bluuebunny/crossref_metadata_2025_split huggingface dataset:
315-OR: Trends in Racial and Ethnic Difference in Glucose-Lowering Medication (GLM) Use, Out of Pocket (OOP) Payment, and HbA1c Control in U.S. Adults with Diabetes, 2005-2018
Authors: LI PIAOPIAO , GUAN DAWEI , GUO JINGCHUAN , WINTERSTEIN ALMUT G. , ZHANG PING , SHAO HUI 
Published: June 2021

Fast escalating price of insulin and introductions of high-cost new GLMs in the last decade could affect racial/ethnic groups differently. This study examined trends in GLM uses, OOP payments for GLMs, and HbA1c control by racial/ethnic group among US adults with diabetes from 2005 to 2018. Data were from the Medical Expenditure Panel Survey and the National Health and Nutrition Examination Survey. Persons with diabetes were identified by self-report or lab test. GLM uses were identified by national drug code. We compared trends in the three study outcomes among non-Hispanic White perons, non-Hispanic Black perons, and Hispanic perons. Between 2005 and 2018, the use of newer GLM (dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose transport protein 2 inhibitors) was higher in non-Hispanic White persons (0% to 24.9%) than non-Hispanic Black persons (0% to 19.9%,) or Hispanic persons (0% to 19.5%, all p&lt;0.05). Use of insulin analogue increased from 43.4% to 87.3% in Non-Hispanic White persons, 22.3% to 78.4% in non-Hispanic Black persons and 32.8% to 77.9% in Hispanic persons. Significant falls in annual OOP payments for GLMs were seen among Hispanic perons ($350 in 2005 to $205 in 2018) and non-Hispanic Black persons ($350 to $210), but not among non-Hispanic White persons ($355 to $345). In 2005, a higher proportion of non-Hispanic White persons achieved the HbA1c goal of &lt;7.0%, compared with Hispanic persons and non-Hispanic Black persons (68.4% vs. 47.2% vs. 52.3%, p&lt;0.05). Non-Hispanic White persons also had a lower average HbA1c level than Hispanic persons or non-Hispanic Black persons (6.7% vs. 7.8% vs. 7.4%, p&lt;0.05). These differences remained throughout the study period. Our findings providevidence on racial/ethnic differences in GLM and insulin usage over time and could assist decision-makers in identifying the means to reduce racial/ethnic disparities in HbA1c control.

Disclosure
P. Li: None. D. Guan: None. J. Guo: None. A. G. Winterstein: Research Support; Self; Merck Sharp & Dohme Corp. P. Zhang: None. H. Shao: Research Support; Self; Sanofi.
331-OR: Joint Exposure to Various Ambient Air Pollutants, Obesity, and Incident Type 2 Diabetes: A Prospective Study in UK Biobank
Authors: LI XIANG , WANG MENGYING , MA HAO , ZHOU TAO , HEIANZA YORIKO , QI LU 
Published: June 2021

Background: Air pollution has been related to type 2 diabetes (T2D). However, little is known about the relation between long-term exposure to multiple ambient air pollutants and the risk of T2D. We aimed to prospectively assess the joint association of various air pollutants with the risk of T2D and examine the modification effect by obesity status on the relationship.
Methods: A total of 449,006 participants from UK Biobank who were free of T2D at baseline (2006-2010) were included in the current study and followed up to March 2020. Ambient air pollutants, including particulate matter (PM) with diameters ≤2.5 µm (PM2.5), between 2.5 µm and 10 µm (PM2.5-10), nitrogen oxides (NO2), and nitric oxide (NO) were estimated by a Land Use Regression model. An air pollution score was created to assess the joint exposure to the four air pollutants.
Results: During a median of 11 years follow-up, we documented 18,239 incident T2D cases. The hazard ratios (95% confidence interval) for T2D associated with the extreme quintiles of PM2.5, PM2.5-10, NO2, and NO were 1.12 (1.05 to 1.18), 1.06 (1.00 to 1.11), 1.11 (1.04 to 1.18), and 1.12 (1.06 to 1.18), respectively. We also found that the air pollution score was significantly associated with an increased risk of T2D. Compared to the lowest quintile of air pollution score, the multivariate-adjusted hazard ratio for T2D was 1.05 (0.99 to 1.10), 1.06 (1.00 to 1.11), 1.09 (1.03 to 1.15), and 1.12 (1.06 to 1.19) for the second to fifth quintile, respectively. In addition, we found a significant interaction between the air pollution score and obesity status on the risk of T2D (p-interaction &lt;0.001). The observed association was more pronounced among overweight and obese participants than in the normal-weight people.
Conclusion: Our results indicate that an air pollution score, which incorporated PM2.5, PM2.5-10, NO2, and NO, is associated with an increased risk of T2D, and such association is strengthened by higher adiposity.

Disclosure
X. Li: None. M. Wang: None. H. Ma: None. T. Zhou: None. Y. Heianza: None. L. Qi: None.
352-P: Assessment of a Deep Learning Model Based on Three-Year Longitudinal Electronic Health Record Data for Predicting Severe Hypoglycemia in Patients with Type 2 Diabetes
Authors: LEE GARAM , KO SEUNG-HYUN , AHN YU-BAE , LEE EUN YOUNG , CHA SEON-AH , KIM DOKYOON , YUN JAE-SEUNG 
Published: June 2021

Background: This study aimed to investigate the ability of a deep learning model to predict the outcome of severe hypoglycemia (SH) using longitudinal electronic medical records data.
Methods: Structured data were extracted from the clinical data warehouse, including demographics, laboratory, medications, and diagnostic information. Between January 2010 and December 2012, 17,670 adult patients were enrolled; participants had type 2 diabetes, were aged over 30 years, and visited the diabetes centers of two hospitals. The primary outcome was SH, defined as diagnostic codes for hypoglycemia (E16.x, E11.63, E13.63, E14.63) in hospitalization or emergency room records. The performance of the longitudinal deep learning model (gated recurrent units) in predicting SH was quantified using the area under the receiver operating characteristic curve (AUROC) and evaluated in terms of net reclassification improvement (NRI) versus a traditional logistic regression model. Based on predicted risk of SH, we stratified patients into four risk groups: low (&lt;1.0%), intermediate (1.0% to &lt;2.0%), high (2.0% to &lt;5.0%), and very high (≥5.0%).
Results: Of 17,670 patients, 528 patients developed SH events during the follow-up period (mean of 6.4 years). The performance of the longitudinal deep learning model was superior to the logistic model for predicting SH (AUROC of logistic model, 0.788 [95% CI 0.781-0.793] vs. longitudinal deep learning model, 0.858 [0.853-0.863]). The very high-risk group of SH categorized using the deep learning model had 73 times higher risk of SH than the low-risk group. The deep learning model improved case reclassification (NRI, 13.4%).
Conclusion: We found that the longitudinal deep learning model showed better performance and classification ability for predicting than the conventional logistic model.

Disclosure
G. Lee: None. S. Ko: None. Y. Ahn: None. E. Lee: None. S. Cha: None. D. Kim: None. J. Yun: None.

Funding
Korean Diabetes Association (2018-F to J-S.Y.)
362-P: Punicalagin Promotes Mitochondrial Fusion and Alleviates Diabetic Cardiomyopathy via Regulating PTP1B-Stat3-Opa1 Pathway
Authors: DING MINGGE , LI MAN , FU FENG , LIU CHAOYANG 
Published: June 2021

This study aims to explore the efficacy of punicalagin on diabetic cardiomyopathy, with a specific focus on the mechanisms underlying the effects of punicalagin on mitochondrial fusion/fission dynamics. Diabetes was induced by a single intraperitoneal injection of streptozotocin intraperitoneally in Sprague-Dawley rats. Cardiac structural and functional abnormalities were ameliorated in diabetic rats receiving punicalagin administration as evidenced by increased ejection fraction and attenuated myocardial fibrosis and hypertrophy. Punicalagin promoted mitochondrial fusion and enhanced mitochondrial function in both diabetic hearts and high glucose-treated cardiomyocytes. Punicalagin-induced increases in Opa1 expression were responsible for the above mitochondrial enhancements, and these changes could be blocked by knockdown of Opa1. Inhibitor screening and chromatin immunoprecipitation analysis showed that Stat3 directly regulated the transcriptional expression of Opa1 by binding to its promoter and was responsible for punicalagin-induced Opa1-mediated mitochondrial fusion. Moreover, pharmmapper screening and molecular docking studies revealed that punicalagin embedded into the activity pocket of PTP1B and inhibited the activity of PTP1B. Overexpression of PTP1B blocked the promoting effect of punicalagin on Stat3 phosphorylation and Opa1-mediated mitochondrial fusion. Collectively, our study has provided the first evidence that punicalagin protects against diabetic cardiomyopathy and uncovered the precise mechanisms on how punicalagin promotes Opa1-mediated mitochondrial fusion under hyperglycemic condition, a process in which punicalagin interacts with PTP1B and inhibits its activity that in turn increasing Stat3 phosphorylation and then enhancing the transcriptional expression of Opa1.

Disclosure
M. Ding: None. M. Li: None. F. Fu: None. C. Liu: None.

Funding
National Natural Science Foundation of China (81970316, 82070387)
407-P: Long-Term Effect of Intensive Lifestyle Intervention on Incidence of Nephropathy in Adult Patients with Diabetes: A Post-hoc Analysis of a 10-Year Longitudinal Study
Authors: TOMAH SHAHEEN , ZHANG HONGXIA , GARDNER HANNAH , AL-BADRI MARWA , HAMDY OSAMA 
Published: June 2021

We previously reported that, in patients with diabetes, intensive lifestyle intervention (ILI) in real-world clinical practice could lead to significant weight loss that was attainable for up to 10 yrs and had favorable impact on glycemic control and lipid profile. These improvements were predicted by achieving ≥7% weight loss at 1 yr. In this secondary analysis, we investigated whether initial weight loss at 1 yr is associated with incidence of nephropathy over 10 yrs. This analysis included 128 patients with diabetes enrolled in a 12-wk ILI (age 53.7±10.1 yrs; 66.4% females; duration of diabetes 9.6±9.4 yrs; body mass index [BMI] 38.3±5.3 kg/m2; and 9.3% had type 1 diabetes). At 1 yr, we divided participants into 2 groups: group A (n=61, 47.7%) maintained &lt;7% weight loss and group B (n=67, 52.3%) maintained ≥7% weight loss. Data on incidence of nephropathy were collected from electronic health records over 10 yrs of follow-up. Cox proportional hazard models were used to calculate hazard ratios after dichotomizing the incidence of nephropathy. After a median of 10 yrs of follow-up, the incidence rate of nephropathy in group A was 3.58 cases per 100 person-years vs. 1.42 cases per 100 person-years in group B (difference 2.16 cases per 100 person-years, sex-adjusted hazard ratio for group B: 0.33, 95% CI: 0.12, 0.94, p=0.039). Moreover, in a multivariable model fitted with terms for age, diabetes type, diabetes duration, BMI, plus group assignment and sex, the group-effect retained independent significance (fully adjusted hazard ratio for group B: 0.32, 95% CI: 0.11, 0.9, p= 0.007). We conclude that adult patients with diabetes who maintained ≥7% weight loss at 1yr after the initial ILI had a 68% lower risk of nephropathy for up to 10 yrs. These data support the essential role of weight reduction in preventing or delaying the progression of chronic kidney disease in patients with diabetes and overweight or obesity.

Disclosure
S. Tomah: Stock/Shareholder; Self; Amarin Corporation plc. H. Zhang: None. H. Gardner: None. M. Al-badri: None. O. Hamdy: Advisory Panel; Self; Nestlé, Consultant; Self; Abbott, AstraZeneca, Sanofi, Research Support; Self; Eli Lilly and Company, Gilead Sciences, Inc., National Dairy Council, Novo Nordisk, Stock/Shareholder; Self; Healthimation, LLC.
412-P: Increased Peripheral Neutrophil Count Is Closely Associated with the Incidence and Progression of Chronic Kidney Disease in Older Type 2 Diabetic Patients
Authors: ZHANG RUI 
Published: June 2021

Preventing and managing chronic kidney disease (CKD) is the primary task of the overall management of T2DM. An increasing number of studies has indicated that low-grade chronic inflammation plays a crucial role in the pathophysiology of CKD. A total of 3345 subjects were recruited in this study of whom 1257 derived from one centre and served as case-controls and 2088 with T2DM derived from two other centres and were followed up annually for 4 years and entered into a retrospective cohort study. In the case-control study, neutrophil count performed best as an independent risk factor for CKD even after 1:1 case-control matching for age, gender, and history of high blood pressure (HBP). Spline regression revealed a significant linear association between CKD incidence and continuous neutrophil count in excess of 3.6 × 109/L. In the cohort study, subjects were grouped based on tertile of neutrophil count and neutrophil-to-lymphocyte ratio (NLR), respectively. COX regression analysis showed that only neutrophil count demonstrated an increased HR for estimated glomerular filtration rate (eGFR) reduction greater than 30% (the highest group vs. the lowest group, 1.604 (1.029 - 2.501), P &lt; 0.05) after fully adjusting for potential confounders. The cumulative incidence of CKD in T2DM patients gradually increased with increasing neutrophil count. This study suggested that neutrophil count is associated with the incidence and progression of CKD in T2DM patients.

Disclosure
R. Zhang: None.

Funding
Medical Key Faculty Foundation of Shanghai (ZK2019B15)
421-P: Genetically Reduced Chondroitin Sulfate Prevents the Progression of Diabetic Neuropathy via Pericyte Functions
Authors: ISHIGURO HAJIME , USHIKI TAKASHI , HONDA ATSUKO , MIKAMI TADAHISA , KITAGAWA HIROSHI , SANGO KAZUNORI , MASUKO MASAYOSHI , IGARASHI MICHIHIRO , SONE HIROHITO 
Published: June 2021

Background: The extracellular matrix is associated with diabetic complications; however, chondroitin sulfate (CS) role remains unclear. Herein, genetically engineered mice lacking the rate-limiting CS-synthesizing enzyme, CS N-acetylgalactosaminyltransferase-1 (T1), were used to clarify CS effects on diabetic neuropathy. Diabetes was induced by streptozotocin injection in 6-week-old male T1 knockout (T1KO) and wild-type (WT) mice.
Results: Previously reported preliminary data at the former ADA meeting revealed that thermal nociception and the number of plantar peripheral nerve fibers were disrupted in diabetic WT mice, whereas in diabetic T1KO were preserved. Moreover, conduction velocity in the sciatic nerve was significantly declined in diabetic WT than in T1KO mice. [A1] Immunohistochemical data revealed loss of calcitonin gene-related peptide-positive neurons in the dorsal root ganglia (DRG) in diabetic WT mice, whereas those neurons were protected in diabetic T1KO mice. Moreover, DRG gene expression analysis showed that caspase-3 and -9 were reduced in T1KO compared with WT mice. To investigate the mechanisms underlying these events, the role of pericytes, which are important CS-expressing components of the blood-nerve barrier (BNB), was explored. Assessment of the retinal vessels, which represent a good model to evaluate pericyte functions and easier to access than peripheral nerves, revealed a higher proportion of pericyte-deficient retina blood vessels in diabetic WT than in T1KO mice upon administration of a platelet-derived growth factor receptor (PDGFR) β antibody. Therefore, pericytes in T1KO mice were more resistant against PDGFRβ antibody than those of WT mice. Thus, it is possible that the BNB in T1KO mice may be more resistant against external stress, including diabetes.
Conclusions: Reduced CS production may induce beneficial effects to prevent diabetic neuropathy by improving pericyte function.

Disclosure
H. Ishiguro: None. T. Ushiki: None. A. Honda: None. T. Mikami: None. H. Kitagawa: None. K. Sango: None. M. Masuko: None. M. Igarashi: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.
433-P: Hyperglycemia-Induced Oxidative Stress Prevents REDD1 Degradation by Chaperone-Mediated Autophagy
Authors: MILLER WILLIAM P. , TORO ALLYSON , SUNILKUMAR SIDDHARTH , GIORDANO JOSEPH , DENNIS MICHAEL D. 
Published: June 2021

Upregulation of the stress response protein REDD1 (regulated in development and DNA damage response 1) has been implicated in diabetes-induced retinal defects in both preclinical models and diabetic patients. In fact, intravitreal administration of a siRNA targeting the REDD1 mRNA has demonstrated promise for improving visual function in patients with diabetic macular edema. However, the mechanism responsible for increased retinal REDD1 protein content in the context of diabetes has never been established. Herein, we investigated the hypothesis that diabetes promotes REDD1 expression by reducing the rate of REDD1 degradation. In the retina of streptozotocin-induced diabetic mice, REDD1 protein content was increased in the absence of a change in REDD1 mRNA. When diabetic mice were administered antioxidants, neither oxidative stress nor REDD1 expression were increased in the retina. In human MIO-M1 retinal Müller cells, the rate of REDD1 degradation was reduced upon exposure to hyperglycemic conditions. Antioxidant addition to culture medium prevented both the increase in oxidative stress and REDD1 stability in cells exposed to hyperglycemic conditions. Surprisingly, the suppressive effect of oxidative stress on REDD1 degradation was independent of the ubiquitin-proteasome pathway. Rather, REDD1 was rapidly degraded upon activation of chaperone-mediated autophagy (CMA) and exposure to hyperglycemic conditions prevented the suppressive effect of CMA activation on REDD1 expression. Additional mechanistic details of this new regulatory pathway will be presented. Overall, the findings provide evidence that diabetes promotes retinal REDD1 protein content via a post-transcriptional effect and potentially identifies superior therapeutic targets for preventing the pathological increase in REDD1.

Disclosure
W. P. Miller: None. A. Toro: None. S. Sunilkumar: None. J. Giordano: None. M. D. Dennis: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-14-INI-04 to M.D.D.); National Institutes of Health (R01EY029702 to M.D.D.), (F31EY031199-01 to W.P.M.)
440-P: Dual Long-Term Effects of Free Fatty Acid on Human Endothelial Barrier In Vitro Are Mediated by NO, Mitochondrial ROS, and Dicarbonyl Stress
Authors: SAMSONOV MIKHAIL , PODKUYCHENKO NIKITA , KHAPCHAEV ASKER Y. , VLASIK TATIANA , LANKIN VADIM , SKULACHEV MAXIM , STAFEEV IURII , VOROTNIKOV ALEXANDER V. , SHESTAKOVA MARINA V. , SHIRINSKY VLADIMIR P. 
Published: June 2021

In diabetes-associated hyperlipidemia, free fatty acids (FFAs) are thought to induce insulin resistance and endothelial dysfunction leading to vascular injury and cardiovascular T2DM complications. However, evidence is scarce regarding the effects of FFA on vascular endothelial barrier. We used human umbilical vein endothelial cells (HUVEC) to model, in vitro, the endothelial barrier and reveal its responses to experimental hyperlipidemia induced by long-term treatment with palmitic acid in complex with albumin. Palmitate was continuously present in the growth medium at 0.8 mM to reproduce FFA levels typical for T2DM. We developed conditions to maintain the HUVEC monolayers in the presence of the high palmitate concentration for up to 2 weeks by adding exogenous carnitine to facilitate mitochondrial β-oxidation of FFA. In this model system, palmitate readily augmented the transendothelial electric resistance (TER) of HUVEC via increased NO production by endothelial NO-synthase (eNOS). Western blots showed that palmitate neither disturbed insulin signaling cascade towards eNOS nor upregulated eNOS expression. After the initial 3-4-day rise in TER, further treatment with palmitate led to barrier stabilization and attenuation as compared to FFA-free conditions. This later phase was associated with increased ROS and malondialdehyde (MDA) accumulation, both prevented by the mitochondria-targeted antioxidant SkQ1. Treatment of HUVEC with exogenous MDA impaired the TER and barrier suggesting that accumulation of MDA-modified proteins may contribute to the barrier dysfunction upon long-term experimental hyperlipidemia. Altogether, obtained evidence suggests that prolonged exposure of vascular endothelium to high levels of palmitate compromises endothelium barrier capacity and insulin-mediated eNOS regulation turning the enzyme permanently active.

Disclosure
M. Samsonov: None. V. P. Shirinsky: None. N. Podkuychenko: None. A. Y. Khapchaev: None. T. Vlasik: None. V. Lankin: None. M. Skulachev: Other Relationship; Self; Mitotech LLC. I. Stafeev: None. A. V. Vorotnikov: None. M. V. Shestakova: None.

Funding
Russian Science Foundation (19-15-00361)
462-P: Factors Associated with Health Literacy among Patients with Type 2 Diabetes in China
Authors: ZHAO XIAOYAN 
Published: June 2021

Background: Health literacy is vital for self-care activities and quality of life among patients with type 2 diabetes. However, no study has been conducted to determine health literacy using Health Literacy Scale in patients with type 2 diabetes in China. Therefore, this study aims to identify factors associated with health literacy in patients with type 2 diabetes.
Methods: A cross-sectional study was performed among 310 patients with type 2 diabetes in the department of endocrinology of four hospitals in China. Health literacy was measured using the Health Literacy Scale. A series of structured questionnaires were used to measure sociodemographic and clinical variables, social support, diabetes knowledge. EpiData 3.1 was used to establish the database. Univariate analysis and multiple linear regression analysis were applied to examine factors associated with health literacy using SPSS 25.0.
Results: The patients’ mean (SD) score of health literacy was 2.82 (0.28) on a range from 1.71 to 3.50. In univariate analysis, health literacy was associated with age, educational level, marital status, complications, income, health education, social support, diabetes knowledge. Multiple linear regression analysis showed that health literacy was positively associated with educational level (β=0.32, 95% CI: 0.26, 0.38), diabetes knowledge (β=0.41, 95% CI: 0.20, 0.62). Similarly, patients who hadn’t received health education (β=-0.14, 95% CI: -0.22, -0.06), divorced or widowed (β=-0.18, 95% CI: -0.30, -0.05) had lower health literacy level. 54.40% of the variability in health literacy can be predicted by educational level, diabetes knowledge, health education, and marital status.
Conclusions: Health professionals should pay attention to the improvement of diabetes knowledge and health education among patients with type 2 diabetes and take corresponding measures. Patients divorced or widowed or with low educational level may need special attention to improve their health literacy level.

Disclosure
X. Zhao: None.