bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Association between Diabetic Peripheral Neuropathy and Diabetic Retinopathy
Authors: JARRY ZYDEN , JOSHI VINAYAK , VAHTEL MARIA , BURGE MARK R. , SOLIZ PETER 
Published: June 2018

Purpose: To quantify the association between diabetic peripheral neuropathy (DPN) and diabetic retinopathy (DR), as expressed in terms of thermal regulation of the plantar foot and vascular abnormalities in the retina.
Background: DPN accounts for around 73,000 lower-limb amputations in diabetics annually in the U.S., partially due to low compliance with periodic screening for DPN. Similarly, annual retinal screening for DR in diabetics is recommended by ADA and others. Identifying and referring individuals at risk for DPN by using biomarkers in retina could improve compliance for DPN screening.
Methods: Subjects (55-75 years) clinically diagnosed with DPN (N=20) and a set of age-matched controls (N=29) were selected. Thermal videos and retinal images were collected for all subjects. Subjects’ feet were imaged with an infrared (thermal) imager to obtain: 1) baseline temperature for 3 min, and 2) thermal recovery temperature for 10 min after a cold-patch provocation. Presence of DPN was determined by clinical examination. Retinal imaging was performed on each eye to obtain macula- and disc-centered images. A certified grader read the retinal images for severity level of DR and other retinal abnormalities. A logistic regression analysis was performed to compare retinal and thermal features, with the clinical diagnosis of DPN.
Results: A logistic regression determined a statistically significant difference (p &lt; 0.05) in DR severity levels between DPN subjects and controls. The association between thermal features and DPN was demonstrated by statistically significant difference in recovery temperatures for both feet obtained in 1 min after cold provocation (p &lt; 0.01), between DPN and controls.
Discussion: This study demonstrates the value of using characteristics of DR screening to identify individuals also at risk for DPN. A thermal imager located at the same screening site as a retinal camera could improve compliance with DPN screening and potentially prevent unnecessary foot complications.

Disclosure
Z. Jarry: None. V. Joshi: None. M. Vahtel: None. M.R. Burge: Research Support; Self; VisionQuest Biomedical LLC.. P. Soliz: None.
Neutrophil Elastase Contributes to the Early Molecular Abnormalities of the Retina in Diabetes
Authors: LIU HAITAO , KERN TIMOTHY 
Published: June 2018

Introduction: Previous studies by our lab indicate that neutrophils are involved with capillary degeneration in diabetic retinopathy (DR). The elastase is a serine protease in neutrophils that plays an important role in a variety of inflammatory diseases, such as chronic obstructive pulmonary disease. We are investigating the potential role of NE in the development of DR.
Method: The activity of neutrophil elastase (NE) was selectively inhibited (by daily sivelestat) or deleted (Elane-/-) from diabetic mice, and the effects of NE loss were compared to the effects of inhibition of general protease activity (over-expression of protease inhibitor, alpha-1 antitrypsin). Molecular abnormalities associated with the development of DR, including retinal superoxide production, expression of proteins associated with inflammation, and leukocyte-mediated cytotoxicity of retinal endothelial cells were used to determine the effects of NE in diabetic mice.
Result: At two months of diabetes, selective inhibition of NE or deletion of the elastase both inhibited diabetes-induced superoxide production and inflammation in the retina. Both also inhibited leukostasis and/or leukocyte mediated damage to endothelial cells in cell cytotoxicity assays. In contrast, over-expression of alpha-1 antitrypsin resulted in increased retinal superoxide production and leukocyte activity in cytotoxicity assays in both diabetic and nondiabetic animals.
Conclusion: NE may play an important role in the development of DR.

Disclosure
H. Liu: None. T. Kern: None.
Angiotensin-(1-7) Attenuates Protein O-GlcNAcylation in the Retina of Mice Fed a High-Fat Diet
Authors: DIERSCHKE SADIE , ARNOLD AMY C. , BARBER ALISTAIR J. , DENNIS MICHAEL D. 
Published: June 2018

Increased retinal protein O-GlcNAcylation occurs in response to hyperglycemia and contributes to diabetic retinopathy (DR). Alternatively, systemic pharmacological blockade of the Renin-Angiotensin System (RAS) lowers the incidence of DR. The classic RAS that systemically regulates blood pressure is defined by the ACE/AngII/AT1R axis; this is counter-regulated by actions of the ACE2/Angiotensin-(1-7) (Ang1-7)/Mas axis of the RAS. Increased endogenous production of Ang1-7 is responsible for many of the beneficial effects of cardioprotective RAS blockers such as ACE inhibitors; however the mechanism whereby DR outcomes are improved remains unresolved. The hypothesis here is that Ang1-7 acts to reduce retinal O-GlcNAcylation by activating Protein Kinase A (PKA) and thereby inhibiting the rate-limiting enzyme of the hexosamine biosynthetic pathway, glutamine-fructose-6-phosphate amidotransferase (GFAT). Mice fed a 60% high fat diet (HFD) for 11 weeks and treated with the ACE inhibitor captopril (50 mg/L) for 3 weeks exhibited a Mas receptor-dependent attenuation of retinal protein O-GlcNAcylation as compared to vehicle treated controls. To determine the mechanism by which Ang1-7 regulates O-GlcNAcylation, R28 retinal neurons were treated with Ang1-7 and the adenylate cyclase activator forskolin. Both Ang1-7 and forskolin increased cAMP concentrations and attenuated levels of protein O-GlcNAcylation induced by treatment with the O-GlcNAcase inhibitor thiamet G. Classically, cAMP activates PKA, which phosphorylates and inhibits GFAT. Overall, these studies establish the first link between dysregulation of the well-studied physiological RAS and diabetes-induced retinal tissue damage as a consequence of excessive protein O-GlcNAcylation.

Disclosure
S. Dierschke: None. A.C. Arnold: None. A.J. Barber: None. M.D. Dennis: None.
Abnormal Electroretinography in Patients with Long-Duration Diabetes but No Retinopathy
Authors: BROOKS BELINDA , YUE DENNIS , LANDY ELLEN , SHI YI 
Published: June 2018

Retinopathy increases with duration of diabetes but the presence of this microvascular complication in individual patients remains unpredictable. Retinal neurophysiological changes have been postulated to be important in modulating susceptibility. We performed electroretinography (ERG) on patients with long duration of diabetes (&gt;15 years) but no retinopathy to determine whether this setting of “normal retinal morphology” is also characterised by normal electrophysiology of the eyes. ERG was performed with a handheld RETeval-DR™ device. Flickering lights at 30Hz was used to stimulate retinal electrical activity recorded by skin electrodes placed below the lower eye lids. Implicit time (electrical conduction time, msec), amplitude (uV) and pupil diameter (mm) were recorded. A composite score &lt; 20 of these three parameters indicates a &lt;1% risk of vision threatening retinopathy. Altogether 26 type 2 and 9 type 1 patients with no retinopathy and diabetes duration 22.5±4.5 and 32.8±9.4 years respectively were studied. Nondiabetic individuals (fasting BGL&lt;6.0mM or HbA1c&lt;6.0% n=25) acted as controls. Results in Table 1 showed the implicit time of individuals with diabetes but no retinopathy was only minimally increased but the amplitude was significantly reduced by ∼30% (p&lt;0.01). We conclude that the eyes of these patients protected from diabetic retinopathy nevertheless showed retinal neural dysfunction.

Disclosure
B. Brooks: None. D. Yue: None. E. Landy: None. Y. Shi: None.
Identification of ProliferAtive Diabetic REtinopathy to Asymptomatic Coronary Heart Disease in Chinese T2D Individuals—The IPAD Reach Study
Authors: ZHOU JIANBO , YANG JINKUI 
Published: June 2018

Aim: Substantial percentage of patients with T2D have asymptomatic Coronary Heart disease (CHD). To explore identification of PDR to asymptomatic CHD. We reported the baseline data from this IPAD reach group study, a China retrospective cohort study on clinical predictors of asymptomatic CHD in type 2 diabetes.
Method: T2D individuals (211non-DR (NDR) and 140 proliferative DR (PDR)) from a national diabetes center in China. The area under the receiver operating characteristic curve (AUC) were created. Discrimination and reclassification were used to assess the value of addition of PDR to the base model.
Results: Investigation included 211 NDR and 140 PDR. With the model estimating risk of asymptomatic CHD based on UKPDS engine, the AUC analysis improved from 0.583 (95% CI, 0.51-0.66) to 0.697 (95% CI, 0.641- 0.752) in the model without PDR and with PDR. The addition of PDR to a base model (8 traditional risk factors) to identify asymptomatic CHD increased the C statistic from 0.746 (95% CI, 0.681-0.811) to 0.762 (95% CI, 0.699-0.825; P=0.73). With the addition of PDR to the base model, there was a continuous net reclassification indexes (NRI) of 5.9% (95% CI, 1.4%-10.2%, p=0.017) for asymptomatic CHD. The absolute integrated discrimination index (IDI) was 0.004 (p= 0.02), with a relative IDI of 10.4%.
Conclusions: The improvement in identification of asymptomatic CHD, compared with traditional risk factors, demonstrates that PDR could identify cardiovascular risk stratification in Chinese diabetic individuals. Follow-up of this cohort will provide reliable information on asymptomatic CHD risk.

Disclosure
J. Zhou: None. J. Yang: None.
Macular Choroidal Thickness in Pregnant Women with Type 1, Type 2, and Gestational Diabetes Mellitus
Authors: BENFICA CAMILA Z. , ZANELLA TERESINHA , FARIAS LUCAS B. , OPPERMANN MARIA LUCIA R. , CANANI LUIS H.S. , LAVINSKY DANIEL 
Published: June 2018

Pregnancy is an independent risk factor for the progression of diabetic retinopathy (DR). A possible relation with morphological changes of the choroid should be studied. The aim of this study was to analyze choroidal thickness measurements of nondiabetic pregnant women and of pregnant women with type 1, type 2 and gestational diabetes mellitus using spectral-domain optical coherence tomography (OCT). This cross-sectional study included 144 eyes of 72 pregnant women in the third trimester divided into four groups: Group 1 consisted of 27 nondiabetic pregnant women (control group); Group 2 consisted of 15 pregnant women with gestational diabetes mellitus (GDM); Group 3 consisted of 16 pregnant women with type 2 diabetes mellitus (T2DM); and Group 4 consisted of 14 pregnant women with type 1 diabetes mellitus (T1DM). Choroidal thickness was measured using EDI-OCT at ten different locations: at the fovea and every 500µm from the fovea up to 2500µm temporally and up to 2000µm nasally. Other variables such as gestational age, glycosylated hemoglobin values (HbA1c), time from DM diagnosis, hypertension and severity of DR were analyzed. The analysis of the 4 groups adjusted for the presence of hypertension showed a thinner choroid in patients with T1DM in all locations, with statistical significance in subfoveal and temporal measurements. In the comparison only between patients with DM, adjusted for HbA1c, time from diagnosis and presence of hypertension and DR, choroid of patients with T1DM remained thinner at all macular points.
In conclusion, our study showed no statistically difference in choroidal thickness between nondiabetic pregnant women, pregnant women with GDM and pregnant women with T2DM during the third trimester. On the other hand, pregnant women with T1DM had significantly thinner choroidal thickness measurements.

Disclosure
C.Z. Benfica: None. T. Zanella: None. L.B. Farias: None. M.R. Oppermann: None. L.H.S. Canani: None. D. Lavinsky: None.
Expression of ApoE Attenuates Differentiation of the White Adipose Tissue from ApoE-Knockout Diabetic Mice
Authors: RAN JIANMIN , PAN XIAMING , ZHANG RUYI , ZHU PING , TAN RONGSHAO , LIU YAN 
Published: June 2018

Background: What and how the adipose-derived ApoE regulates biological features and lipid metabolism in the diabetic adipose tissue remain little known.
Methods: ApoE-/- and wild type mice were randomly divided into 4 groups: ApoE-/- group (EKO); streptozotocin (STZ)-induced diabetic apoE-/- group (EKODM); wild type group(WT); and STZ-induced diabetic wild type group (WTDM). Epididymal white adipose tissue isolated from part EKODM mice were transplanted into backs of WT mice and WTDM mice respectively, all recipient mice were fed with standard chow for 8 weeks. Vital signs, fasting plasma glucose, serum triglycerides(TG) and total cholesterol(TC) were measured every 4 weeks. After sacrifice, epididymal and transplanted white adipose tissue were harvested from all recipient mice. Histomorphologic alterations of adipose tissue were observed. Lipid ingredients of adipose tissue were extracted and measured. Genes expression of ApoE,lipoprotein lipase (LPL),hormone sensitive lipase(HSL),fatty acid synthase(FAS) in adipose tissue were detected by the RT-PCR.
Results: 1) After transplantation, the donor adipocytes size from EKODM→WT and EKODM→WTDM mice were both larger than that of EKODM itself. 2) Adipose TG contents of EKO and WTDM group were both lower than that of WT group, while EKODM→WT transplantation increased TG content but kept TC content unchanged compared with the EKODM→WTDM. 3) Adipose tissues of EKODM→WT and EKODM→WTDM group both significantly expressed ApoE. 4) Gene expressions of HSL, LPL, and FAS in donor adipose tissues from either EKODM→WT and EKODM→WTDM group were all significantly increased if compared with the EKODM group.
Conclusions: Adipose-derived ApoE may facilitate adipocyte differentiation in mice, even in a diabetic state.

Disclosure
J. Ran: None. X. Pan: None. R. Zhang: None. P. Zhu: None. R. Tan: None. Y. Liu: None.
Increased Angiopoietin Like Proteins 4 (ANGPTL4) Is Associated with Higher Concentration of LDL-Triglycerides in Type 2 Diabetes
Authors: NAGAIKE HIROE , HAYASHI TOSHIYUKI , NAKANISHI NORIKO , OHARA MAKOTO , YAMAMOTO TAKESHI , FUKUI TOMOYASU , HIRANO TSUTOMU 
Published: June 2018

Background/Aims: Diabetic dyslipidemia is typically characterized by an increase in plasma triglycerides (TG), a concomitant increase in small dense (sd) low density lipoprotein (LDL) and atherogenic LDL-TG. Angiopoietin like protein 4 (ANGPTL4) is well established regulators of plasma TG level through regulating the activity of lipoprotein lipase. Plasma level and association between ANGPTL4 and sdLDL or LDL-TG is not well established in human subjects. We aimed to examine the level of ANGPTL4 and investigate the association between ANGPTL4 with sdLDL-C and LDL-TG in type 2 diabetes (T2D).
Methods: 250 (M176/F 74) Japanese diabetic patients and 9 of healthy controls (Controls) were enrolled in this study. SdLDL-C and LDL-TG were measured by homogeneous assays. ANGPTL3 and ANGPTL4 protein levels were measured by ELISA.
Results: As compared with Controls, plasma ANGPTL3, ANGPTL4, sdLDL-C and LDL-TG levels were increased in T2D. ANGPTL3 was not collated with sdLDL-C or LDL-TG. ANGPTL4 was positively correlated with HbA1c(r=0.15, p=0.019), TG(r=0.15, p=0.018)and LDL-TG(r=0.17,p=0.008), whereas ANGPTL4 was not collated with sdLDL-C. Furthermore, ANGPTL4 was also significantly associated with LDL-TG/LDL-C ratio (r=0.15, p=0.022) and LDL-TG/apoB ratio (r=0.18, p=0.009).
Conclusions: The ANGPTL4 level was increased in T2D and associated with atherogenic higher LDL-TG levels. ANGPTL4 may play a role in modulating lipid metabolism in LDL particles.

Disclosure
H. Nagaike: None. T. Hayashi: None. N. Nakanishi: None. M. Ohara: None. T. Yamamoto: None. T. Fukui: None. T. Hirano: Speaker's Bureau; Self; Novo Nordisk Inc., AstraZeneca.
Effects of Gly-LDL on LRP5/DKK1 Pathway in MC3T3-E1 Osteoblasts
Authors: LEI TAO , CHEN LIN , ZHANG BINGYU , TANG WENJUN 
Published: June 2018

Background: The aim of this study was to investigate the effect of glycated low density lipoprotein (Gly-LDL) on the proliferation, differentiation and expression of low-density lipoprotein receptor-related protein-5 (LRP5), dickkopf-1(DKK1) in mouse MC3T3-E1 cells.
Methods: The MC3T3-E1 cells of mouse were cultured with native LDL(n-LDL) without chemical, and various levels of Gly-LDL was cultured respectively with 5mmol/L(A), 20mmol/L(B), 100mmol/L(C) of D+glucose for 4 weeks) for 48h. The proliferation of MC3T3-E1 cell was measured by CCK8, the osteocalcin level in the medium was determined by ELISA, the mRNA expression of LRP5,β-catenin and DKK1 was analysed by real-time PCR and proteins in Wnt signaling pathway by western blot.
Results: After cells incubation with group A of Gly-LDL, the inhibition of MC3T3-E1 cells was apparently promoted than that of n-LDL control group (P&lt;0.01),The higher Gly-LDL level the more inhibited. The effects of Gly-LDL on the proliferation of MC3T3-E1 was dose-dependent under certain conditions. The levels of Osteocalcin in cells cultured with Gly-LDL were significantly inhibited compared with the control group. The mRNA expression of DKK1 was significantly up-regulated while the mRNA expression of β-catenin and LRP5 were down-regulated(P&lt;0.01) in MC3T3-E1 cells, which cultured with group A Gly-LDL. According to the results of western blot, it also showed that, compared with n-LDL group,the effect of Gly-LDL on osteoblasts was down-regulated the LRP5 and β-catenin while up-reglulated the DKK1.
Conclusions: The Wnt signaling pathway being involved might be the possible mechanism of Gly-LDL effect on the proliferation and differentiation in MC3T3-E1 cells.

Disclosure
T. Lei: None. L. Chen: None. B. Zhang: None. W. Tang: None.
Enhancement of Insulin Sensitivity Contributes to Polychlorinated Biphenyl-126–Induced Hepatic Steatosis and Injury
Authors: WANG XIN 
Published: June 2018

Background: In the last decades, the prevalence of diabetes and related diseases of metabolic disorders has a dramatic increase. The global prevalence of diabetes and its related diseases is closely associated with the exposure to polychlorinated biphenyls (PCBs).
Aim: To investigate the the effect of PCB-126 on glucose/lipid metabolism and hepatic steatosis and to elucidate the molecular mechanisms.
Methods: C57BL/6J mice were orally administrated with PCB-126 (1.5 mg/kg) twice in a week with or without the injection of GDC-0941 (1 mg/kg) before the administration of PCB-126. The experimental period was two weeks.
Results: PCB-126 significantly decreased fasting blood glucose level, reduced glucose levels in the glucose and insulin tolerance tests, indicating that PCB-126 treatment increased insulin sensitivity in mice. In addition, PCB-126 exposure resulted in a significant increase in hepatic lipid content, as reflected by biochemical determination, Oil Red O staining and Bodipy staining. Using transmission electron microscope, we observed that PCB-126 increased the number and size of lipid droplets in liver tissues. We showed that injection of GDC-0941, an inhibitor of insulin signaling, slightly inhibited the effect of PCB-126 on glucose levels and glucose and insulin tolerance. Although GDC-0941 did not significantly affect the content of triglyceride in liver of PCB-126-treated mice, the size of hepatic lipid droplet was significantly reduced by GDC-0941, as evidence by Bodipy staining and observation under transmission electron microscope. Moreover, PCB-126-induced expression of aryl hydrocarbon receptor and lipogenesis-related regulators, such as sterol regulatory element-binding protein 1, was inhibited by GDC-0941.
Conclusion: The data suggest that enhancement of insulin sensitivity contributes to PCB-126-induced hepatic steatosis and injury.

Disclosure
X. Wang: None.
The Validity and Reliability of Japanese Version of the Diabetes Distress Scale for Adult Patients with Type 2 Diabetes
Authors: MATSUMOTO HIROHIDE , OKAZAKI KENTARO , OYA TOSHIKI , TAKAHASHI NORIYUKI , SUEMATSU MINA 
Published: June 2018

Diabetes related distress is common for patients with type 2 diabetes (T2D), which exacerbates glycemic control through negative effects on emotional and physical well-being and self-care behaviors. Diabetes Distress Scale (DDS) is a widely used instrument to measure diabetes related distress. The aim of this study was to develop the Japanese version of the DDS (DDS-J) and examine its psychometric properties. DDS-J was developed conceptually equivalent to the original English version by forward and backward translations and adjustments of inappropriate terms. The investigation was conducted in 132 (mean age 64.5 years, 67.4% male, mean duration 14.2 years, mean HbA1c 7.7%) T2D patients at outpatient department of 2 hospitals in Aichi, Japan from February to March 2017. Cronbach’s α was used to assess reliability, and factor analysis to analyze validity. The 5-item World Health Organization Well-Being Index (WHO-5) and Patient Health Questionnaire-9 (PHQ-9) scale were adopted to evaluate the criteria-related validity. The scores of DDS-J, WHO-5 and PHQ-9 were calculated, then their relationship analyzed using Pearson correlation analysis. Four factors of regimen-related distress (RD), emotional burden (EB), physician-related distress (PD), and diabetes-related interpersonal distress (ID) were extracted by exploratory factor analysis. This factor structure was the same as the original. The overall Cronbach’s α was 0.91, while ones for RD, EB, PD, and ID were 0.86, 0.87, 0.73 and 0.86, respectively. The total DDS-J score was 24.4±18.7, WHO-5 15.3±5.4 and PHQ-9 3.5±4.4. The total DDS-J score showed a weak but significant correlation with WHO-5 (r=-0.376, p&lt;0.01) and PHQ-9 (r=0.425, p&lt;0.01).
In conclusion, DDS-J have good validity and reliability, and can be used as an effective tool to assess diabetes related distress of Japanese adult T2D patients. Furthermore, diabetes related distress is associated with well-being and depression in the studied patients.

Disclosure
H. Matsumoto: None. K. Okazaki: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Taisho Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Astellas Pharma US, Inc., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation, MSD K.K., Sanwa Kagaku Kenkyusho Co., Ltd.. Other Relationship; Self; Aichi prefecture government and Nagoya city government. T. Oya: None. N. Takahashi: Other Relationship; Self; Archie prefecture government and Nagoya city government. M. Suematsu: Other Relationship; Self; Aichi prefecture government and Nagoya city government.