bluuebunny/crossref_metadata_2025_split huggingface dataset:
389-P: Pathological Significance of Renal Tubular ROCK2 in Chronic Kidney Disease
Authors: SEKIGUCHI KENSUKE , MATOBA KEIICHIRO , UKICHI RIKAKO , NAGAI YOSUKE , TAKEDA YUSUKE , AKAMINE TOMOYO , KANAZAWA YASUSHI , UTSUNOMIYA KAZUNORI , NISHIMURA RIMEI 
Published: June 2021

The small GTPase Rho and its effector Rho-kinase (ROCK) are implicated in the pathogenesis of diabetic kidney disease. In chronic kidney diseases including diabetic nephropathy, progressive tubulointerstitial fibrosis is the final common pathway to end-stage renal disease and deeply related to renal prognosis. We have previously reported that a chemical ROCK inhibitor suppressed the progression of diabetic nephropathy. ROCK has two isoforms, ROCK1 and ROCK2. ROCK1 is known to be involved in the endocytosis of albumin in tubular epithelial cells via megalin/cubilin-dependent mechanism. On the other hand, the role of renal ROCK2 remains unclear. In the present study, we investigated the role of renal tubular ROCK2 in the pathogenesis of chronic kidney disease using an established model to cause renal fibrosis, unilateral ureteral obstruction (UUO). Masson’s trichrome staining revealed that the collagen deposition was significantly increased in the kidneys of UUO group compared with Sham-operated group. We detected upregulation of ROCK2 at both mRNA and protein levels in UUO group, relative to sham operated group. The kinase activity of ROCK2 was also elevated in UUO group. Based on our research, we suggest that ROCK2 may have an important role in tubulointerstitial fibrosis. ROCK2 may be a potential therapeutic target for the treatment of diabetic nephropathy.

Disclosure
K. Sekiguchi: None. K. Matoba: Research Support; Self; Eli Lilly Japan K. K. R. Ukichi: None. Y. Nagai: None. Y. Takeda: None. T. Akamine: None. Y. Kanazawa: None. K. Utsunomiya: None. R. Nishimura: Speaker’s Bureau; Self; Abbott Japan Co., Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K. K., Kissei Pharmaceutical Co., Ltd., Medtronic, MSD Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.
394-P: ROCK1/AMPK Axis Regulates the Development of Diabetic Kidney Disease via Modulation of Fatty Acid Metabolism
Authors: NAGAI YOSUKE , MATOBA KEIICHIRO , SEKIGUCHI KENSUKE , UKICHI RIKAKO , TAKEDA YUSUKE , AKAMINE TOMOYO , KANAZAWA YASUSHI , UTSUNOMIYA KAZUNORI , NISHIMURA RIMEI 
Published: June 2021

The small GTPase Rho and its effector Rho-kinase (ROCK) are involved in the pathogenesis of diabetic kidney disease. Accumulating evidence shows that renal dysfunction in diabetic patient is associated with abnormal fatty acid oxidation in the kidney. However, the interaction of ROCK and fatty acid oxidation in diabetic kidneys remains unclear. Extracellular flux analyzer demonstrated that deficiency of ROCK1, one of the ROCK isoforms, improves TGF-β-induced mitochondrial dysfunction of cultured mesangial cells. ROCK1 deficiency rescued TGF-β-induced downregulation of fatty acid oxidation mediators such as peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1A (CPT1A). An investigation of mechanisms underlying this observation revealed activated ROCK1 functions through the phosphorylation of AMPK and increased expression of PGC-1α. Furthermore, fluorescence histochemistry showed that ROCK1 deficiency suppresses ROS production as a result of mitochondrial damage due to abnormal fatty acid metabolism. Consistent with this result, ROCK1 knockout mice exhibited reduced albuminuria and histological abnormalities along with the recovery of impaired fatty acid utilization and mitochondrial fragmentation. These observations indicate that ROCK1 is a key player in the development of diabetic renal injury. Glomerular ROCK1 may be a potential therapeutic target for the treatment of diabetic kidney disease.

Disclosure
Y. Nagai: None. K. Matoba: Research Support; Self; Eli Lilly Japan K. K. K. Sekiguchi: None. R. Ukichi: None. Y. Takeda: None. T. Akamine: None. Y. Kanazawa: None. K. Utsunomiya: None. R. Nishimura: Speaker’s Bureau; Self; Abbott Japan Co., Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K. K., Kissei Pharmaceutical Co., Ltd., Medtronic, MSD Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.
395-P: Identification of Key Genes and Transcriptional Factors Associated with Podocyte Functions in Human Diabetic Nephropathy
Authors: AKIL AMMIRA S. , PADMAJEYA SUJITHA SUBASH , FAKHRO KHALID , HABIB TANWIR 
Published: June 2021

Background: Direct podocyte injury in Diabetic nephropathy (DN) leads to proteinuria, glomerular hypertrophy, and accumulation of extra cellular matrix. By using six publicly available gene expression profiles from early DN, DN, advanced DN, and healthy controls. We have analyzed each of the DN stages against healthy controls and also analyzed the datasets using network inference technique to identify genes playing key role in DN pathogenesis.
Methodology: We performed modular repertoire analysis for each dataset separately, then, we performed meta-analysis by merging the datasets to obtain robust differentially expressed genes (DEG). Network inference technique was used to explore and detect novel associations between the DEG and to infer the interaction between the set of genes using mutual information (MI) measure. Statistically significant interactions were selected using a threshold p &lt; 10-7 and visualized using force-directed layout in Cytoscape. MCODE tool was used to find densely connected regions in the network. STRING database utilized for functional enrichment of the clusters in the network and for in silico validation of the gene interactions.
Results: A total of 193 samples from the gene expression datasets of human kidney tissues were used, where 79 samples from DN, 21 of advanced DN, 10 early DN, 10 DKD, and 73 from controls. Several key genes have been identified in addition to a highly connected small cluster of genes enriched for podocyte differentiation. Two transcription factors, DACH1 and WT1, are important for podocyte differentiation and proper kidney function have been identified. Also, the expression level of TYRO3 which is a podocyte protective factor increased in early DN but was decreased as the disease progressed, per our analysis.
Conclusion: This meta-analysis found some of the key genes associated with DN. The level of contribution and relevance of the identified genes in the pathogenesis of DN should be functionally analyzed.

Disclosure
A. S. Akil: None. S. Subash padmajeya: None. K. Fakhro: None. T. Habib: None.

Funding
Qatar National Research Fund (NPRP9-229-3-041)
403-P: Plasma Renin Level and Aldosterone-to-Renin Ratio Are Associated with Diabetic Kidney Disease
Authors: HIGA MARIKO , SUZUKI TAKAYUKI , KIDO TAKASHI , ZENRI MARIKO , NAO KEIKO , HIJIKATA MAI , YAMASHITA KAORU , IKEHARA KAYOKO , ICHIJO TAKAMASA 
Published: June 2021

Aim: A close association between primary aldosteronism (PA) and atherosclerosis has been well established. We aimed to determine the association between plasma renin activity (PRA) and aldosterone levels (PAC) as well as their ratios (PAC-to-PRA ratio: ARR) with urinary albumin excretion (UAE) in type 2 diabetic patients who did not fulfill PA confirmatory criteria.
Methods: The subjects were 70 type2 diabetic patients (age: 53.3±11.0 years, male: 51, female: 19) with UAE ≤100 mg/gCr. They did not take ACE inhibitors, angiotensin receptor blockers (ARB) or diuretic agents. Patients were selected for this study based on various criteria: PRA level ˂10 ng/ml/hr, PAC ˂20 ng/dl, and ARR ˂20 (ng/dl per ng/ml/hr). They were divided into three groups according to UAE levels: NL group (N=33) ˂ 10mg/gCr, N group (N=22) 10-29 mg/gCr, and M group (N=15) 30-100 mg/gCr.
Results: There were no significant differences in age, BMI, HbA1c, and eGFR levels among the three groups. The systolic blood pressure in the M group was significantly higher than those in the NL and N groups. The ARR in the M group was 10.1±4.6, which was significantly higher than those in NL (6.5±0.3) or N (7.0±2.7) groups. In the M group, the levels of PRA and PAC were significantly lower than those in NL or N groups. Log UAE was positively correlated with ARR (r=0.34, p&lt;0.0001) and negatively correlated with PRA (r=-0.32, p&lt;0.001). Systolic blood pressure showed a significant positive correlation with ARR and negative correlation with PRA.
Conclusion: These results suggest that a high ARR level, which did not fulfill confirmatory criteria for PA, was associated with diabetic nephropathy. The relative increase in PAC to PRA might contribute to the development of diabetic nephropathy, even if PAC remains normal level.

Disclosure
M. Higa: None. T. Suzuki: None. T. Kido: None. M. Zenri: None. K. Nao: None. M. Hijikata: None. K. Yamashita: None. K. Ikehara: None. T. Ichijo: None.
424-P: Autoantibodies to Glutamic Acid Decarboxylase in Type 1 Diabetes Are Not a Marker of Asymptomatic Cardiac Autonomic Neuropathy
Authors: NATTERO-CHÁVEZ LÍA , SILVA JHONATAN QUIÑONES , MONTANEZ LAURA , DURÁN ELENA FERNÁNDEZ , AVENDAÑO BEATRIZ DORADO , RODRÍGUEZ CRISTINA SÁNCHEZ , LORENZO MAR , ARGÜESO MARÍA FERNÁNDEZ , ROJANO NURIA BENGOA , LECUMBERRI EDURNE , ESCOBAR-MORREALE HÉCTOR F. , LUQUE-RAMÍREZ MANUEL 
Published: June 2021

Aim: To clarify whether autoantibodies against glutamic acid decarboxylase (GAD-ab) are associated with cardiac autonomic neuropathy (CAN).
Methods: 319 consecutive patients with type 1 diabetes (DM1) were included. We assessed CAN by responses of heart rate variability to deep breathing (E/I index), Valsalva maneuver, standing (30:15 ratio), low-frequency activity (LFa), and high-frequency activity (HFa). We assayed GAD-ab by immunoprecipitation radioligand.
Results: Mean age was of 40 ± 14 years, with 20 ± 12 years as mean duration of diabetes. Mean A1c was 7.2 ± 1.0%. We confirmed CAN in 66 patients resulting in a 21% (95% CI 17-25) prevalence of asymptomatic CAN. GAD-ab were present in 199 individuals (62%), with no significant differences as a function of the presence of CAN or not [44 (70%) vs. 144 (66%), respectively; P = 0.544]. GAD-ab titles were similar between both groups (431 ± 695 U/mL in CAN subjects vs. 390 ± 662 U/mL in subjects without CAN, P = 0.688). Considering all patients as a whole, GAD-ab titles only correlated with duration of DM1 (r = -0.346, P &lt; 0.001). HFa correlated with age (r = -0.523, P &lt; 0.001), duration of DM1 (r = -0.374, P &lt; 0.001), and A1c (r = -0.261, P &lt; 0.001), but not with GAD-ab. Similarly, LFa correlated with age (r = -0.473, P &lt; 0.001), duration of DM1 (r = -0.223, P &lt; 0.001), and A1c (r = -0.294, P &lt; 0.001). Age, sex, A1c, duration of DM1, GAD-ab, and systolic blood pressure were introduced as independent variables into a binary regression analysis. The stepwise model (R2: 0.106, P &lt; 0.001) retained only age (β: -0.933, 95% CI: 0.933-0.976) as the significant predictor of the presence of CAN.
Conclusion: GAD-ab unlikely have a role as a CAN marker in patients with DM1.

Disclosure
L. Nattero-chávez: None. E. Lecumberri: None. H. F. Escobar-morreale: Consultant; Self; InsudPharma. M. Luque-ramírez: None. J. Quiñones silva: None. L. Montanez: None. E. Fernández durán: None. B. Dorado avendaño: None. C. Sánchez rodríguez: None. M. Lorenzo: None. M. Fernández argüeso: None. N. Bengoa rojano: None.

Funding
Menarini International Foundation
431-P: Gaps in Retinal Screening among Medicaid Patients with Diabetes: A Natural Experiment for Translation in Diabetes (NEXT-D) 2 Study
Authors: MOIN TANNAZ , HARWOOD JESSICA , DASKIVICH LAUREN , QUINTON JACOB , VASILYEV ARSENIY , TURK NORMAN , DURU O. KENRIK , MANGIONE CAROL 
Published: June 2021

Background: Medicaid patients face many challenges in diabetes treatment and have higher rates of complications, including diabetic retinopathy (DR). We evaluated eye exam rates over a seven year period among Medicaid patients with diabetes and assessed variation by state, Medicaid eligibility category, and race/ethnicity.
Methods: Using United Healthcare claims (eligibility, medical, pharmacy) and lab data, we identified Medicaid patients with diabetes &gt;21 years of age who received care in practices with &gt;1000 Medicaid patients between 2010-2016. Diabetes was defined by diagnostic codes, AIC &gt; 6.5% and/or anti-glycemic medication prescriptions. DR was defined by diagnostic codes. We used serial cross sections to calculate annual eye exam frequencies and our logistic regression covariates included age group, gender, race/ethnicity, language, Medicaid program, common comorbidities, indicators for type 1 vs. type 2 DM, indicators for chronic eye disease, state and and state by year fixed effects. We also adjusted for clustering at the 3-digit zip code level and excluded states with vision care carve-outs.
Results: Among 160,108 Medicaid person-years with diabetes, overall unadjusted rates of annual eye exams ranged between 23-36% per year. Adjusted annual eye exam rates varied significantly between states (range: TN at 24%, NV at 44%,). Adjusted rates were also significantly higher in 2014-2016 (30-33%) as compared to the baseline rate in 2010 (26%) and among patients with chronic eye disease as compared to those without (53% vs. 22%). There were no significant differences in eye exam rates by race/ethnicity or Medicaid program.
Conclusions: The majority of Medicaid patients with diabetes in our study did not receive annual eye exams between 2010-2016. These findings highlight significant gaps in care and interventions are needed to increase adherence to DR screening for underserved Medicaid patients with diabetes.

Disclosure
T. Moin: None. J. Harwood: None. L. Daskivich: None. J. Quinton: None. A. Vasilyev: None. N. Turk: None. O. Duru: None. C. Mangione: None.

Funding
Centers for Disease Control and Prevention; National Institute of Diabetes and Digestive and Kidney Diseases (U18DP006128)
439-P: A Promising Regulatory Role for MicroRNA-133b in Controlling Lipid Metabolism and Dyslipidemia Gene Expression in Diabetic Retinopathy: The 1000 Qataromics Cohort
Authors: AKIL AMMIRA S. , PADMAJEYA SUJITHA SUBASH , JERMAN LAILA A. , HABIB TANWIR , AL-KURBI ALYA , ALIYEV ELBAY E. , ANBARI MOHAMMED EL , FAKHRO KHALID 
Published: June 2021

A number of hyperglycemia- and dyslipidemia- triggered pathways, and numerous protein-encoding genes boosting the diabetic retinopathy (DR) progression. Evolving data suggests vast number of microRNAs(miRNAs) which exhibit no protein-coding capacity, are expressed and play key roles in DR pathogenesis.
Purpose: of this pilot is to identify the miRNAs involved in pathways altered in lipid metabolism and dyslipidemia and to explore the association of dyslipidemia with the progression of DR.
Methodology: 460 patients with diabetes type 2 (T2D) aged 23-77 years including 37 with DR and 490 matched healthy controls age range 18-74, from Qatar biobank cohort. The circulating miRNA profile was assessed in this pilot study. Logistic regression analysis was performed on the phenotypic data to investigate the level of association between A1C, low-density lipoproteins (LDL) and Triglycerides (TG) covariants and the miRNA expression profile in T2D with and without DR.
Results: The most broadly characterized miRNAs in lipid metabolism are miR-33a/b; however, we identified another three miRNAs (miR-133b, miR-142-3p and miR-483-5p) shared between LDL and TG phenotypes. In particular, miR-133b appeared to be directly linked to retinal degeneration identified through our miRNA-target disease interaction network analysis. Our results indicated that all three miRNAs are significantly associated with VEGFR2 mediated vascular permeability, insulin signaling, apoptosis, EGFR, TGF-Beta signaling, cellular senescence and degradation pathways leading to the DR initiation than development.
Conclusions: miRNAs are not only small regulators of lipid metabolism, but vital influencers in lipid homeostasis and lipoproteins formation and secretion. Dysregulation of these regulatory elements most likely augment the underlying metabolic flaws perceived in lipid disorders and related microvascular complications.

Disclosure
A. S. Akil: None. S. Subash padmajeya: None. L. A. Jerman: None. T. Habib: None. A. Al-kurbi: None. E. E. Aliyev: None. M. El anbari: None. K. Fakhro: None.

Funding
Qatar National Research Fund (NPRP9-229-3-041)
45-LB: Improving Resiliency in Children with Type 1 Diabetes
Authors: PUFFENBERGER SYNTHIA S. , HOEKSTRA FRANCINE , KAPADIA CHIRAG R. , SHAIBI GABRIEL Q. , CHAMBERS MELISSA 
Published: June 2021

Type 1 diabetes (T1D) is a chronic medical condition that can negatively impact both physical and psychological health. Diabetes resilience can be protective against the physical and social/emotional consequences among children with T1D yet few studies have examined the ability to increase resiliency in the pediatric population. Forty children with T1D (Age 14.1±2.3 years, 48% female, Hba1c 12.0±1.6%) were enrolled in a 4-month multi-disciplinary intervention that included medical management, Psychology-led motivational interviewing, and frequent support from a Certified Diabetes Care and Education Specialist (CDCES). Participants completed the Diabetes Strengths and Resilience (DSTAR) measure at baseline and post-intervention. The DSTAR is a validated assessment tool aimed to assess both self and parent reported measures of general and diabetes-related child self-efficacy and level of perceived support, as well as diabetes distress. HbA1c was assessed at baseline and 4 months. At baseline, higher DSTAR scores were associated with lower HbA1c (r=-0.34, p=0.03). DSTAR scores increased significantly in response to the intervention from 43.9±6.4 to 47.2±6.9 at 4 months (p&lt;0.001). Additionally, HbA1c significantly improved from baseline to post-intervention (12.0±1.6% to 11.0±1.9%, p&lt;0.001). A multifaceted approach to children with diabetes can improve levels of resilience, a factor involved in improving and maintaining both physical and psychological health.

Disclosure
S. S. Puffenberger: None. F. Hoekstra: None. C. R. Kapadia: None. G. Q. Shaibi: None. M. Chambers: None.

Funding
Thomas J. Beatson Jr. Foundation
458-P: The Current Status and Influencing Factors of In-Home Handling of Disposable Needles among Diabetic Patients in Beijing
Authors: YANG YUMO , ZHOU LIXIN 
Published: June 2021

Objective: Diabetes mellitus is a chronic progressive disease that requires insulin injection to control blood glucose at a certain stage of development, and the used needles are a high-risk medical waste. This study was to understand the current situation and influencing factors of disposable needles handling among diabetic patients treated by injection in Beijing.
Methods: From October to November 2020, 420 diabetic patients were recruited from 3 tertiary hospitals and 3 community healthcare centers in Beijing. A questionnaire was conducted on disposal methods of injection needles at home. SPSS statistical software was used to establish the data set and to carry out data analysis.
Results: 405 complete questionnaires were retrieved in this survey(the response rate 96.4%). The mean age of patients was 60.3±13.2 years. The average number of injections per day was 2.1±1.1. 73.3% of the patients were aware that needles may transmit diseases, and 71.6% believed that needles need harmless treatment, but only 37.0% of the patients had received education and training in needle treatment, of which 15.1% had used sharps disposal containers. The ways of patient’s disposal of needles were as follows: 64.2% of patients discarded to household waste, 31.6% of patients collected needles in bottles or other containers before discarded to household waste bins, only 3.7% of patients collected them in sharps containers and sent back to the hospital for harmless treatment. Multivariate binary logistic regression analysis showed that only “having received education in needle handling” was independently and positively associated with “needle properly disposed of” (OR = 7.317).
Conclusion: Most of the patients did not properly handle the needles used in daily life. It is necessary to strengthen education on patients’ knowledge of correct disposal of medical waste, and relevant government authorities should take actions to strengthen the waste classification as soon as possible.

Disclosure
Y. Yang: None. L. Zhou: None.
46-OR: Hypoglycemia Increases the Left Ventricular Ejection Fraction in People with Diabetes and Healthy Controls
Authors: FABRICIUS THERESE W. , VERHULST CLEMENTINE E. , WIENBERG MALENE , DUIJNHOUWER ANTHONIE L. , KRISTENSEN PETER L. , DE GALAN BASTIAAN E. , PEDERSEN-BJERGAARD ULRIK 
Published: June 2021

Background: Insulin-induced hypoglycemia, the most common adverse event in people with diabetes treated with insulin, is associated with increased risk of cardiovascular events. The effect of hypoglycemia on cardiac function has not yet been fully clarified. Our aim was to investigate the effect of hypoglycemia on left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) in people with type 1 diabetes (T1DM) and in healthy controls (HC).
Methods: We enrolled 15 adults with T1DM (M/F 9/6, age 47±19 years, HbA1c 7.9±2.9%, diabetes duration 22.5±12.6 years) and 14 HCs (M/F 7/7, age 39±17 years). All participants underwent a hyperinsulinemic normoglycemic (5.3±0.4 mmol/L, 30 min) hypoglycemic (2.8±0.5 mmol/L, 60 min) glucose clamp. At baseline and approximately 30 min into the hypoglycemic phase (steady-state), a cardiac ultrasound was performed (by the same person), for later analysis.
Results: All participants had sinus rhythm at baseline and none developed arrhythmias during hypoglycemia. We found no difference between T1DM and HC for LVEF measured at baseline. In response to hypoglycemia, LVEF increased from 58.1±2.6% at baseline to 63.7±4.0% in the T1DM group (p&lt;0.0005) and from 58.0±3.8% to 64.7±2.4%, (p&lt;0.005) in the HC group. GLS was unchanged (-20.9±1.5% to -21.3±3.5% (p=0.800)) in the T1DM group, but a numerical decrease from -19.6±3.0% to -22.0±2.7% (p=0.084) was seen in the HC. Age did not modulate the effect of hypoglycemia on LVEF or GLS.
Conclusion: An event of hypoglycemia increases the LVEF significantly in people with diabetes. Presumably due to the catecholamines chronotropic, inotropic and peripheral contracting effect. The result of this would be increased cardiac output, increased oxygen consumption and metabolism and thereby increased load on the heart. This may contribute to explain the link between hypoglycemia and cardiovascular disease.

Disclosure
T. W. Fabricius: None. C. E. Verhulst: None. M. Wienberg: None. A. L. Duijnhouwer: None. P. L. Kristensen: Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company. B. E. De galan: Research Support; Self; Novo Nordisk. U. Pedersen-bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis, Consultant; Self; Abbott, Speaker’s Bureau; Self; Novo Nordisk A/S.

Funding
Innovative Medicines Initiative 2 Joint Undertaking (777460); European Union Horizon 2020 Research and Innovation Program; European Federation of Pharmaceutical Industries and Associations; T1D Exchange; JDRF; International Diabetes Federation; The Leona M. and Harry B. Helmsley Charitable Trust