whereas, participants with lowest tertile of GS had higher values of age, DD, Cr, and UAE and had lower values of BMI, DBP, HDL, and LDL than those with highest. The prevalence of CVD, CHD, CI, and PAD with decreasing tertile of ASM/BMI and GS increased proportionally (p&lt;0.001). Odd ratios (ORs) for presence of CVD after adjusted for age with decreasing tretile of ASM/BMI and GS were significantly increased: OR (95% CI) = 1.93 (1.23-3.03) and 2.01 (1.28-3.16) in middle vs. 3.35 (2.16-5.20) and 2.87 (1.80-4.57) in lowest. ORs were maintained significantly after further adjusted for hypertension, current smoking, DD, WC, BMI, BP, HDL, CRP, Cr, HbA1c, and UAE. We found that lower muscle mass and strength were independently associated with CVD in patients with type 2 diabetes.

Disclosure
J. Shin: None.
44-LB: Hypothalamic Glucocorticoid Action Regulates Lipid Metabolism
Authors: CARDOSO MIGUEL , WANG MARK , LING EMILY , LEE HONGJU (JENNIFER) , BEAULIEU-BAYNE EMILIE , YUE JESSICA T. 
Published: June 2019

Aberrant lipid homeostasis is a feature of diabetes and obesity. This metabolic imbalance is associated with excessive levels and/or actions of glucocorticoids (GCs) and contributes to dyslipidemia including elevated hepatic triglyceride (TG)-rich very low-density lipoprotein (VLDL-TG) secretion. The mediobasal hypothalamus (MBH) is a nutrient and hormone sensing brain region that regulates whole-body lipid metabolism and VLDL-TG secretion. We aimed to assess GC action in the MBH in regulating VLDL-TG secretion in health and diet-induced hyperlipidemia.
Sprague Dawley rats received stereotaxic MBH cannulation and vascular catheterizations to enable direct MBH infusions, intravenous injections, and blood sampling. Plasma TG levels and the rate VLDL-TG secretion were measured in 10h-fasted rats following intravenous poloxamer injection with concomitant MBH infusions. In healthy rats, direct MBH GC infusion increased VLDL-TG secretion compared to controls. MBH GC action is mediated via its receptor (GR) since mifepristone (GR antagonist) co-infusion, chronic inhibition of GRs in the MBH with GR shRNA, or inhibition of heat shock protein 90 (required for in vivo GR function) negated the MBH GC-induced increases in VLDL-TG secretion rate. High-fat diet-fed rats had both elevated basal plasma GC levels and hepatic TG secretion compared to healthy rats. Remarkably, chronic MBH GR loss-of-function lowered VLDL-TG secretion in high-fat diet-induced hyperlipidemic rats, independent of changes in body weight.
Here, we provide novel in vivo evidence that MBH GC action modulates VLDL-TG secretion and suggest that blocking excessive GC action in the brain improves lipid homeostasis in diet-induced hyperlipidemic rats. These findings may provide insight on lowering lipid levels in diabetes and obesity.

Disclosure
M. Cardoso: None. M. Wang: None. E. Ling: None. H. Lee: None. E. Beaulieu-Bayne: None. J.T. Yue: None.

Funding
Diabetes Canada; Natural Sciences and Engineering Research Council of Canada; Canadian Lipoprotein Conference
45-OR: The Role of the Angiopoietin-Tie2 Pathway in Microvascular Complications of Diabetes Mellitus
Authors: GONZALEZ VICTOR H. 
Published: June 2019

Introduction: The Tie2 pathway is a key regulator of vascular stability. Deactivation of this pathway, caused by hyperglycemia or ischemia, results in pathological vascular inflammation, permeability and neovascularization. AKB-9778 is a small molecule Tie2 activator. The TIME-2 study (NCT02050828) was performed to examine the efficacy of AKB-9778 for the treatment of diabetic retinopathy and nephropathy.
Methods: TIME-2 was a multicenter randomized trial in which 144 diabetic patients with center-involved diabetic macular edema (DME) were randomized (1:1:1) to 3 months of treatment with 15 mg AKB-9778 administered subcutaneously (SC) BID plus monthly intravitreal treatment (IVT) with 0.3 mg ranibizumab (RBZ), 15 mg AKB-9778 plus sham IVT, or RBZ plus placebo SC injections BID. DME was measured by optical coherence tomography (OCT), severity of diabetic retinopathy was measured by grading of 7-field color fundus photos (ETDRS DRSS scale), and kidney function was measured by UACR and eGFR.
Results: Reduction of DME was 50% greater after 3 months of combination AKB-9778 + RBZ treatment than with RBZ treatment alone (-164 µm vs. -110 µm; P&lt; 0.01). Diabetic retinopathy was improved by ≥ 2 steps in 11.4%, 8.8%, and 10% of patients in study eyes of the combination, RBZ, and AKB-9778 treatment groups, respectively. In fellow eyes (no RBZ) 11.4% showed ≥ 2-step improvement in retinopathy with systemic AKB-9778 compared to 4.2% of untreated eyes in the placebo group. UACR geometric mean was improved by 21% in patients with albuminuria at baseline (UACR ≥ 30 mg/g) in patients treated with AKB-9778 for 3 months.
Conclusions: The TIME-2 study provides evidence that restoration of Tie2 activity by AKB-9778 has beneficial effects on retinal and kidney function in patients with diabetes mellitus. AKB-9778 is a promising therapeutic for the prevention of end-organ damage in diabetic patients.

Disclosure
V.H. Gonzalez: Consultant; Self; AbbVie Inc., Alcon/Novartis, Alimera Sciences, Inc., Allegro Ophthalmics, LLC., Allergan, Bausch and Lomb, Bayer US, Clearside Biomedical, Genentech, Inc., PanOptica, Regeneron Pharmaceuticals, Santen Pharmaceutical Co., Ltd., Thrombogenics, Topcon, Valeant Pharmaceuticals International, Inc. Research Support; Self; 60 Pharmaceuticals, Alcon/Novartis, Allegro Ophthalmics, LLC., Allergan, Apellis Pharmaceuticals, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Chengdu Kanghong Biotechnology Co, LTD, Clearside Biomedical, DRCR NET, EyeGate Pharma, Genentech, Inc., Graybug Vision, Inc., ICON plc., Iconic Therapeutics, Insite Vision Inc, Mallinckrodt Pharmaceuticals, Opthea Ltd., Regeneron Pharmaceuticals, Santen Pharmaceutical Co., Ltd., Thrombogenics. Stock/Shareholder; Self; Alimera Sciences, Inc., PanOptica.
451-P: SGLT2 Inhibitor Protects Cardiomyocytes against Palmitate-Induced Lipotoxicity by Increasing Activation of AMPK and Lipid Oxidations
Authors: LEE HAN BYEOL , CHOI SUNGE , KANG YUP , KIM TAE HO , LEE NAMI , MOON HYUN UK , HAN SEUNG JIN , KIM DAE JUNG , LEE KWANWOO 
Published: June 2019

Aim: This study was designed to evaluate the effects of SGLT2 inhibitor on palmitate-induced lipotoxicity of cardiomyocytes and the underlying mechanism involved with palmitate.
Methods: We checked SGLT2 expression in muscle cells, including H9C2. H9C2 cells were palmitate treated with/without SGLT2 inhibitor. Then, insulin resistance was measured, 2-NBDG uptake, and immunoblotting using insulin signaling pathway antibodies. Inflammation and cardiac metabolism were analyzed several related genes. Cardiomyocyte apoptosis was also detected using DNA fragmentations assay and immunoblotting using cleaved caspase 3.
Results: Low doses of palmitates evoked lipotoxicity in cardiomyocytes. Treatment of SGLT2 inhibitor dramatically reduced palmitate-induced expression levels of inflammatory cytokines. Immunoblotting analysis showed treatment of cardiomyocytes, with SGLT2 inhibitor, recovered impaired insulin signaling, such as phospho-IR and phospho-AKT, but total IR and AKT did not change. SGLT2 inhibitor also restored insulin-stimulated glucose uptake, which was destroyed by lipotoxicity. Treatment with SGLT2 inhibitor decreased the level of ER stress markers as well as inflammatory signaling markers. In particular, SGLT2 inhibitor stimulated phosphorylation of AMPK and fatty acid beta-oxidation. Cardiomyocyte exposure to high doses of palmitates evoked apoptotic features such as caspase 3 activation and DNA fragmentations. But pretreatment of SGLT2 inhibitor significantly protected palmitate-induced apoptotic features.
Conclusions: This data suggests SGLT2 inhibitors protect palmitate-induced cardiomyocytes inflammation, impaired cardiac metabolism, insulin resistance, and cardiomyocyte apoptosis. Therefore, attempts to use treatment of SGLT2 inhibitor might be a useful strategy for preventing diabetes-associated ventricular remodeling and diabetic cardiac complication.

Disclosure
H. Lee: None. S. Choi: None. Y. Kang: None. T. Kim: None. N. Lee: None. H. Moon: None. S. Han: None. D. Kim: None. K. Lee: None.
467-P: Estimation of 10-Year Cardiovascular Risk among Newly Diagnosed Type 2 Diabetes Patients in the “Evaluation of Effectiveness of Treatment Paradigm for Newly Diagnosed Type 2 Diabetes Patients in China (NEW2D)” Study Population
Authors: YAN YU , CAI XIAOLING , XU JIE , MANNER DAVID , BAE JAY P. , HEINE ROBERT J. , JI LINONG 
Published: June 2019

Introduction: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D). This study aimed to estimate the distribution of 10-year predicted CVD risk among newly diagnosed T2D patients, using China-PAR (Prediction for Atherosclerotic cardiovascular disease Risk in China) model, in the NEW2D population.
Methods: CVD was defined as the first occurrence of acute myocardial infarction, stroke, or death from cardiovascular causes. Risk factors included in the China-PAR model were age, geographic region, urbanization, smoking, waist circumference, systolic blood pressure, total cholesterol, HDL-C, and family history of CVD.
Results: Of the total population of 5770 patients, 2301 fulfilled the inclusion criteria (e.g., no glucose-lowering therapy) and were included in the current analyses. The model-predicted mean CVD risk was 7.4%, with 54% of patients having a medium or high risk to develop CVD within 10 years (Table 1).
Conclusions: Our study demonstrates that the majority of newly diagnosed patients with T2D in China have a medium or high risk to develop CVD. SBP appears to be a prominent driver of this elevated risk. These results underscore the importance of primary prevention and management of CVD in patients with T2D.

Disclosure
Y. Yan: Employee; Self; Eli Lilly and Company. X. Cai: None. J. Xu: None. D. Manner: Employee; Self; Eli Lilly and Company. J.P. Bae: Employee; Self; Eli Lilly and Company. R.J. Heine: Employee; Self; Eli Lilly and Company. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi.
469-P: The Scavenging Product of Metformin and Methylglyoxal Improves Endothelial Cell Function in I1R and/or α2R-AKT-ERK1/2-eNOS-NO Dependent Pathway
Authors: NGUYEN HUONG 
Published: June 2019

Methylglyoxal (MG) is highly elevated in type 2 diabetes (T2D) patients. MG covalently reacts with proteins to form non-enzymatic advanced glycation end products (AGEs), which cause cellular damage during diabetic cardiovascular complications. The T2D first-line drug therapy, metformin (MF), significantly reduces adverse diabetic endpoints more effectively than other antihyperglycemic agents. However, the exact mechanism(s) is far from well characterized. We previously discovered that MF scavenges MG to form a novel imidazoline (IMZ) metabolite, thus reducing MG-derived AGEs. We hypothesize that IMZ improves endothelial cell function and contributes to the therapeutic effects of MF. In the current studies we examined the in-vitro effects of IMZ on endothelial cell function using HUVECs cells and characterized potential signaling pathways. IMZ at physiological relevant concentrations induces the production of the endothelial derived relaxation factor, nitric oxide (NO), concomitant with an increase in the activation of eNOS. IMZ-induced NO production was blunted by pretreatment with imidazoline 1 receptor (I1R) and alpha-2 receptor (α2R) antagonists, suggesting that IMZ action is receptor mediated. We also observed that IMZ cause the activation of Akt and ERK1/2, in a concentration and time-dependent manner. IMZ-induced activation of Akt, ERK1/2, eNOS was inhibited in the presence of a PI3K inhibitor. ERK1/2 phosphorylation mediated by IMZ was also reduced in the presence of Akt1/2 specific inhibitors, suggesting that ERK1/2 might lie downstream of Akt. The effects of IMZ on angiogenesis function was examined by a tube-formation assay. IMZ treatment significantly increased tube length compared to untreated controls. Collectively, the data demonstrate that IMZ might contribute to the protective effects of metformin on endothelial cell function by activating I1R and/or α2R-Akt-ERK1/2-eNOS-NO pathway.

Disclosure
H. Nguyen: None.
470-P: Combined Use of Sulforaphane and Zinc Provides a Better Protection against Diabetic Cardiomyopathy than Either One Alone in Type 1 Diabetic OVE26 Mice
Authors: WANG JIQUN , WANG WANNING , CAI LU 
Published: June 2019

Diabetic cardiomyopathy (DCM) is the main cause of heart failure in diabetic patients. Oxidative stress is considered to be one of the most important mechanisms. Thus, treatments targeting oxidative stress may represent suitable strategies for the effective prevention of DCM. Nuclear factor-E2-related factor 2 (Nrf2), a transcription factor responsible to oxidative stress, goes to nuclei and binds to antioxidant response elements of promoters of several antioxidant genes. Metallothionein (MT) is a protein that can bind heavy metal ions such as zinc (Zn) and also a potent scavenger of free radicals because of its high thiol contents. Genetically overexpressing either Nrf2 or MT specifically in the heart protects from DCM. In addition, we also showed that induction of MT with Zn or activation of Nrf2 with sulforaphane (SFN) also partially protects from DCM. Here we further explore whether up-regulation of both simultaneously with Zn and SFN combination would provide a better protection against DCM than either alone. OVE26 mouse is one genetic type 1 diabetic model with the diabetes onset at 3 weeks old and survival more than one year without insulin treatment, so it is very good model for diabetic complication study. 5-week old OVE26 mice were confirmed with hyperglycemia and then treated with SFN (0.5 mg/kg) and/or Zn (5 mg/kg) for 18 weeks. 23-week old OVE26 mice showed typical DCM, reflected by cardiac dysfunction and remodeling fibrosis by echocardiography and collagen staining, along significantly oxidative damage, and inflammatory responses using western blotting and real-time PCR. Treatment of OVE26 mice either with SFN or Zn significantly prevented the development of DCM, along with up-regulating Nrf2 function and overexpressing MT protein, respectively, but the best protection from DCM is in the SFN/Zn group. Therefore, combined use of SFN with Zn may provide a better protection against DCM than SFN or Zn alone for diabetic patients.

Disclosure
J. Wang: None. W. Wang: None. L. Cai: None.

Funding
American Diabetes Association (1-15-BS-018, 1-18-IBS-082 to L.C.)