bluuebunny/crossref_metadata_2025_split huggingface dataset:
566-P: Mild Increase of Proinflammatory Macrophages Correlates with Reduction of Nerve Fiber Density in Sural Nerve of Human Type 2 Diabetic Subjects
Authors: MIZUKAMI HIROKI , OSONOI SHO , TAKAHASHI KAZUHISA , KUDO KAZUHIRO , ITABASHI CHIEKO , YAGIHASHI SOROKU 
Published: June 2019

The dominant infiltration of pro-inflammatory M1 macrophages (M1) compared to anti-inflammatory M2 macrophages (M2) exerts insulin resistance in peripheral tissues of type 2 diabetes (T2DM). This inflammatory reaction is also associated with the pathogenesis and development of diabetic complications including neuropathy (DPN). It is still unclarified, however, regarding macrophage infiltration in human DPN. The aim of this study is to clarify the significance of macrophage infiltration in sural nerve (SN) in subjects with T2DM. SN of autopsy cases was dissected from 2014 to 2016. Eleven cases (Male 6, Female 5) of non-T2DM (nDM) and 11 cases (Male 3, Female 8) of T2DM (T2D) were subjected to the evaluation. Double immunohistochemistry was performed in cross section of SN for CD68 (Pan-macrophage) and CD206 (M2). M1 was defined as CD68+ and CD206- and M2 was as CD206+, respectively. Epon-embedded semithin section was used for morphometrical assessment of SN fibers. In frozen SN, mRNA expression was evaluated by qPCR. Average age and BMI were comparable between 2 groups. HbA1c was significantly greater in T2D (mean±SE) (7.2±0.5%) than nDM (5.5±0.2%) (p&lt;0.05). Pathological evaluation showed 2.4 times M1 in T2D more than that in nDM (p&lt;0.05). On the other hand, M2 was comparable between 2 groups. Expression of iNOS for M1 in T2D was 1.8 times increased compared to that of nDM (p&lt;0.05), whilst, that of CD163 for M2 was comparable between two groups. Correlation analysis between macrophage infiltration and clinical parameters disclosed that the M1 infiltration proportionally correlated with the value of HbA1c (p&lt;0.05), whereas there was no correlation between M2 infiltration and HbA1c. SN fiber density inversely correlated with M1 population (p&lt;0.05). Collectively, mild, but significant pro-inflammatory condition is associated with SN fiber loss, suggesting the pathogenic role of M1 in DPN.

Disclosure
H. Mizukami: None. S. Osonoi: None. K. Takahashi: None. K. Kudo: None. C. Itabashi: None. S. Yagihashi: None.
577-P: Increased Symptoms of Peripheral Neuropathy and Depression in Insulin-Treated Type 2 Diabetic Patients Are Associated with Reduced BDNF Serum Protein Levels and Val66Met-SNP
Authors: BASHKIN AMIR , SAFADI AKRAM , GROSS BELLA , HOROWITZ NETANEL A. , SHARON RIVKA , SHAOUL ESTHER , NODELMAN MARINA , AZOULAY DAVID 
Published: June 2019

Background: BDNF is a neuronal growth factor essential for nervous system maintenance.
Objective: We have evaluated peripheral neuropathy (PN) and depression in patients with type 2 diabetic mellitus and looked for an association with serum protein levels of BDNF and the BDNF-Val66Met-SNP.
Methods: Symptoms of PN were clinically assessed and graded using Total Neuropathy Score (TNSr) scale. Small nerve fiber testing was performed using the Q-sense device. Depression was assessed using PHQ9 questionnaire. BDNF protein levels and Val66Met-SNP were determined with ELISA and Sanger sequencing respectively.
Results: 42 patients, 18 non-insulin treated (NIT) and 24 insulin treated (IT) were included. Albeit similar disease duration, the IT group show increased HbA1c and glucose levels as compared to NIT group, suggesting a more aggressive disease in the IT group. Higher TNSr-sensory and autonomic scores and low sensitivity thresholds to cold, warm and hot-pain signals were found in the IT group. Likewise, PHQ9 score was higher in the IT group. Serum BDNF protein levels were lower in the IT group. Met-BDNF proportion among female patients was lower relative to male patients (23.5% vs. 76.5% respectively, Prob&gt;ChiSq=0.01). Of note, Met-BDNF female patients were all in the IT group and show a trend of increased TNSr and PHQ9 score as compared to Val-BDNF female patients. Correlations between patients' PHQ9 score and TNSr score or Q-sense cold and warm sensitivity thresholds were found only in Met-BDNF carriers, suggesting that PN and depression are coincided in Met-BDNF carriers.
Conclusion: A diminished peripheral BDNF resource in our IT patients is associated with uncontrol diabetes and underlined augmented symptoms of PN and depression. The negative effect of Met-BDNF in female patients and the correlation of depression and PN in Met-BDNF should be further studied.

Disclosure
A. Bashkin: None. A. Safadi: None. B. Gross: None. N.A. Horowitz: None. R. Sharon: None. E. Shaoul: None. M. Nodelman: None. D. Azoulay: None.

Funding
D-Cure
58-LB: Coordination of Care to Reduce Hypoglycemia: Everybody Counts...Including Patients
Authors: CHMELNIK SANDRA , ABDOLLAHI SHAGHAYEGH , NEAL CHANTÉ N. , CAMERON DEBORAH R. 
Published: June 2019

The management of inpatient blood glucose control requires expertise among many healthcare providers. The purpose of this quality improvement project was to involve all processes of care, from patients calling to order a meal, to delivery at bedside. Learning about management of patients with diabetes in the hospital requires the participation of dietary personnel, dietitians, nurse assistants, nurses, physicians, diabetes educators, and patients. To reduce hypoglycemic events, physicians participated by chart reviews, evaluation of standardized order sets, improve insulin regimen to match intake. Nurses education was conducted via competencies on safe insulin management, annual updates, daily unit meetings. Regular feedback was provided by quality on glucometrics, timeliness of hypoglycemia management and monthly recurrent hypoglycemic events. Dietary participated by placing a 3x5 card “insulin tray tent card” at eye level, to encourage patient call the nurse when tray was delivered. Avoiding hypoglycemia requires coordination of insulin and meals and prompt response to concerns raised by the patients or their families. The inpatient setting is a rich learning environment, where also patients learn to improve clinical practice and facilitates a collaborative learning environment.

Disclosure
S. Chmelnik: None. S. Abdollahi: None. C.N. Neal: None. D.R. Cameron: None.
585-P: Identifying Clinical Variables Critical for Effective Diabetic Retinopathy Prediction
Authors: WANG RU , MIAO ZHUQI 
Published: June 2019

Objective: To identify essential predictors to build a cost-effective prediction model for early detection of diabetic retinopathy (DR).
Methods: We performed a retrospective case/control cohort study based on data extracted from a large electronic health records (EHR) database. Univariate association was used to evaluate patient demographics and 26 lab results in relation to incidence of DR within a 6-month window in future. Backward variable selection was implemented with logistic regression to develop a model based on significantly associated variables. The model was further simplified by narrowing down to shared predictors with previous models in literature. Highly correlated lab variables were further investigated to evaluate the impact of substituting or removing them from the model.
Results: A case cohort of 3,817 DR patients and a control cohort consisted of an equal number of non-DR diabetic patients were studied. Age, gender, race, and 22 lab values were found to be significantly associated with DR. The full model based on the 25 variables had AUC=0.817. Age, gender, race, and 4 lab variables - HbA1c, creatinine, red blood cell (RBC) count, and white blood cell count were efficient to predict DR. The AUC of the reduced model based on the 7 variables was 0.8, which was close to the accuracy of the full model. Furthermore, RBC could be replaced by its highly correlated equivalents, hematocrit (correlation coefficient r=0.9) and hemoglobin (r=0.86), without noticeably impacting the accuracy (AUC with variable substitution ranged from 0.798 to 0.801).
Conclusion: HbA1c, creatinine, RBC, and WBC were found to be key lab variables that can form an accurate DR prediction model. RBC could be replaced by one of their correlated equivalents. The choice of which variables are most cost-effective and efficient to include will depend on the expense and informativeness of the lab test performed in various clinical settings. Future work of this study will focus on external validation of proposed model.

Disclosure
R. Wang: None. Z. Miao: None.
587-P: miR34a-Induced Loss of Nicotinamide Phosphoribosyltransferase Mediates Diabetes-Induced Retinal Vascular Senescence
Authors: BARTOLLI MANUELA , JADEJA RAVIRAJSINH , THOUNAOJAM MENAKA , GUTSAEVA DIANA , MARTIN PAMELA 
Published: June 2019

Stress-associated premature senescence (SAPS) has been implicated in diabetes-induced vascular dysfunction. We have shown that microRNA34a (miR-34a) is involved in promoting senescence of the retinal microvasculature. Loss of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme of NAD+ biosynthesis from nicotinamide mononucleotide (NMN), has been implicated in aging and metabolic diseases. Interestingly NAMPT is a target of miR34a, therefore, herein, we investigated the role and reciprocal relationship of miR34a and NAMPT on diabetes-induced senescence of the retinal vasculature. NAMPT expression and NAD+ content were significantly reduced in retina of streptozotocin-induced diabetic rats (STZ-rats, 8-12 weeks of hyperglycemia) and in human postmortem diabetic retinas. On the contrary, miR34a expression was found increased and positively correlated with augmented levels of senescence markers. Exposure of human retinal endothelial cells (HuREC) to glucidic stress (25mM) also decreased NAMPT and NAD+ levels while augmented the expression of miR34a and of senescence markers. Transfection of HuREC with miR-34a mimic, but not a scramble construct, in normal glucose conditions inhibited the expression of NAMPT and reduced NAD+ levels while promoting the expression of senescence markers. These effects of miR34a mimic on HuREC were halted by supplementation with NMN (0.05-1mM), but without modifying NAMPT expression. Lastly, NMN supplementation also prevented high glucose-induced loss of NAD+ and elevation of senescence markers. Our data show that high glucose/diabetes-induced SAPS in the retinal microvasculature involves miR34a-mediated blockade of NAMPT and consequent loss of NAD+. Moreover, our data suggest that NMN supplementation could be a viable therapeutic strategy to improve endothelial dysfunction in diabetic retinopathy.

Disclosure
M. Bartolli: None. R. Jadeja: None. M. Thounaojam: None. D. Gutsaeva: None. P. Martin: None.

Funding
National Institutes of Health (EY022416, EY028714)
600-P: The 1000 Qatar Omics Study: Development of New Analytical Tools for Early Prediction and Treatment of Diabetic Retinopathy in Qatar
Authors: PADMAJEYA SUJITHA SUBASH , JERMAN LAILA , AL-KURBI ALYA , FAKHRO KHALID , JENKINS ALICIA J. , HARDIKAR ANAND , AKIL AMMIRA SARAH 
Published: June 2019

Background: According to WHO, Qatar is one of the countries most affected by type 2 diabetes T2D worldwide. Despite current treatments, patients suffering from diabetes are still at risk of developing microvascular complications. Of which, Diabetic Retinopathy DR is a debilitating microvascular complication, which leads to blindness, if left untreated.
Hypothesis and Aims: the genetic variants SNPs, circulating non-coding RNAs, mRNAs, and proteins, detected in diabetic individuals progressing to DR are accurate biomarkers for DR detection, progression and can be utilized effectively in future screening programs for at-risk individuals as well as for monitoring the outcome of interventions/treatments for DR. The aim is to investigate the SNPs using WGS data, and assess microRNA, mRNA and protein signature of DR progression in T2D patients with and without DR comparing to the healthy controls.
Methodology: plasma samples, WGS data of 500 T2D with and without DR and 500 healthy controls subjects were included in this study. Retinal scans are available for all the study participants to assess and classify the DR stages. Total RNA was extracted from plasma samples, microRNA customes assays profiling, proteins and mRNAs are currently at the final stages of analysis and will be ready at the time of the presentation.
Preliminary Results: our preliminary analyses through genome-and proteome-wide discovery studies using cellular systems and clinical samples, identified an omics signature of DR comprising of: four mRNAs of endothelial stress, 45 microRNAs of progressing to DR, eight proteins of proliferative DR vs. no DR and candidate SNPs identified in a Qatari cohort that are associated with DR progression.
Conclusion: This information will significantly impact the development of newer analytical tools and better therapies that will allow early prediction and treatment of DR, thereby reducing the burden of sight threatening diabetes complications in Qatar.

Disclosure
S. Subash Padmajeya: None. L. Jerman: None. A. Al-Kurbi: None. K. Fakhro: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A. Hardikar: None. A.S. Akil: None.

Funding
Qatar National Research Fund
602-P: Explaining an Artificial Intelligence (AI) System for Diabetic Retinopathy (DR) Screening in Primary Care
Authors: PAREKH NISHIT UMESH , BHASKARANAND MALAVIKA , RAMACHANDRA CHAITHANYA , BHAT SANDEEP , SOLANKI KAUSHAL 
Published: June 2019

We have developed a novel technique to explain results of an AI system and demonstrate its ability in explaining the EyeArt AI eye screening system for DR. Besides providing clinically consistent and accurate results, AI systems in healthcare must be explainable (be able to provide reasons for their decisions). This is paramount in making them trustworthy. The EyeArt system is intended for use by healthcare providers to screen for referable DR using color fundus photographs from 18 years or older diabetic patients who do not have persistent visual impairment. It is designed to provide screening results in under a minute and enable DR screening at point of care in endocrinology and primary care clinics. Figure shows that the explainability technique highlights image regions that most significantly contribute to the EyeArt system’s results. These highlighted regions correspond to lesions marked by an expert human grader. In a previous study on 107,001 consecutive patient visits, the EyeArt system has been shown to achieve sensitivity of 91.3% (95% CI: 90.9%-91.7%), specificity of 91.1% (95% CI: 90.9%-91.3%), NPV of 97.6% (95% CI: 97.5%-97.7%), and PPV of 72.5% (95% CI: 71.9%-73.0%). The work presented here provides evidence that the EyeArt system is explainable and has been designed to report DR screening results based on lesions considered important by the ophthalmology community for DR severity grading.

Disclosure
N. Parekh: Employee; Self; Eyenuk Inc. M. Bhaskaranand: Employee; Self; Eyenuk Inc. C. Ramachandra: Employee; Self; Eyenuk Inc. S. Bhat: Employee; Self; Eyenuk Inc. K. Solanki: Employee; Self; Eyenuk Inc. Stock/Shareholder; Self; Eyenuk Inc.

Funding
National Institutes of Health
610-P: Sphingosine Kinase 1 Dissociates Glucocorticoid-Induced Insulin Resistance and Hepatic Dyslipidemia
Authors: LEE REBECCA A. , TSAY ARIEL , CHANG MAGGIE , YIV NICHOLAS , TAN JENNA H. , WANG JEN-CHYWAN 
Published: June 2019

It is well established that chronic and/or excess glucocorticoid (GC) exposure causes glucose and lipid homeostasis disorders. Previous studies have shown that chronic glucocorticoid exposure elevates hepatic ceramide production to inhibit insulin action and increase triglyceride accumulation in the liver. Glucocorticoid treatment not only increases the levels of hepatic ceramides, but also the levels of sphingosine-1-phosphate (S1P). This is because glucocorticoids not only promote the ceramide synthetic pathway, but also increase the expression of sphingosine kinase 1 (Sphk1). Ceramides can be converted to sphingosine, which is further converted to S1P through Sphk1. Here, we reduced the expression of Sphk1 in liver to evaluate its role in chronic glucocorticoid exposure-induced glucose and lipid disorders. We found that mice with reduced hepatic Sphk1 expression had improved glucose and pyruvate tolerance, while no significant difference in insulin tolerance was found upon glucocorticoid treatment. In contrast, glucocorticoid treatment-induced hepatic steatosis and hypertriglyceridemia were exacerbated in these mice with reduced hepatic Sphk1 expression. These results are surprising, as insulin resistance is frequently associated with the development of hepatic dyslipidemia. In this case, while Sphk1 is involved in the insulin resistance induced by glucocorticoids, it plays a negative role in chronic glucocorticoid treatment-induced hepatic dyslipidemia. Here, we will report our recent analysis on the mechanism underlying the role of Sphk1, ceramides, and S1P, in chronic glucocorticoid exposure-induced metabolic disorders.

Disclosure
R.A. Lee: None. A. Tsay: None. M. Chang: None. N. Yiv: None. J.H. Tan: None. J. Wang: None.

Funding
National Institutes of Health (R01DK113019)
613-P: Preventive Effect of Sulforaphane on Type 2 Diabetes-Induced Diabetic Cardiomyopathy via AMPK-Mediated Activation of Glucose/Lipid Metabolism and Nrf2 Function
Authors: SUN YIKE , CAI LU , LI ZHUO 
Published: June 2019

Dyslipidemia has been shown to play a crucial role in the development of diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D). AMP-activated protein kinase (AMPK), particularly α2 isoform can improve energy metabolism in cardiomyopathy. Sulforaphane (SFN), a natural isothiocyanate in vegetables, is important in cardiac protection from diabetes. We investigated whether SFN can protect heart from T2D damage, which is mediated by AMPKα2 via improving energy metabolism and activating Nrf2-mediated anti-oxidative pathways. AMPKα2 knockout (AMPKα2-KO) mice and their wild type (WT, C57BL/6J) mice were fed high-fat diet (HFD) for 3 months to induce insulin resistance, and then intraperitoneal injection of streptozotocin to induce hyperglycemia as T2D model. Age-matched mice were fed with normal diet (ND) without streptozotocin as control. T2D and control mice were treated with or without SFN for 3 months (3m) and then stop SFN treatment, remained feeding either ND or HFD for additional three months (6m). Echocardiography were performed before sacrifice both in 3m and 6m group. SFN treatment improved cardiac remodeling and dysfunction induced by T2D both in 3m and 6m group. The cardiac pathogenic changes induced by T2D, including fibrosis, lipotoxicity, inflammation, oxidative stress/damage along with suppression of AMPK signaling pathways was prevented by SFN in WT diabetic mice, as evidenced by down-regulating FN, TGF-β PAI-1, TNF-α, SCD-1and up-regulating CPT1-B, PPARα, Nrf2. The cardiac protection by SFN for 3 months from T2D could last till 6 months. AMPKα2-KO mice are also susceptible to T2D-induced cardiomyopathy; however, the protective effect of SFN on the heart from diabetes was lost in diabetic AMPKα2-KO mice. These results suggest that SFN treatment can attenuate cardiac damage induced by T2D both in the 3m and 6m group, and AMPKα2 plays the pivotal role in the SNF-mediated cardiac protection.

Disclosure
Y. Sun: None. L. Cai: None. Z. Li: None.

Funding
American Diabetes Association (1-18-IBS-082 to L.C.)
628-P: Insulin's Regulation of CXCL1 Expression Is Critical for Neutrophil Recruitments and the Development of Periodontitis and Poor Wound Healing in Diabetes
Authors: SHINJO TAKANORI , LI QIAN , ISHIKADO ATSUSHI , PARK KYOUNGMIN , ST-LOUIS RONALD , YOKOMIZO HISASHI , FU JIALIN , YU MARC GREGORY , WANG HAIYAN , HASTURK HATICE , VAN DYKE THOMAS E. , KING GEORGE L. 
Published: June 2019

A major cause of poor wound healing and periodontitis in diabetes is defective immune response to infections. Insulin signaling via the PI3K/Akt pathway is selectively inhibited in the gingival and wound fibroblasts of diabetic rodents and patients. To determine how loss of insulin actions in gingival fibroblasts can affect periodontitis development, myofibroblast insulin receptors (IR) were deleted by crossbreeding IRβ-flox/flox mice with SM22-Cre C57BL/6 (SMIRKO) mice, which were fed with regular diet (RD), while wild type (WT) littermates were fed with high-fat diet (HFD) for 10 weeks. To induce periodontitis, 7-0 silk ligatures were tied around maxillary molars for 4, 7 or 14 days. When mice were sacrificed to assess alveolar bone loss, immune cell populations and inflammatory cytokine expression in the gingiva was assessed. Gingival IRβ expression in SMIRKO and HFD-fed mice was decreased by 70% and 50%, respectively, with comparable reductions in insulin-induced (100nM) phosphorylation of Akt (pAkt). Ligature-induced alveolar bone loss in SMIRKO and HFD-fed mice was greater by 70% and 40%, respectively, as compared to RD-fed WT mice. Post-ligature time course analysis showed that while neutrophil recruitment was delayed significantly, macrophages and lymphocyte numbers were elevated in both SMIRKO and HFD-fed mice. Similarly, neutrophil-recruiting factors CXCL1 and 2 expression were decreased in the gingiva, whereas TNFα and IL-1β expression were elevated. Gingival myofibroblasts from SMIRKO and HFD-fed mice showed dramatic reductions of IRβ expression and insulin-induced pAkt with parallel lowering of E.coli LPS-induced CXCL1 expression via downregulation of TLR2, compared to RD-fed mice. These data provided the first evidence that insulin action is critical for neutrophil recruitment during infection by enabling CXCL1 expression in gingival myofibroblasts, which is inhibited in diabetes.

Disclosure
T. Shinjo: None. Q. Li: None. A. Ishikado: Employee; Self; SunStar Inc. Employee; Spouse/Partner; SunStar Inc. K. Park: None. R. St-Louis: None. H. Yokomizo: None. J. Fu: None. M. Yu: None. H. Wang: None. H. Hasturk: None. T.E. Van Dyke: None. G.L. King: Research Support; Self; Sanofi.

Funding
Sunstar Foundation; Iacocca Family Foundation