bluuebunny/crossref_metadata_2025_split huggingface dataset:
55-OR: Cerebral Blood Flow Is Lower in Youth with Type 2 Diabetes Compared with Obese Controls
Authors: REDEL JACOB M. , DIFRANCESCO MARK W. , LEE GREGORY R. , DOLAN LAWRENCE M. , SHAH AMY S. 
Published: June 2020

A causal link between youth-onset type 2 diabetes (T2D) and vascular complications is well-established. The brain, as a highly vascular structure, may also be susceptible to the adverse effects of T2D. Brain structural and cognitive differences have been demonstrated in adolescents with T2D, and vascular disease is hypothesized to be a mechanism. We sought to evaluate cerebral blood flow (CBF) in youth with T2D vs. obese, euglycemic controls, and to explore the association between CBF and a non-invasive measure of atherosclerosis, carotid intima medial thickness (IMT). We compared global and regional CBF between 20 youth with T2D (mean T2D duration 2.8 ±2.1 years and mean hemoglobin A1C 7.9 ±2.1%) and 19 age, race, and sex similar obese controls (mean hemoglobin A1C 5.2 ±0.2%), adjusted for socioeconomic status. CBF data were obtained using arterial spin labeling (ASL) MRI. We compared mean CBF values, voxel-wise and globally averaged, between groups using two-sample t-tests. Voxel-wise results were evaluated for statistical significance (p&lt;0.05) after adjustment for multiple comparisons. Carotid IMT in the T2D group was measured using ultrasound and correlated with CBF, both globally and voxel-wise. Compared to obese controls, the T2D group had significantly lower global CBF (49.7 ± 7.2 vs. 63.8 ±11.5 mL/gm/min, p&lt;0.01). There were seven voxel clusters with ≥100 voxels identified with significantly lower CBF in the T2D group, and no clusters with higher CBF. In the T2D group, IMT of the common carotid artery was inversely correlated with CBF, both globally (r= -0.7, p&lt;0.01) and in regional voxel clusters. Global and regional cerebral blood flow is lower in youth with T2D compared to obese controls. Further work is needed to determine whether these CBF findings are related to brain structural or cognitive differences previously reported in youth-onset T2D. The association found between carotid IMT and CBF suggests this may represent a practical way to track CBF in youth with T2D.

Disclosure
J.M. Redel: None. M.W. DiFrancesco: None. G.R. Lee: None. L.M. Dolan: None. A.S. Shah: None.

Funding
Cincinnati Diabetes and Obesity Center Pilot Grant Program; Endocrine Fellows Foundation; National Institute of Environmental Health Sciences (ES010957-16); Cincinnati Children’s Hospital
56-OR: Degree of ß-Cell Function (ßCF) Impairment and Glycemic Alterations in Obese Youth (OY) Spanning from Normal Glucose Tolerance (NGT) to Impaired Glucose Tolerance (IGT) to Type 2 Diabetes (T2D): Does Race Matter?
Authors: KIM JOON YOUNG , TFAYLI HALA M. , BACHA FIDA , GEBARA NOUR , ARSLANIAN SILVA A. 
Published: June 2020

In OY it is not clear what degree of βCF impairment translates to increases in OGTT glucose area under the curve (G-AUC) commensurate with transition from NGT to IGT to T2D, and whether there are racial differences. Given the high rates of T2D in Black (BY) vs. White youth (WY), we hypothesized that βCF decline in BY is more detrimental and results in larger increases in G-AUC than in WY. Here we report the quantitative relationship between differences in clamp disposition index (DI=insulin sensitivity [IS] by a 3-hr hyperinsulinemic (80 mu/m2/min)-euglycemic clamp x 1st-phase insulin by a 2-hr hyperglycemic (225 mg/dL) clamp) and OGTT G-AUC in 152 OY. Two-way ANOVA (race x glycemic status) showed that in BY vs. WY larger decrements in DI from NGT to IGT and from NGT to T2D (all p&lt;0.05) correspond to comparable increments in G-AUC (p=NS, Table), with no significant race interaction from IGT to T2D. Contrary to our hypothesis, loss of βCF in IGT and T2D is less detrimental in BY because a ∼2-3 fold greater impairment in βCF corresponds to a similar increase in G-AUC to that of WY. Such observations of preserved glucose regulation in BY compared with WY in the face of larger declines in βCF suggest an adaptive glucose-stimulated glucoregulatory mechanism protecting against dysglycemia consequent to insulin deficiency.

Disclosure
J. Kim: None. H.M. Tfayli: None. F. Bacha: Research Support; Self; AstraZeneca, Takeda Development Center Americas, Inc. N. Gebara: None. S.A. Arslanian: Research Support; Self; National Institutes of Health. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc.

Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (K24-HD01357, R01HD27503); National Center for Advancing Translational Sciences (UL1TR000005); National Center for Research Resources (UL1RR024153)
566-P: Sulodexide Suppresses NLRP3 Inflammasome Activation via NOX4/ROS Signaling in the Retinal Microvasculature
Authors: LI TING , HE XUEMIN , PENG RONGDONG , FU XIANAN , SHI GUOJUN , CHEN YANMING 
Published: June 2020

Aims: Sulodexide (SDX) protects endothelial cells via restoring endothelial glycocalyx, but the effect of SDX on endothelial inflammation remains unknown. We showed that SDX potently inhibited the activation of NLRP3 inflammasome in diabetic retinas, but the underlying mechanism was not clear. As reactive oxygen species (ROS) activates NLRP3 inflammasome, and NADPH oxidase 4 (NOX4) is a key generator of ROS in endothelial cells, this study thus investigated if NOX4/ROS signaling mediates the effect of SDX on NLRP3 inflammasome, hoping to provide novel insights into SDX in treating diabetic retinopathy (DR).
Methods: Diabetes was induced in mice by high fat diet and streptozotocin, followed by i.p. injection of SDX (10mg/kg) every other day for 3 months. Human retinal microvascular endothelial cells were exposed to high glucose, accompanied with overexpression or knocking down of NOX4 and a serial concentration of SDX. The retinal levels of NOX4, NLRP3 inflammasome, inflammatory factors, junction components, vascular leakage and ROS levels were determined.
Results: SDX treatment dramatically suppressed the hyperglycemia-induced overexpression of NOX4 and activation of NLRP3 inflammasome in retinas compared to controls. Moreover, SDX preserved the levels of ZO-1, VE-cadherin and ameliorated the retinal vascular permeability. In addition, SDX significantly ameliorated high glucose-induced NOX4 up-regulation, ROS production and NLRP3 inflammasome activation, and restored the reduction of ZO-1 and VE-cadherin in endothelial cells. Conversely, overexpression of NOX4 exacerbated endothelial inflammation through over production of ROS and subsequent activation of NLRP3 inflammasome, which was rescued by SDX treatment.
Conclusion: Our study suggests that SDX protects the retinal microvasculature by inhibiting NOX4/ROS-induced NLRP3 inflammasome activation, thus provides novel evidence of utilizing SDX for the treatment of DR.

Disclosure
T. Li: None. X. He: None. R. Peng: None. X. Fu: None. G. Shi: None. Y. Chen: None.

Funding
Research and Development Plans in Key Areas of Guangdong Province (2019B020227003); National Natural Science Foundation of China (81770826); National Key Research and Development Program of China (2017YFA0105803)
57-LB: The 4 I’s of Adolescent Transition in Type 1 Diabetes Care: A Qualitative Study
Authors: LEUNG JOSEPH M. , TANG TRICIA S. , LIM CATHERINE , LAFFEL LORI M. , AMED SHAZHAN 
Published: June 2020

Introduction: Adolescents with type 1 diabetes have worsening glycemic control as they transition from pediatric to adult care. The most effective clinical interventions for this population remain elusive. The aim of this study was to gain adolescent perspectives on the transition preparation experience and the preferred approaches to the transition process in type 1 diabetes care.
Methods: We conducted 5 focus groups with a total of 22 adolescents with type 1 diabetes. Participants also completed an embedded survey where they rated various transition interventions. Transcriptions of audio recordings were analyzed with 3 iterations of thematic content analysis using the grounded theory approach and we determined that saturation was reached.
Results: Four themes related to transition of care were identified: (1) Identity - how the world relates to my diabetes (stigma of type 1 diabetes, confusion with type 2 diabetes, diagnosis disclosure, and resilience); (2) Interconnection - how my support system can help me with my diabetes (peer support, near peer support, parental support, loss of bond with pediatric team, and fear of not having a bond with adult team); (3) Impediment - how my diabetes limits me (self-care takes work and time, unpredictability and restrictiveness, and emotional burden); and (4) Individualization - how to personalize the transition experience (having choices in the transition experience, meeting adult provider before transition, and specific transition preparation). The top interventions rated by adolescents on the survey were: good communication between the pediatric and adult teams, medical summary of past diabetes care, and having pediatric and adult teams in the same building.
Conclusions: The design of future transition interventions for adolescents with type 1 diabetes should address the issues of Identity, Interconnection, Impediment, and Individualization. Adolescents also identified collaborative processes between pediatric and adult providers as most important.

Disclosure
J.M. Leung: Research Support; Self; Lilly Diabetes. T.S. Tang: None. C. Lim: None. L.M. Laffel: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Insulogic LLC, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi US. S. Amed: None.

Funding
Eli Lilly and Company
574-P: Antioxidant Defence and Long Noncoding RNA in Diabetic Retinopathy
Authors: KOWLURU RENU , RADHAKRISHNAN RAKESH 
Published: June 2020

Retinal oxidative stress is increased and the antioxidant defence system is compromised in diabetic retinopathy. Expression of many key antioxidant genes is regulated by a master regulator, nuclear factor erythroid 2-related factor (Nrf2). The transcriptional activity of Nrf2 is mediated by an intracellular inhibitor Kelch-like ECH-associated protein 1 (Keap1), which regulates its nuclear movement. In diabetes, Nrf2 transcriptional activity is decreased and Keap1 levels are increased. A long noncoding RNA (IncRNA), Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), plays a role in regulating Keap1 expression, and retinal MALAT1 levels are upregulated in diabetes. Our aim is to investigate the role of MALAT1 in maintaining the antioxidant defence system in diabetic retinopathy. Human retinal endothelial cells (untransfected or transfected with MALAT1-siRNA) were incubated in 20mM glucose for 96 hours. MALAT1 expression was analysed by q-RTPCR and RNA sequencing, and role of MALAT1 in Keap1 transcription was quantified using MALAT1 RNA pull down assay. Simultaneous occupancy of MALAT1 and transcription factor Sp1 on Keap1 promoter was quantified by Chromatin Isolation by RNA Purification (ChIRP)-reChIP technique, nuclear translocation of Nrf2 by immunofluorescence imaging, and Nrf2-responsive genes superoxide dismutase 2 (Sod2) and heme oxygenase 1 (HO1) by q-RTPCR. Compared to cells in 5mM glucose, high glucose increased co-occupancy of MALAT1 and Sp1 at Keap1 promoter. MALAT1-siRNA ameliorated glucose-induced increase in co-occupancy of MALAT1-Sp1 at its promoter and decreased Keap1 expression. MALAT1-siRNA also restored nuclear localization of Nrf2 and the transcription of Sod2 and HO1. Thus, IncRNA MALAT1, via Keap1, modulates the transcriptional activity of Nrf2 and the antioxidant defence system in diabetic retinopathy. Regulation of MALAT1 can protect the retina from oxidative damage, and prevent/slow down the development of diabetic retinopathy.

Disclosure
R. Kowluru: None. R. Radhakrishnan: None.

Funding
EY014370, EY017313, EY022230
575-P: Improvement in HbA1c after Flash Monitoring Is Not Associated with Risk of Retinopathy Progression in Type 1 Diabetes
Authors: LINTON KATHRYN , GIBB FRASER W. 
Published: June 2020

Background: Rapid improvement in HbA1c has been associated with significant short-term worsening of diabetic retinopathy. Flash monitoring (FM) is associated with significant improvement in HbA1c, particularly in those with high HbA1c at baseline.
Methods: We identified all adults with type 1 diabetes, using NHS reimbursed FM, attending our center. This assessment was limited to those with high microvascular risk defined as duration of diabetes &gt; 3 years and pre-FM HbA1c &gt;9%. From this cohort 40 individuals were selected with the largest post-FM fall in HbA1c (responders) and compared with a further 35 with the smallest change in HbA1c (non-responders). Information on retinopathy status and laser photocoagulation was derived from electronic patient records.
Results: Baseline HbA1c was significantly higher in the responder category (10.5 vs. 9.8%, P = 0.002). Median change in HbA1c, following FM, was -2.5% in responders and +0.2% in non-responders. At baseline, 32% had retinopathy classed as more severe than background (25% had proliferative retinopathy). Median duration from FM commencement to next ophthalmological assessment was 36 weeks (IQR 16 - 50). The percentage with worsening retinopathy did not significantly differ between responders (18%) and non-responders (11%) (P = 0.458). The percentage requiring laser photocoagulation after FM commencement did not differ between responders (17.5%) and non-responders (14.3%) (P = 0.704). Logistic regression analysis identified previous laser (OR 19.9, P = 0.001) but not baseline HbA1c (P = 0.139), age (P = 0.115) or HbA1c response after FM (P = 0.473) as predictive of requiring laser photocoagulation after FM commencement.
Discussion: These data suggest that rapid improvement in HbA1c following FM, in a high-risk population, is not independently predictive of subsequent requirement for laser photocoagulation.

Disclosure
K. Linton: None. F.W. Gibb: None.
582-P: Triglycerides, Uric Acid, and Incidence of Type 2 Diabetes Mellitus in Northwest China: The Jinchang Cohort Study
Authors: HUANG WENYA , YANG JINGLI , LIU NIAN , HUANG PEIYAO , ZHANG RUI , WANG RUONAN , BAI ZHAO , CHENG NING , WANG MINZHEN , ZHENG SHAN , BAI YANA 
Published: June 2020

Objective: To study the association of triglycerides(TG), uric acid and incidence of type 2 diabetes mellitus(T2DM), evaluate whether there would be an additive interaction between two factors.
Methods: Based on the follow-up population of Jinchang cohort, an ongoing occupational-based prospective cohort study of 48,001 participants at baseline, the nested-case control study was used to explore the relationship of TG, uric acid and incidence of T2DM, and calculate the odds ratio(OR) and 95% confidence intervals(CI). The interaction additive model was used to evaluate whether there would be an additive interaction between two factors.
Results: Among 18,195 participants with normal fasting plasma glucose(FPG) at baseline, there were 267 incident diabetes cases during a median of 2.2 years of follow-up. With the increase of serum TG and uric acid, the cumulative incidences of diabetes in people with normal FPG at baseline were all rising (P for trend&lt;0.05). After multivariable adjustments, the risk factors of diabetes were overweight/obesity(OR=2.30, 95%CI:1.72-3.08), hypertension(OR=2.42, 95%CI:1.78-3.29),hypertriglyceridemia(OR=1.49,95%CI:1.11-2.00), hyperuricemia(OR=2.32,95%CI:1.62-3.30), hypo high density lipoprotein cholesterolemia(OR=2.35, 95%CI:1.60-3.46). There was a positive additive interaction between hypertriglyceridemia and hyperuricemia on the development of diabetes from normal FPG. When they were co-existing, the risk of diabetes(OR, 95%CI) in the total, male and female population were 7.13 (4.70-10.83), 8.42 (5.13-13.83) and 7.09 (2.94-17.14),respectively.
Conclusion: Increased triglycerides and uric acid were strong risk factors of diabetes. Furthermore, there was a positive additive interaction between hypertriglyceridemia and hyperuricemia on the development of diabetes from normal fasting plasma glucose.

Disclosure
W. Huang: None. J. Yang: None. N. Liu: None. P. Huang: None. R. Zhang: None. R. Wang: None. Z. Bai: None. N. Cheng: None. M. Wang: None. S. Zheng: None. Y. Bai: None.

Funding
National Institutes of Health (1R01ES02908201A1); Lanzhou University (2018LDBRZD008)
590-P: Modulation of Adenine Phosphoribosyltransferase-Mediated Purine Salvage to Accelerate Diabetic Wound Healing
Authors: YOUNG GUANG-HUAR , LIN JIUN-TSAI , CHENG YI-FANG , CHEN HAN-MIN 
Published: June 2020

Aim: Adenine phosphoribosyltransferase (APRT) is the key enzyme in purine salvage by the incorporation of adenine and phosphoribosyl pyrophosphate to provide adenylate nucleotide. Our aim was to evaluate the role of APRT in diabetic wound healing.
Methods: The molecular mechanism of APRT-mediated cell survival was validated by the haploid HAP1 cell. The adenylate nucleotides in NIH-3T3 fibroblast response to adenine was monitoring by HPLC-MS/MS method. The effects of cell behaviors were evaluated by mice NIH-3T3 fibroblast and human epithelial keratinocytes. Genetically diabetic mice received surgery for full-thickness of the cutaneous wound and the adenine addition as the substrate for APRT on the wound.
Results: In the wild type and APRT knockout HAP1 cell, our data revealed that APRT utilized adenine to rescue cellular ATP levels and proliferation against hydrogen peroxide-induced oxidative damage. The time-course of monitoring the total adenylate nucleotides in NIH-3T3 fibroblast showed that adenine addition enlarged the cellular adenylate pool, reduced the adenylate energy charge, and provided more AMP for the generation of ATP in further. In mice NIH-3T3 fibroblasts and human NHEK keratinocytes, adenine elevated cellular ATP levels in a dose-dependent manner and facilitated cell migration. The up-regulated APRT found in wound skin was correlated with the demands of wound repair in diabetic mice. Administration of adenine on the wound of diabetic mice exhibited elevated ATP levels in organismic skin and accelerated wound healing.
Conclusions: Our data indicated the role of APRT during diabetic wound healing by regulating the nucleotide pool after injury and demonstrated the improvement by topical adenine, which highlights its value as a promising agent in therapeutic intervention. This study provided an explanation for the up-regulation of APRT in tissue repair and adenine supplement resulted in an enlargement of the adenylate pool for ATP generation.

Disclosure
G. Young: Employee; Self; Energenesis-Biomedical. J. Lin: Employee; Self; Energenesis-Biomedical. Y. Cheng: Employee; Self; Energenesis-Biomedical. H. Chen: Board Member; Self; Energenesis-Biomedical.
62-OR: Childhood Adipokine Profiles Predict the Incidence and Trajectory of Obesity in Young Adults: The BCAMS Study
Authors: GAO SHAN , LI MING , WILLI STEVEN M. , GROUP BCAMS 
Published: June 2020

Adipokine dysregulation is an early biomarker of adipose tissue dysfunction, which has been shown to relate to metabolic health. We aimed to investigate whether the profiles of certain adipokines in childhood might predict the incidence of obesity and contribute to BMI trajectory from childhood to young adulthood. A total of 3211 children aged 6-18ys from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study were evaluated at baseline, and 989 of these participants were assessed at 10-year follow-up. Physical activity, dietary and sleep information were collected by questionnaires. Baseline plasma adiponectin, leptin, resistin, retinol binding protein 4, osteonectin and fibroblast growth factor 21 (FGF-21) were measured by ELISA. The sex-adjusted z scores for adipokine levels were examined for their association with adiposity measures (BMI and waist circumference). Only 10.4% of the children who were non-obese at baseline developed obesity at 10-year follow-up, while over 65% of children presenting with obesity remained obese at follow-up, suggesting a well-established obesity trajectory over time. After adjusting for age, tanner stage, diet, exercise and sleep, decreased adiponectin and FGF-21 levels, as well as increased leptin, were associated with obesity risk both at baseline and 10-year follow-up (all P &lt; 0.05). Multivariate analysis showed that after adjusting for confounding factors, each 1-SD increment in the leptin : adiponectin ratio was associated with a 3.26-fold (95% CI:2.08 - 5.10) higher risk for obesity at 10-year follow-up, while each 1-SD increment in FGF-21 level reduced the risk of obesity by 30% (95% CI: 0.48 - 0.96). Finally, among children with obesity at baseline, each 1-SD of elevation in resistin increased the risk of persistent obesity by 1.41-fold (95% CI: 1.13 - 1.77). These findings suggest that certain aberrant patterns of adipokine regulation during childhood may serve as biomarkers for the subsequent development of obesity.

Disclosure
S. Gao: None. M. Li: None. S.M. Willi: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Tolerion, Inc. Other Relationship; Self; Caladrius Biosciences, Inc.

Funding
National Natural Science Foundation of China (81970732); National Key Research Program of China (2016YFC1304801); Key Program of Beijing Municipal Science and Technology Commission (D111100000611001, D111100000611002); Beijing Natural Science Foundation (7172169); Beijing Science and Technology Star Program (2004A027), Novo Nordisk Union Diabetes Research Talent Fund (2011A002); National Key Program of Clinical Science (WBYZ2011-873); Central Research Institute Fund of Chinese Academy of Medical Sciences (2017PT32020, 2018PT32001); Beijing Chaoyang Hospital (JXPY201606)