bluuebunny/crossref_metadata_2025_split huggingface dataset:
Skin Autofluorescence Predicts Macrovascular Events in Type 1 Diabetes
Authors: BLANC-BISSON CHRISTELE , CEPHISE FRITZ-LINE VELAYOUDOM , HELMER CATHERINE , BLANCO LAURENCE , MOHAMMEDI KAMEL , MONLUN MARIE , RIGALLEAU VINCENT 
Published: June 2018

Advanced Glycation end-products play a role in diabetic vascular complications. Their optical properties allow to non invasively evaluate their accumulation in tissue by measuring skin autofluorescence (SAF). SAF predicts macrovascular complications in type 2 diabetes mellitus but it was not demonstrated in type 1 diabetes. The aim of our study was to search for an association between SAF and macrovascular event (MVE) incidence: myocardial infarction, stroke, gangrene or artery revascularization procedures during a 7 years follow-up. In 2009, 246 subjects with type 1 diabetes patients were included. SAF measurement, clinical (age, sex, BMI, comorbidities) and biological data (glycemia, HbA1C, renal parameters, blood lipids) were recorded. MVE were registered at visit in the center or phone call to medical practitioner until 2016. They were mainly men 58.8% (n=143), mean age 51.2 years (±16.7) with BMI 24.9 kg/m2 (± 4.1), diabetes duration 21.4 years (±13.8), HbA1C 7.6% (± 1.1). Among these DT1 patients, 25.7% (n=59) were smokers, 44.9% (n=109) had arterial hypertension, LDL cholesterol was 1.04 (± 0.29) g/L. Estimated Glomerular Filtration Rates (CKD-EPI) was 86.3 ml/min/1.73m2 (±26.6) and albumin excretion rates was 54.9mg/24H (± 220.0). Twenty-four subjects had a history of previous MVE (9.9%). From 2009 to 2016, 18 patients had new MVE: 4 myocardial infarctions, 2 gangrene, 17 artery revascularizations. Their SAF was 2.46 (±0.71) UA vs. 2.10 (±0.55) for others patients (p=0.02). After adjustment for cardiovascular risk factors (age, sex, diabetes duration, BMI, hypertension, smoking status, blood lipids, albumin excretion rates, statins treatment and MVE previous to 2009), the association between high level SAF in 2009 and MVE incidence during seven years was still significant(OR=9.7 p=0.004). A high SAF is predictive of MVE incidence in patients with type 1 diabetes.

Disclosure
C. Blanc-Bisson: None. F. Velayoudom Cephise: None. C. Helmer: None. L. Blanco: 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.. M. Monlun: None. V. Rigalleau: None.
Insulin Rescues Diabetes-Induced Pulmonary Complications
Authors: CAMPOLO ALLISON , MARIA ZAHRA , HINSDALE MYRON , LIU LIN , LACOMBE VERONIQUE 
Published: June 2018

Hyperglycemia is an independent risk factor for the development of respiratory diseases, including influenza infections. Although the lung is a major organ to utilize glucose, the regulation of glucose transport in the healthy and diabetic lung has received little attention. We hypothesized that hyperglycemia would predispose diabetic mice to alterations in pulmonary glucose transport and pulmonary complications during Influenza A infection. To test this hypothesis, we used a streptozotocin-induced type 1 diabetic mouse model (n=8-12/group). A subset of diabetic mice was treated with insulin via a subcutaneous insulin pump to restore euglycemia. After 8 weeks, an additional subset of mice was intranasally infected with influenza A H1N1 (A/PR/8/34; 250 PFU). Viral titer was determined from bronchoalveolar lavage (BAL) fluid by plaque assay. Glucose concentration in BAL fluid was measured spectrophotometrically. Glucose transporter (GLUT) protein content was quantified in whole lung homogenates by Western blotting. Both infected and uninfected diabetic mice had higher glucose concentrations in BAL fluid than their control or insulin-treated counterparts (p&lt;0.05). There was a trend towards a decrease in protein content of GLUT4 (the major insulin-sensitive isoform) and GLUT1 (a basal isoform) in the diabetic lung (p&lt;0.1). Total protein content of GLUT12 (a novel isoform) was increased in the diabetic lung (p&lt;0.05). Diabetic mice possessed a significantly higher percentage of lymphocytes in their BAL fluid (p&lt;0.05). GLUT protein content and lymphocyte alterations were rescued when mice were treated with insulin. Influenza-infected diabetic mice also had a higher percentage of lymphocytes (p&lt;0.05), and a trend toward an increase in viral load in BAL fluid vs. infected control mice. These novel findings suggest that 1) the regulation of glucose transport is altered in the lung during hyperglycemia, and 2) diabetic mice are predisposed to pulmonary inflammation and viral replication during influenza infection.

Disclosure
A. Campolo: None. Z. Maria: None. M. Hinsdale: None. L. Liu: None. V. Lacombe: None.
Type 2 Diabetes Mellitus Is Not Associated with the Incidence or the Outcome of Pneumonia in Patients with Acute Ischemic Stroke
Authors: PAPAGIANNI MARIANTHI , TZIOMALOS KONSTANTINOS , KOSTAKI STAVROULA , ANGELOPOULOU STELLA-MARIA , CHRISTOU KONSTANTINOS , SOFOGIANNI ARETI , ALKAGIET STELINA , DIDANGELOS TRIANTAFYLLOS , SAVOPOULOS CHRISTOS , HATZITOLIOS APOSTOLOS I. 
Published: June 2018

Background/Aims: The association between T2DM and the incidence and outcome of pneumonia in patients with acute ischemic stroke is unclear. The aim of the present study was to evaluate this association.
Patients and Methods: We prospectively studied 922 consecutive patients admitted with acute ischemic stroke (42.2% males, age 79.6±6.9 years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). The outcome was assessed with dependency rates at discharge (modified Rankin scale 2-5) and in-hospital mortality.
Results: During hospitalization, 113 patients developed pneumonia. Patients who developed pneumonia had higher fasting plasma glucose (FPG) levels at the second day of hospitalization than patients who did not develop pneumonia (7.4±3.4 and 6.3±2.6 mmol/l, respectively; p&lt;0.005) whereas the prevalence of T2DM and HbA1c levels did not differ between the two groups. Independent risk factors for pneumonia were obesity (relative risk (RR) 2.05, 95% confidence interval (CI) 1.10-3.79, p&lt;0.05) and NIHSS at admission (RR 1.13, 95% CI 1.09-1.16, p&lt;0.001). Among patients who developed pneumonia, 50.4% were dependent at discharge and 43.4% died during hospitalization. Patients who were dependent at discharge had similar prevalence of T2DM and similar FPG and HbA1c levels with patients who were independent at discharge. Patients who died during hospitalization had higher FPG levels than patients who were discharged (8.3±4.4 and 6.7±2.3 mmol/l, respectively; p&lt;0.05) whereas the prevalence of T2DM and HbA1c levels did not differ between the two groups. Independent risk factors for in-hospital mortality were diastolic blood pressure at admission (RR 1.05, 95% CI 1.01-1.09, p&lt;0.05) and NIHSS at admission (RR 1.16, 95% CI 1.09-1.23, p&lt;0.001).
Conclusions: T2DM does not appear to be associated with the incidence or the outcome of pneumonia in patients admitted with acute ischemic stroke.

Disclosure
M. Papagianni: None. K. Tziomalos: None. S. Kostaki: None. S. Angelopoulou: None. K. Christou: None. A. Sofogianni: None. S. Alkagiet: None. T. Didangelos: None. C. Savopoulos: None. A.I. Hatzitolios: None.
Gut Incretin Release as a Mediator of Metabolic Effects of Metformin in Type 2 Diabetic Patients with Chronic Heart Failure
Authors: STOLARIKOVA EVA , KOPECKY JAN , VELEBA JIRI , VELEBOVA KATERINA , BELINOVA LENKA , MELENOVSKY VOJTECH , KOPECKY JAN , PELIKANOVA TEREZIE 
Published: June 2018

Introduction: Metformin (MET) is a 1st choice drug used in patients with type 2 diabetes (DM). Treatment with MET in patient with DM and heart failure (HF) is associated with better cardiovascular outcomes, but mechanisms of MET-mediated effects are unexplained. Our aim was to evaluate the effects of MET on substrate metabolism, cardiac function and structure in patient with DM and HF.
Methods: 40 patients with DM and stable chronic HF (age: 59 ± 9 years) were studied in a random sequence cross-over clinical study testing the effect of 3-month usage of MET vs. placebo. The subjects were randomized to MET (2 g/day) or to placebo group. After the three months of treatment the medication was changed and the treatment continued for next 3 months. At the beginning and the end of each intervention period (3 times in total) the panel of various metabolic and cardiovascular tests was done: echocardiography, spiroergometry and meal test with evaluation of several variables like incretins (GLP-1 and peptide YY) and parameters of oxidative stress (MCP-1, TNFα).
Results: Compared to placebo, MET was accompanied with significantly higher increase of selected gut-related hormones. GLP-1 area-under-curve increased during the meal test (MET vs. PL: 8571.39±6899.57 vs. 5665.82±4580.57pmol.hour.l-1; p&lt;0.01). Also the peptide YY area-under-curve increased during the meal test (MET vs. PL: 29809.67±13442.43 vs. 23636.21±8183.08pmol.hour.l-1; p&lt;0.05). MCP-1 showed inconsistent trend to increase during meal test. Fasted levels of TNFα were higher after MET, but there was no change during the meal test compared to placebo. MET therapy led to reduction of HbA1C (p&lt;0.001) and reduced glucose area-under-curve (p&lt;0.001) during glucose tolerance test. MET had neutral effect on cardiac structure and function.
Conclusions: Our results suggest that metabolic effects of MET might be mediated by improvement of gut endocrine function. MET had neutral effect on cardiac function or structure.

Disclosure
E. Stolarikova: None. J. Kopecky: None. J. Veleba: None. K. Velebova: None. L. Belinova: None. V. Melenovsky: None. J. Kopecky: None. T. Pelikanova: None.
Novel "Dual Hit" Rat Model of Diabetic Cardiomyopathy
Authors: THISTED LOUISE , LINDSAY ROSS T. , FOSGERAU KELD , SECHER THOMAS , THOMSEN MORTEN B. , JESPERSEN THOMAS , MURRAY ANDREW J. , PEDERSEN PHILIP J. , VRANG NIELS , FINK LISBETH N. , PEDERSEN TANJA X. , ZOIS NORA E. 
Published: June 2018

The pathogenesis of diabetic cardiomyopathy (DC) is poorly understood and new drugs targeting the myocardium are absent. This may be ascribed to the failure of available pre-clinical models to recapitulate essential clinical features of DC and heart failure. We hypothesized that the combination of experimental diabetes and pharmacologically induced cardiac stress might provide a novel rat model displaying a distinct profile of DC. Non-insulin dependent type 1 like diabetes mellitus was induced by partial (90%) pancreatectomy (Px). Pronounced hyperglycemia was established within two weeks (blood glucose levels of 23.3 ± 3.7 mM). Five weeks post Px or sham surgery, vehicle or the sympathomimetic agent, isoproterenol (Iso, 1 mg/kg, SC) was administered for 10 days. Ten weeks after surgery, the heart was isolated for detailed histological and molecular characterization. The relative weight of the left ventricle (LV) was significantly increased in Px-Iso rats compared to sham-vehicle treated control rats (0.22 ± 0.03 vs. 0.25 ± 0.02 mg/g BW, p&lt;0.05), indicating Px-Iso-induced cardiac hypertrophy. Compared to sham-vehicle rats, cardiac muscle fibers of Px-vehicle rats had attenuated respiratory function and increased reliance upon oxidation of fatty acid substrates, measured by high-resolution respirometry. Interestingly, this aggravation was reversed in Px-Iso rats. Moreover, Iso induced cardiac fibrosis demonstrated by quantitative histology (area fraction; Px-vehicle vs. Px-Iso: 3.1 ± 0.2% vs. 6.3 ± 0.5%; Sham-vehicle vs. Sham-Iso: 3.7 ± 0.4% vs. 7.6 ± 0.5%, p&lt;0.001). Echo- and electrocardiography as well as transcriptome analyses were applied to further assess LV remodeling and cardiac function.
In conclusion, the Px-Iso rat model may provide a state-of-the-art model of DC displaying key features of the clinical condition. Hereby, this model may be useful in the evaluation of cardiovascular effects of novel compounds in the pre-clinical phase of drug development.

Disclosure
L. Thisted: Employee; Self; Gubra. R.T. Lindsay: None. K. Fosgerau: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. T. Secher: Employee; Self; Gubra. Employee; Spouse/Partner; Novo Nordisk A/S. M.B. Thomsen: None. T. Jespersen: None. A.J. Murray: None. P.J. Pedersen: None. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. T.X. Pedersen: Employee; Self; Gubra. N.E. Zois: Employee; Self; Gubra.
Effects of NAFLD on Acetyl-CoA Partitioning and Ketone Kinetics in Response to a 24-Hour Fast
Authors: FLETCHER JUSTIN A. , DEJA STANISLAW , BURGESS SHAWN C. , BROWNING JEFFREY 
Published: June 2018

During an overnight fast (12 hour), the liver provides glucose as fuel for other tissues via glycogenolysis and the energetically expensive process of gluconeogenesis. During this period, energy to support this process is generated primarily by the tricarboxylic acid (TCA) cycle. As the duration of fasting prolongs, and glycogen stores are depleted (&gt;24 hour), the liver shifts to the production of ketone bodies that can be used as a secondary fuel source by peripheral tissues. In healthy humans, this period of fasting is generally associated with increased β-oxidation and partitioning of acetyl-CoA away from the TCA cycle and toward ketone body production. We have previously shown that subjects with nonalcoholic fatty liver disease (NAFLD) have increased rates of acetyl-CoA oxidation in the TCA cycle after a 12 hour fast. To examine how NAFLD affects hepatic response to a 24 hour fast, we infused stable isotope tracers into BMI and age matched subjects with (n=12) and without (n=12) NAFLD. At enrollment, NAFLD subjects had greater liver triglycerides (P&lt;0.05) and hepatic insulin resistance (P&lt;0.05), as well as higher fasting plasma concentrations of cholesterol, triglycerides, and glucose (P&lt;0.05). After fasting for 24 hours, subjects with NAFLD failed to suppress endogenous glucose production as compared to controls. This was associated with a higher ratio of plasma insulin to glucagon as well as a blunted increase in the concentration of plasma free fatty acids as fasting duration prolonged. As previously shown in overnight fasted subjects, TCA cycle activity was significantly higher in NAFLD subjects after a 24 hour fast. However, despite elevated TCA cycle flux, NAFLD subjects failed to increase overall β-oxidation compared to controls due to reduced utilization of acetyl-CoA for ketone synthesis.
In conclusion, after a 24 hour fast, the liver of NAFLD subjects produced more glucose and disposed of less fat via β-oxidization by shuttling more acetyl-CoA to the TCA cycle but much less to ketogenesis.

Disclosure
J.A. Fletcher: None. S. Deja: None. S.C. Burgess: None. J. Browning: None.
Nrf2 Exaggerates Cardiomyopathy Associated with Type 1 Diabetes in Mice
Authors: ZANG HUI M. , WU WEIWEI , QI LEI , BOWEN CHRISTOPHER , CUI TAIXING , NAGARKATTI PRAKASH , NAGARKATTI MITZI 
Published: June 2018

Nuclear factor-erythroid factor 2-related factor 2 (Nrf2), a transcription factor for cellular defense against oxidative stress and other insults, has been postulated to be an inhibitor of diabetes and diabetic cardiomyopathy. However, this notion has been challenged by the detrimental role of Nrf2 in the pathogenesis of diabetes and diabetic cardiomyopathy. Thus, we investigated the nature of the Nrf2-mediated dichotomy in a mouse model of streptozotocin (STZ)-induced type 1 diabetes over a time period of 9 months. We found that global Nrf2 knockout (Nrf2 KO) increased the death rate in the setting of STZ-induced diabetes, but it partly protected against STZ-induced diabetes and insulin-resistance in both male and female mice. Nrf2 KO hardly affected the onset and the progression of cardiac dysfunction associated with the diabetes by 6 months in both male and female mice; however, it partly prevented the progression of cardiac dysfunction at 9 months. Cardiomyocyte hypertrophy, cardiac fibrosis, and cardiac oxidative stress associated with the diabetes not at 3 months but at 6 and 9 months were inhibited by Nrf2 KO in both male and female mice. In addition, cardiomyocyte-restricted (CR) Atg5 KO had minimal impact on the blood glucose level, but exaggerated the diabetic cardiomyopathy, which could be attenuated in part by additional Nrf2 KO. At the molecular level, diabetes-induced autophagy impairment turned off Nrf2-operated antioxidant defense while switching on Nrf2-mediated detrimental signaling to cardiomyocytes. Taken together, our findings reveal that Nrf2 is cardiac protective when myocardial autophagy is intact; however, it becomes detrimental to the heart when myocardial autophagy is impaired due to a chronic diabetic setting.

Disclosure
H.M. Zang: None. W. Wu: None. L. Qi: None. C. Bowen: None. T. Cui: None. P. Nagarkatti: None. M. Nagarkatti: None.
Poldip2 Affects Collagen I Accumulation by Regulating the Expression of Zyxin in Vascular Smooth Muscle Cells
Authors: FUJII MASAKAZU , SONODA NORIYUKI , OKAMOTO MISATO , MORINAGA HIDETAKA , OGAWA YOSHIHIRO , GRIENDLING KATHY 
Published: June 2018

Objectives: Polymerase delta interacting protein 2 (Poldip2) has previously been implicated in migration, proliferation and extracellular matrix (ECM) production in vascular smooth muscle cells. Thereby, regulation of Poldip2 protein expression is suggested to prevent the development and progression of diabetic macroangiopathy. We recently reported that Poldip2+/- mouse aortic smooth muscle cells (MASMs) exhibit higher β1-Integrin expression and activity of the PI3K/Akt/mTOR signaling pathway, leading to increased ECM protein synthesis. We further investigated the mechanism of Podlip2 in regulating the β1-Integrin expression.
Approach and Results: Cell adhesion and cell signaling, below the focal adhesion, were investigated. Poldip2+/- MASMs (HET) showed both quicker cell attachment and detachment than Poldip2+/+ MASMs (WT). Paxillin, one of the components of focal adhesion, is expressed in all areas (from front to back) of lamellipodia in WT, on the other hand HET express the Paxillin only front area, which may induce weaker cell adhesion. The mature focal adhesion marker, Zyxin, expression is decreased in HET significantly. Intriguingly, the activity of RhoA is increased in HET and induced MRTF-A translocation from cytosol to nacreous.
Conclusions: It is revealed that Poldip2 is positive regulator of Zyxin. HET has weak cell adhesion, and may induce Poldip2+/- MASMs exhibit higher β1-Integrin expression as a compensation against immature focal adhesion. Thus PI3K/Akt/mTOR signaling pathway is activated, leading to increased ECM protein synthesis. Translocation of MRTF-A from cytosol to the nucleus, may contribute to bind to transcriptional factor for Collagen I. This phenomenon is suggested as one more pathway, which Collagen I accumulates in HET. These findings have important implications for atherosclerotic vascular diseases such as diabetic macroangiopathy in which ECM accumulation plays a role.

Disclosure
M. Fujii: None. N. Sonoda: None. M. Okamoto: None. H. Morinaga: None. Y. Ogawa: Research Support; Self; AstraZeneca. Advisory Panel; Self; Gilead Sciences, Inc.. Research Support; Self; Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.. K. Griendling: None.
Renin-Angiotensin System Inhibition Alters Triacylglycerol Metabolism in Diabetic Kidney Disease
Authors: SAS KELLI , LIN JIAHE , NAIR VIJI , KRETZLER MATTHIAS , BROSIUS FRANK , PENNATHUR SUBRAMANIAM 
Published: June 2018

Lipids are essential metabolites with diverse functions impacting physiology. We recently identified several lipidomic abnormalities in diabetic kidney disease (DKD), including remodeling of triacylglycerol (TAG) fatty acid composition to increase availability of long, polyunsaturated TAGs. Using the BKS eNOS-/- db/db diabetic mouse model, we studied the effect of renin-angiotensin system (RAS) inhibition with combination treatment of lisinopril (20 mg/kg/d) and losartan (30 mg/kg/d) for 12 weeks, an intervention which ameliorates DKD in this mouse model without impacting glycemia. We examined the kidney cortical lipidome to identify lipid alterations that may be pathogenic in DKD. As expected, RAS inhibition did not significantly alter glycemic control or total plasma triglycerides or cholesterol, but decreased the 24-hour urine albumin/creatinine ratio (2564 vs. 615 μg/mg creatinine) and decreased the glomerular periodic acid-Schiff stained area by 13% (p&lt;0.05). We performed mass-spectrometry based untargeted lipidomic profiling to quantify 635 lipids across 17 lipid classes in kidney cortex. Lisinopril/losartan treatment remodeled TAG fatty acid composition and increased conversion between TAGs and several glycerophospholipid classes, particularly medium-chain phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols and cardiolipins (p&lt;0.05). These correlations in lipid levels were associated with changes in corresponding enzymes of lipid metabolism, suggesting increased metabolism of TAGs into glycerophospholipids, which are key components of cell membranes and precursors for signaling molecules. In addition to the known salutary effect of RAS inhibition on DKD, our results suggest a previously unrecognized role of RAS inhibition on kidney complex lipid levels through increased TAG metabolism. These findings raise the possibility that TAG metabolism might be a target for intervention aimed at decreasing DKD progression.

Disclosure
K. Sas: None. J. Lin: None. V. Nair: None. M. Kretzler: Research Support; Self; AstraZeneca, Novo Nordisk Inc., Boehringer Ingelheim GmbH, National Institute of Diabetes and Digestive and Kidney Diseases, Eli Lilly and Company, Gilead Sciences, Inc.. F. Brosius: None. S. Pennathur: None.