bluuebunny/crossref_metadata_2025_split huggingface dataset:
Skin Autofluorescence, a Marker of Glycaemic Memory in Type 2 Diabetes
Authors: MARINE RIGO , MARIE MONLUN , MOHAMMEDI KAMEL , BLANCO LAURENCE , RIGALLEAU VINCENT 
Published: June 2018

Glycaemic memory is defined as the deferred consequences of prior hyperglycaemic exposition on the risk of complications. The accumulation of advanced Glycation End products, assessed by the skin autofluorescence (AF), may explain this phenomenon. We evaluated the associations of AF with HbA1c and vascular complications in patients with type 2 diabetes (T2D). We assessed previous HbA1c from the last 120 months (median [IQR] 14 [4, 30]) and the history of vascular complications in T2D patients. The skin AF was measured using an AGE Reader. Association between prior HbA1c and AF tertiles was tested using a mixed regression model with random effects after multiple adjustments. To test the glycaemic memory, analyses were stratified by rising interval time of HbA1c measurements: recent (3 [2, 4]), medium (14 [12, 18]), and old (36 [30, 60] months). The association between AF tertiles and complications was tested by logistic regression model. We collected 2485 HbA1c (mean±SD 8.9±1.9%) measurements in 9patients: 57% men, age 62±10 years, diabetes duration 14±10 years. AF was 2.67±0.66 AU. The highest main [95% CI] HbA1c was observed in the upper AF tertile: T1 8.8 [8.6-9.0], T2 8.9 [8.7-9.1], T3 9.1 [8.9-9.3], p=0.03. This association was greater in patients with the oldest HbA1c measurements: T1 8.4 [8.0-8.9], T2 8.9 [8.4-9.3], T3 9.3 [8.8-9.8], p=0.002. Micro- and macrovascular diseases were observed in 577 and 316 patients, respectively. AF was higher in participants with microvascular (2.79±0.67 vs. 2.46±0.57, p&lt;0.0001) and macrovascular complications (2.78±0.66 vs. 2.61±0.65, p=0.0004) compared to others. Microvascular (T2 vs. T1, OR [95% CI] 1.39 [0.88-2.18], p=0.16; T3 vs. T1 2.20 [1.38-3.57], p=0.001) and macrovascular disease (1.51 [1.02-2.22], p=0.03; 0.99 [0.66-1.49], p=0.96) were associated with the upper AF tertiles in the adjusted model. A high AF was associated with a high HbA1c during the 5 previous years, and related to vascular complications: 2 criteria for being a glycaemic memory marker in T2D patients.

Disclosure
R. Marine: None. M. Marie: None. K. Mohammedi: Speaker's Bureau; Self; Novo Nordisk Inc.. Other Relationship; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Sanofi. Other Relationship; Self; Sanofi, Takeda Development Centre Europe Ltd., Boehringer Ingelheim Pharmaceuticals, Inc.. L. Blanco: None. V. Rigalleau: None.
Association between Arterial Stiffness and Cardiovascular Autonomic Neuropathy in Youth with Type 2 Diabetes—SEARCH for Diabetes in Youth Study
Authors: JAISWAL MAMTA , DIVERS JASMIN , DABELEA DANA , LAWRENCE JEAN M. , KIM GRACE , LIESE ANGELA D. , URBINA ELAINE M. 
Published: June 2018

Accelerated vascular aging in youth with type 2 diabetes (T2D) makes them vulnerable for a cardiovascular event in early adulthood. We explored the relationship between increased arterial stiffness (AS) and reduced heart rate variability (HRV) in youth with T2D.
193 youth with T2D (age 22 ± 4 years, duration 8 ± 2 years, HbA1c 8.9 ± 4.4%, 40% non-Hispanic black) enrolled in the SEARCH study had PWV (pulse wave velocity carotid-femoral segment) and HRV [standard deviation (SDNN) and root mean square successive difference(RMSSD) of normal RR interval] assessed. AS+ was defined as the PWV &gt; 90th percentile for age and gender-matched healthy controls.
Youth with increased AS were older, had higher blood pressure (BP), BMI, triglycerides and lower HDL-c (P ≤ 0.05) (Table). In linear regression analysis, increased PWV was associated with lower SDNN independent of age, gender, race/ethnicity, BP and BMI (β= -0.03, SE=0.02, P=0.04). However, the association was attenuated and non-significant when controlled for triglyceride suggesting that the relationship between AS and HRV is mediated partly by dyslipidemia.
TABLE 1. Characteristics of the youth with type 2 diabetes stratified by their arterial stiffness (AS) statusVariableAS –AS +P-valueAge, years22 ± 423 ± 40.008Systolic Blood Pressure, mm Hg115 ± 10121 ± 11&lt;0.001BMI z-score1.9 ± 0.42.4 ± 0.37&lt;0.001HDL-cholesterol, mg/dL43 ± 939 ± 90.002Triglycerides, mg/dL104 (73,175)139 (87,248)0.02HbA1c, %8.7 ± 4.49.5 ± 4.10.28SDNN, msec52(36,79)42(29,62)0.003
Early subclinical atherosclerosis was associated with cardiovascular autonomic neuropathy in young people with T2D which could potentially increase the risk of early cardiovascular events. Interventions targeting the risk factors for AS and CAN are needed.

Disclosure
M. Jaiswal: None. J. Divers: None. D. Dabelea: None. J.M. Lawrence: None. G. Kim: None. A.D. Liese: None. E.M. Urbina: None.
Roles of Histone Deacetylases in Arteriovenous Fistula Failure Under Disturbed Flow
Authors: CHIU JENG-JIANN , YANG TUNG-LIN 
Published: June 2018

Chronic kidney disease, which affects 11.9% of adults and its prevalence of the end-stage renal disease (ESRD) is highest in Asia, is a major health problem in the world. More than 90% of the ESRD patients receive hemodialysis, with the creation of hemodialysis vascular access (HVA), including arteriovenous fistula (AVF). Although AVF is the preferred form of permanent hemodialysis access, it still remains significant problems, such as thrombosis, stenosis and vascular access infections. AVF operation has been shown to change hemodynamic environments. However, the relationship between hemodynamic factors and AVF failure remains unclear. By using Doppler ultrasound to detect the flow patterns in human patients with AVF and rat AVF models, we found that flow disturbance with high and oscillatory shear stress (HOSS, ∼30±100 dynes/cm2) is generated in the anastomotic site of AVF. Venous endothelial cells (ECs) in regions of anastomosis showed higher expression of class I histone deacetylases (HDAC-1/2/3) and lower expression of thrombomodulin (TM) in both human patients and rat AVF models in comparison to control subjects. We further developed in vitro flow system to generate HOSS at 30±100 dyne/cm2 and laminar shear stress (LSS) at 5 dyne/cm2 to mimic flow patterns in the pathophysiological and physiological flow environments of human AVF, respectively. Application of HOSS to venous ECs induces the association of HDAC-3 with krüppel-like factor 2 (KLF2) to deacetylate KLF2, resulting in the down-regulation of TM. Intraperitoneal administration of valproic acid (VPA), which is a specific inhibitor of class I HDACs, into AVF rats inhibits the increased formation of stenosis at anastomotic sites. Our findings demonstrate that flow disturbance with HOSS can induce HDAC-3 to deacetylate KLF2 and repress TM, and hence contribute to AVF stenosis and failure. Such information may help to generate new approaches for therapeutic interventions against inflammation and thrombosis in AVF in patients.

Disclosure
J. Chiu: None. T. Yang: None.
Insulin Deficiency Is a Major Contributor to Atrial Fibrillation
Authors: MARIA ZAHRA , CAMPOLO ALLISON , SCHERLAG BENJAMIN J. , RITCHEY JERRY W. , LACOMBE VERONIQUE 
Published: June 2018

Diabetes has been identified as a major independent risk factor for atrial fibrillation (AF), the most common sustained cardiac arrhythmia. However, it is unknown whether glucose and insulin disturbances observed during diabetes directly affect the function of the atria, leading to AF. Thus, we hypothesized that insulin deficiency and impaired glucose transport provide a metabolic substrate for the development and maintenance of AF during diabetes. Transesophageal atrial pacing was used to induce AF in healthy, streptozotocin-induced type 1 diabetic and insulin-treated (via a subcutaneous pump) diabetic mice (n=4-11/group). Translocation of insulin-sensitive glucose transporters (GLUTs) was measured using a photolabeled biotinylation assay in the perfused heart. Atrial fibrosis and glycogen accumulation were measured using histological analyses. As expected, insulin-deficient diabetic mice displayed hyperglycemia (434 ± 50.9 mg/dl) while insulin-treated diabetic mice remained euglycemic (118.8 ± 3.3 mg/dl, p&lt;0.05). At 8 weeks, diabetic mice displayed increased duration and frequency of AF episodes vs. age-matched controls (e.g., AF duration: 18.7 ± 6.2 s vs. 1.8 ± 1.1 s, respectively, p=0.032), whereas insulin-treated diabetic animals did not. In addition, the frequency of AF episodes was significantly correlated to blood glucose level (p=0.01). GLUT-4 and -8 translocation to the atrial cell surface was significantly downregulated in diabetic mice (by 67% and 79%, respectively; p≤0.001), and rescued by insulin treatment. We did not observe any fibrosis or glycogen accumulation in the atria of (treated and untreated) diabetic mice. We conclude that, in the absence of structural remodeling and atrial fibrosis, insulin and glucose disturbances were sufficient to induce AF during diabetes. Therefore, these data suggest that insulin deficiency during diabetes leads to alterations in glucose transport and energy production in the atria, which enhances its vulnerability to atrial fibrillation.

Disclosure
Z. Maria: None. A. Campolo: None. B.J. Scherlag: None. J.W. Ritchey: None. V. Lacombe: None.
Impact of Type 2 Diabetes Mellitus and Myocardial Perfusion on Long-Term Risk of Heart Failure and All-Cause Mortality following Interventional Treatment of ST-Elevation Myocardial Infarction
Authors: TOMASIK ANDRZEJ , NABRDALIK KATARZYNA , KWIENDACZ HANNA , SAWCZYN TOMASZ , KUKLA MICHAL , RADZIK EDYTA , PIGON KATARZYNA , MłYńCZAK TOMASZ , GUMPRECHT JANUSZ , GRZESZCZAK WLADYSLAW , NOWALANY-KOZIELSKA EWA 
Published: June 2018

Patients with type 2 diabetes mellitus (T2DM) who undergo primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) have worse myocardial perfusion than normoglycemic patients. It is not known whether these factors combined influence prognosis in term of heart failure (HF) and/or all-cause mortality. We aimed to evaluate the impact of T2DM and myocardial perfusion on long-term risk of HF and/or all-cause mortality following interventional treatment of STEMI. 4STEMI patients (104 with T2DM) treated with pPCI were enrolled into the study. Myocardial perfusion was reassessed with: myocardial blush grade (MBG), Quantitative myocardial Blush Evaluator (QuBE), resolution of ST-segment elevation (STR). Follow-up data was collected during 6 years. 23.1% patients with T2DM developed HF vs. 16.9% without T2DM (P=NS). 34.6% of patients with T2DM have died vs. 14.9% patients without T2DM (P=0.000). Patients with T2DM and HF have had the highest mortality rate of 75%. Survival of patients with T2DM in relation to QuBe score is presented in the Figure. There was no difference in myocardial perfusion assessed by STR. T2DM and diminished myocardial perfusion increase the risk of HF and/or all cause death in 6 years follow-up.

Disclosure
A. Tomasik: None. K. Nabrdalik: None. H. Kwiendacz: None. T. Sawczyn: None. M. Kukla: None. E. Radzik: None. K. Pigon: None. T. Młyńczak: None. J. Gumprecht: Speaker's Bureau; Self; AstraZeneca. Consultant; Self; Bayer AG. Speaker's Bureau; Self; Bioton, Berlin-Chemie AG, Eli Lilly and Company, Merck Sharp & Dohme Corp., Boehringer Ingelheim GmbH, Novo Nordisk A/S, Polfa Tarchomin S.A., Polpharma. W. Grzeszczak: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Bioton, Merck & Co., Inc., Novo Nordisk A/S. Stock/Shareholder; Self; Eli Lilly and Company. Speaker's Bureau; Self; Bayer AG. E. Nowalany-Kozielska: None.
Association of Serum Sestrin2 Level with Metabolic Risk Factors in Newly Diagnosed Drug-Naïve Type 2 Diabetes
Authors: CHUNG HYE SOO , ROH EUN , HONG SO-HYEON , KIM JUNG A. , LEE YOU-BIN , BAIK SEI HYUN , CHOI KYUNG MOOK , YOO HYE JIN 
Published: June 2018

Objective: Previous in vitro and in vivo experimental studies have shown that Sestrin2 attenuates oxidative stress and the pro-inflammatory pathway, resulting in improving metabolic homeostasis. However, the relationship between circulating Sestrin2 concentration and cardiometabolic risks in humans has not been explored.
Methods: Sestrin2 concentration was measured in 240 subjects (46 nondiabetics and 194 diabetics) using an enzyme-linked immunosorbent assay, and the associations between Sestrin2 level and various cardiometabolic risk factors including body composition, insulin resistance, and atherosclerosis was assessed.
Results: Sestrin2 concentration showed a trend of increasing in subjects with metabolic syndrome. After adjustment for age and gender, Sestrin2 level had a positive relationship with serum triglyceride, alanine aminotransferase (ALT), and creatinine levels, but no association with carotid atherosclerosis. Especially, in subjects with type 2 diabetes Sestrin2 concentration exhibited a significant positive correlation with body mass index (P =0.015), waist circumference (P =0.020), high-sensitivity C-reactive protein (P =0.008), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (P =0.041), percentage body fat (P =0.001), and truncal fat mass (P =0.005) after adjusting age and gender. Multiple stepwise regression analysis identified age, serum ALT and creatinine levels, and percentage body fat as independent determining factors for Sestrin2 concentration in patients with type 2 diabetes (R2 = 0.173).
Conclusions: This study is the first to demonstrate a trend for increased Sestrin2 level in subjects with metabolic syndrome. In particular, in subjects with type 2 diabetes, Sestrin2 was significantly related to insulin resistance and percentage body fat, suggesting its potential as a novel modulatory factor for metabolic disorders in humans.

Disclosure
H. Chung: None. E. Roh: None. S. Hong: None. J.A. Kim: None. Y. Lee: None. S. Baik: None. K. Choi: None. H. Yoo: None.
Intermittent Hypoxia Induces Expression of Epiregulin mRNA via Upregulation of Interleukin-6 in Human Coronary Artery Smooth Muscle Cells
Authors: KYOTANI YOJI , ZHAO JING , ITAYA-HIRONAKA ASAKO , YAMAUCHI AKIYO , SAKURAMOTO-TSUCHIDA SUMIYO , MAKINO MAI , TAKASAWA SHIN , YOSHIZUMI MASANORI 
Published: June 2018

Sleep apnea syndrome (SAS) is characterized by repetitive episodes of oxygen desaturation and re-saturation, such as intermittent hypoxia (IH), and well known as an independent risk factor for diabetes and atherosclerosis. We previously showed that IH directly induced the proliferation of cultured rat aorta smooth muscle cells through upregulations of epidermal growth factor family, especially epiregulin (EREG), and their erbB2 receptor. However, its underlying mechanism remains unclear. On the other hand, we also reported that IH increased interleukin (IL)-6 mRNA in pancreatic beta cells. In this study, we investigated the influence of IH on IL-6 production, and the impact of IL-6 on the expression of EREG, using human coronary artery smooth muscle cells (hCASMC) and in vitro IH system. Quantitative RT-PCR revealed that EREG mRNA was significantly increased by IH, but not by sustained hypoxia. IH also increased expression of IL-6 mRNA in IH cycle dependent manner (3∼72 cycles in 1∼24 hours). Mature IL-6 increased in IH-exposed cell conditioned medium as similar time-dependent manner as seen in mRNA. We next investigated whether IL-6 increases the expression of EREG mRNA in hCASMCs. The addition of IL-6 (100 ng/mL) induced a significant upregulation of EREG mRNA expression. Taking into account the IH-induced increase of IL-6 and IL-6-induced upregulation of EREG mRNA in hCASMCs, we hypothesized that elevated IL-6 production due to IH was responsible for the IH-induced increase in EREG mRNA. To determine the direct role of IL-6 in IH-induced increases in EREG mRNA expression, we applied siRNAs for IL-6 and the IL-6 receptor and obtained the result that both siRNAs for IL-6 and IL-6 receptor significantly suppressed the IH-induced increase of EREG mRNA. These results indicated that IL-6 plays a pivotal role in EREG upregulation by IH and consequently OSA-related atherosclerosis.

Disclosure
Y. Kyotani: None. J. Zhao: None. A. Itaya-Hironaka: None. A. Yamauchi: None. S. Sakuramoto-Tsuchida: None. M. Makino: None. S. Takasawa: None. M. Yoshizumi: None.
ROCK2 Regulates the Expression of Cell Adhesion Molecules and Cell-to-Cell Adhesion in Vascular Endothelial Cells
Authors: TAKEDA YUSUKE , MATOBA KEIICHIRO , KAWANAMI DAIJI , NAGAI YOSUKE , AKAMINE TOMOYO , ISHIZAWA SHO , KANAZAWA YASUSHI , YOKOTA TAMOTSU , UTSUNOMIYA KAZUNORI 
Published: June 2018

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 cell adhesion molecules (CAMs). LPA levels are elevated in the circulation of patients with acute coronary syndrome and has also been described inside human atherosclerotic specimens. However, the involvement of Rho-kinase isoforms (i.e., ROCK1, ROCK2) in LPA-mediated expression of CAMs in endothelial cells is not fully understood. In this study, we investigated isoform-specific roles of Rho-kinase in LPA-mediated E-selectin expression using human aortic endothelial cells (HAEC). Exposure of HAEC to LPA resulted in an increase of E-selectin expression at both mRNA (real-time PCR) and protein (Western blot) levels. We confirmed increased Rho-kinase activity in the LPA-stimulated cells. Y-27632, a specific Rho-kinase inhibitor, completely abolished E-selectin protein expression, indicating that LPA induces E-selectin expression via Rho-kinase activation. LPA-induced E-selectin gene expression was strongly suppressed by a chemical inhibitor of NF-κB, indicating the contribution of NF-κB transactivation in this pathway. Intriguingly, phosphorylation of NF-κB RelA/p65 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 E-selectin expression and cell adhesion between HAECs and human monocytic cells (THP-1). In the present study, we demonstrate that ROCK2 mediates LPA-induced expression of E-selectin via NF-κB signaling in endothelial cells. ROCK2 could be an important therapeutic target against atherosclerosis.

Disclosure
Y. Takeda: None. K. Matoba: None. D. Kawanami: None. Y. Nagai: None. T. Akamine: None. S. Ishizawa: None. Y. Kanazawa: None. T. Yokota: None. K. Utsunomiya: None.
Diabetes-Induced Vascular Dysfunction Can Be Attenuated with a Naked G7 Polyamidoamine Dendrimer In Vivo
Authors: AKHTAR SAGHIR , CHANDRASEKHAR BINDU , EL-HASHIM AHMED Z. , BENTER IBRAHIM 
Published: June 2018

Upregulation of epidermal growth factor receptor (EGFR) signaling is involved in development of diabetes-induced vascular dysfunction. Polyamidoamine (PAMAM) dendrimers (branch-like polymers) might be novel inhibitors of EGFR for they inhibit EGFR phosphorylation in vitro. Here, we investigated whether chronic administration of a generation (G) 7 PAMAM dendrimer could have beneficial effects on diabetes-induced vascular dysfunction by inhibiting EGFR signaling in a model of type 1 diabetes. Dendrimer administration (daily i.p for up to 4 weeks) to Male Wistar rats bearing streptozotocin-induced diabetes dose- and time-dependently inhibited EGFR-ERK1/2-ROCK signaling- a key pathway in the development of diabetic vascular complications. Dendrimer-induced inhibition of EGFR signaling correlated well with a significant correction in hyper-responsiveness of the diabetic mesenteric vascular bed to norephinephrine- a routinely used experimental measure of vascular dysfunction. The dendrimer also inhibited high glucose-induced EGFR-ERK1/2-ROCK signaling in primary vascular smooth muscle cells grown in high (25mM) glucose. These data show for the first time that a PAMAM dendrimer administered chronically in vivo can lead to inhibition of EGFR-ERK1/2-ROCK signaling and attenuate diabetes-induced vascular dysfunction in an experimental model of diabetes.

Disclosure
S. Akhtar: None. B. Chandrasekhar: None. A.Z. El-Hashim: None. I. Benter: None.
NMR-Based Lipidomic Analysis of Red Blood Cells Membranes in Type 2 Diabetes
Authors: KOSTARA CHRISTINA , BAIRAKTARI ELENI , ELISAF MOSES , TSIMIHODIMOS VASILEIOS 
Published: June 2018

Changes in the composition of red blood cells membranes may lead to in an altered blood rheological pattern. Experimental studies suggest that hyperglycemia affects red cell rheology via direct effects on the membrane, including alterations of the lipid membrane bilayer composition and microviscosity and changes in membrane Na+/K+ ATP-ase function.
We aimed to investigatate the 1H NMR-based lipid profile of RBC membranes in type 2 diabetic patients and compare it to that of nondiabetic subjects.
Blood samples from 25 nondiabetic and 15 diabetic individuals were collected after an overnight fast. The groups were matched for age, sex and conventional lipid parameters. RBC were lysed and their lipid content was extracted according to a standard procedure. The lipid profile of membranes was recorded on Bruker DRX-500 NMR Spectrometer and analyzed by multivariate data techniques.
The NMR-based lipidomic analysis showed that diabetic patients presented a significantly different lipid profile in RBC membranes compared to that recorded in nondiabetic individuals. RBC membranes from patients with diabetes were characterized by altered fatty acid pattern e.g., higher saturated and lower unsaturated fatty acid levels and lower concentrations of omega-3 fatty acids, mainly docosahexaenoic acid. In addition, lower levels of phosphatidylcholine and phosphatidylethanolamine, and higher levels of sphingomyelin and cholesterol were observed in diabetic patients compared to nondiabetic individuals.
In conclusion, the lipid composition of RBC membranes in the diabetic state is significantly altered. These disturbances may be involved in the pathogenesis of the microvascular complications of diabetes through the disruption of tissue delivery of oxygen. Additionally, the increased cholesterol content of red cell membranes that reach the lipid core of the atherosclerotic plaques through the vasa vasorum may lead to core expansion, decrease their stability and make them prone to rupture.

Disclosure
C. Kostara: None. E. Bairaktari: None. M. Elisaf: None. V. Tsimihodimos: None.