bluuebunny/crossref_metadata_2025_split huggingface dataset:
451-P: Palmitic Acid–Induced lncRNA PARAIL Regulates Inflammation via Restricting HuR Localization to Cytoplasm in Human Monocytes and Macrophages
Authors: TANWAR VINAY S. , REDDY MARPADGA A. , DAS SADHAN , SAMARA VISHNU AMARAM , ABDOLLAHI MARYAM , DEY SUCHISMITA , GANGULY RITUPARNA , LANTING LINDA L. , STAPLETON KENNETH , NATARAJAN RAMA 
Published: May 2022

Obesity and diabetes are associated with chronic inflammation induced by the elevated circulating levels of Palmitic acid (PA) and also result from impaired resolution of inflammation in macrophages. Here, we examined the role of PA-induced long non-coding RNAs (lncRNAs) in the resolution of inflammation. Our RNA-seq analysis showed that PA induced several lncRNAs including a novel PA-regulatedanti-nflammatoryIncRNA (PARAIL) in CD14+ human monocytes. We found PARAIL was also upregulated by lipopolysaccharide and bacterial infection in human monocytes and macrophages, suggesting its role in adaptive immunity. PARAIL knockdown in human macrophages enhanced PA-induced key inflammatory cytokine genes and delayed resolution of inflammation. RNA-pulldown coupled with mass spectrometry showed that PARAIL interacts with Hu Antigen R (HuR) an RNA-binding and AU-rich element (ARE) binding protein that regulates inflammation. We also identified AREs in PARAIL that interact with HuR. Further, knockdown of HuR and PARAIL additively increased the expression of inflammatory genes compared to knockdown of HuR or PARAIL alone suggesting PARAIL mediated resolution of inflammation relies on HuR function. Moreover, PARAIL knockdown decreased HuR protein levels, suggesting PARAIL increases HuR stability to decrease inflammatory genes and promote resolution of inflammation. In addition, Parail was also downregulated in macrophages from mouse models of diabetes and accelerated atherosclerosis. Together, these data suggest that upregulation of PARAIL under inflammatory conditions can contribute to unique feedback pro-resolution mechanisms via PARAIL-HuR interaction to restrain fatty acid-induced inflammation. However, PARAIL downregulation during obesity/ diabetes can further augment inflammation. LncRNAs like PARAIL therefore represent novel tools to combat inflammation associated with these metabolic disorders.

Disclosure
V.S.Tanwar: None. R.Natarajan: None. M.A.Reddy: None. S.Das: None. V.Samara: None. M.Abdollahi: None. S.Dey: None. R.Ganguly: None. L.L.Lanting: None. K.Stapleton: None.

Funding
National Institutes of Health (NIH RDK 065073)
452-P: Liraglutide Decreases Neointimal Growth in Control and Western Diet–Fed Mice, and Its Effect Is Insulin Dependent
Authors: GONZALEZ MAREL , LIU ZHIWEI , GIACCA ADRIA 
Published: May 2022

Restenosis following percutaneous transluminal angioplasty and stenting is increased in subjects with insulin resistance and diabetes. Our preclinical models of restenosis show that insulin treatment is vasculoprotective in insulin sensitive conditions but insulin's effect is diminished or lost in Western diet induced insulin resistant conditions. Accordingly, early insulin treatment has not proven to provide cardiovascular disease (CVD) protection in subjects with dysglycemia, while the effect of intensive insulin treatment of type 2 diabetes (T2D) is debated. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are a new class of antidiabetic drugs that reduce the CVD risk of T2D. Several animal studies have shown that GLP-1RA decrease neointimal growth in models of restenosis; however, the mechanisms of the CVD actions of these drugs remain elusive. GLP-1RA are insulin secretagogues, therefore their effect may be partly mediated by the insulin receptor (IR) . The objective of this study was to determine if insulin receptor (IR) deficiency in endothelial cells (EC) attenuates the effect of GLP-1RA to decrease neointimal growth after arterial injury. Endothelial deficient IR mice were generated by crossing IR floxed mice with mice expressing tamoxifen-inducible Cre recombinase under the control of Tie2 promoter. Mice were fed a low-fat (LFD) or a high-fat-high-sucrose (HFSD) Western diet and implanted with an osmotic pump delivering liraglutide, a GLP-1RA prototype (1mol/kg/day) , or vehicle prior to femoral artery wire injury. In LFD- as well as in HFSD-fed IR-floxed controls, liraglutide decreased neointimal area (NA) and intima-to-media ratio (I/M) . In LFD-fed endothelial IR deficient mice liraglutide had no effect. These data suggest that IR in ECs is important for the anti-restenotic effect of GLP1-RA, which is preserved in Western diet induced insulin resistant conditions unlike the effect of insulin. *First and second authors contributed equally

Disclosure
M.Gonzalez: None. Z.Liu: None. A.Giacca: None.
463-P: Effects of Imeglimin, a New Oral Hyperglycemic Agent, on High Glucose and Low Glucose–Induced Cell Death and Mitochondrial Dysfunction in Schwann Cells
Authors: KATO AYAKO , TATSUMI YASUAKI , NIHEI WATARU , YAKO HIDEJI , HIMENO TATSUHITO , KONDO MASAKI , KATO YOSHIRO , NAKAMURA JIRO , KAMIYA HIDEKI , SANGO KAZUNORI , KATO KOICHI 
Published: May 2022

It is known that hyperglycemia-induced oxidative stress is a major cause of the pathogenesis of diabetic neuropathy, and hyperglycemia-induced mitochondrial ROS production is considered as one pivotal mechanism of increased oxidative stress. On the other hand, imeglimin is a new class of oral hypoglycemic agents called “glymines” containing tetrahydrotriazines, which targets mitochondrial dysfunction. We investigated the effects of imeglimin on cell death and mitochondrial dysfunction induced by high glucose and low glucose in Schwann cells. Immortalized adult mouse Schwann (IMS32) cells were cultured for 1 hour in the medium with normal glucose concentration of 5.5 mM, low glucose of 2.5 mM, and high glucose of 25 mM. Compared to normal glucose, not only high glucose but also low glucose decreased cell viability of IMS32 cells and increased mitochondrial oxidative stress. Mitochondrial membrane potential was also decreased either by high glucose or low glucose. In addition, mitochondrial oxygen consumption rate (OCR) was increased by low glucose as well as high glucose. Mitochondria isolated from IMS32 cells exposed to high glucose and low glucose for 1 hour exhibited increased activity of complex I. The expression of complex I protein was unchanged by high glucose for 1 hour. Imeglimin ameliorated the decrease in cell viability and improved the mitochondrial dysfunctions via inhibiting the increase of mitochondrial oxidative stress, OCR and the activity of complex I caused by high glucose and low glucose. These results indicate that hyperglycemia and hypoglycemia induce mitochondrial dysfunction in nerves, and that imeglimin may prevent against diabetic neuropathy by attenuation mitochondrial dysfunction and cell death in Schwann cells.

Disclosure
T. Himeno: None. J. Nakamura: None. H. Kamiya: Research Support; Abbott Japan Co., Ltd., Eli Lilly and Company, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Terumo Corporation. Speaker's Bureau; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. K. Sango: None. K. Kato: None.
467-P: The Relationship between Diabetic Peripheral Neuropathy and Metformin Treatment in Type 2 Diabetes Mellitus
Authors: PAN QI , LUO JINGYI , GUO LIXIN 
Published: May 2022

Background: Metformin is the first-line therapy for the treatment of Type 2 diabetes mellitus (T2DM) . However, the use of metformin may lead to neuropathy by affecting the absorption of vitamin B12. Our objective was to explore the association between the application of metformin and diabetic peripheral neuropathy (DPN) .
Methods: The multicenter randomized cross-sectional study was conducted in 13 hospitals in Beijing from October 2015 to April 2016. T2DM Patients were divided into confirmed DPN group, suspected DPN group and non-DPN group by the five physical examinations (Ankle reflex, acupuncture pain, temperature, vibration, and pressure) . Non-parametric Mann-Whitney test was used for the comparison between non-normally distributed variables between two groups. Chi-square test was used for the comparison of categorical variables. The risk factors of DPN in T2DM Patients were assessed using logistic regression.
Results: Compared with patients without metformin, patients taking metformin were more likely to suffer from DPN and suspected DPN (P &lt; 0.0for both) . Similar results were obtained after stratifying the data based on age, BMI, and HbA1c. It was shown that the application of metformin was a risk factor for DPN (OR = 5.06, 95%Cl: 3.90-6.56; P &lt; 0.001) and suspected DPN (OR = 3.58, 95%Cl: 2.78-4.62; P &lt; 0.001) in T2DM patients after the adjustment for age, BMI and HbA1c. In addition, prolonged application of metformin, increased cumulative and single doses would also be associated with the risk of DPN (P &lt; 0.0for all) .
Conclusion: The application of metformin was observed relate to DPN in T2DM patients. The vitamin B12 concentration and peripheral nerve function of T2DM patients with the application of metformin should be monitored.

Disclosure
Q.Pan: None. J.Luo: None. L.Guo: None.

Funding
National Key R&D Program of China (2020YFC2009006)
469-P: Sodium–Glucose Cotransporter 2 Inhibitors Decrease the Frequency of Antivascular Endothelial Growth Factor Agent Injection in Patients with Type 2 Diabetes Complicated by Diabetic Macular Edema
Authors: ISHIBASHI RYOICHI , KOSHIZAKA MASAYA , MAEZAWA YOSHIRO , YOKOTE KOUTARO , TAKATSUNA YOKO , TATSUMI TOMOAKI , YAMAMOTO SHUICHI , INABA YOSUKE , SHIKO YUKI , KAWAKAMI EIRYO 
Published: May 2022

Aims: Diabetic macular edema (DME) leads to impaired vision. The first line of treatment is intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent. However, there are patients who are refractory to this. We reported patients whose DME were refractory to anti-VEGF agents and showed improvement by using sodium glucose cotransporter 2 inhibitors (SGLT2is) . The effectiveness of SGLT2is for DME was assessed using a health insurance claim database.
Methods: The JMDC inc. database covering million Japanese patients between 2005-20was used for analysis. Patients with type 2 diabetes (T2D) with DME were included, and those who were undergo dialysis, had other ocular diseases that may be treated by anti-VEGF agents, or were not on treatment with any antidiabetic drug introduced after 2014 were excluded. Propensity score matching was performed between SGLT2i users and non-users. The frequency and the duration of intravitreal injection of anti-VEGF agent after the period from the start of SGLT2is or other antidiabetic drugs were analyzed.
Results: In this study, 340 matched patients with T2D were analyzed. Initiation of SGLT2is revealed a decrease in the frequency of anti-VEGF agent injection (2.7 ± 4.1 vs. 3.8 ± 4.6 times, p &lt; 0.001; the Wilcoxon signed rank test, p &lt; 0.001, 95%CI -0.25 to -0.085; the Poisson regression, p &lt; 0.001, HR 0.80, 95% CI 0.73 to 0.87; the recurrent event analysis) and an extension in the duration for the requirement of the first injection of anti-VEGF agent (the number of patients who received no anti-VEGF agents, 96 vs. 32, p &lt; 0.001; the log-rank test) .
Conclusion: Using SGLT2is for patients with T2D complicated by DME extended the duration for the requirement of the first anti-VEGF agent injection and decreased the frequency of anti-VEGF agent injection. SGLT2is may be an option for DME treatment.

Disclosure
R.Ishibashi: Research Support; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., YL Biologics, ZERIA Pharmaceutical Co.,Ltd. E.Kawakami: None. M.Koshizaka: None. Y.Maezawa: None. K.Yokote: None. Y.Takatsuna: None. T.Tatsumi: None. S.Yamamoto: None. Y.Inaba: None. Y.Shiko: None.
472-P: Sex Differences in the Effect of High Serum Uric Acid on the Incidence of Vision-Threatening Retinopathy in Those with Type 2 Diabetes
Authors: YAMAMOTO MASAHIKO , FUJIHARA KAZUYA , ISHIGURO HAJIME , YAGUCHI YUTA , ISHIZAWA MASAHIRO , YAMADA MAYUKO H. , OSAWA TAEKO , KITAZAWA MASARU , KANEKO MASANORI , MATSUBAYASHI YASUHIRO , IWANAGA MIDORI , YAMADA TAKAHO , KODAMA SATORU , SONE HIROHITO 
Published: May 2022

Elevated serum uric acid reportedly increases the risk of development and progression of diabetic retinopathy with conflicting results. However, whether it also increases the incidence of severe vision-threatening diabetic eye diseases has been scarcely investigated. Also unknown is whether there are sex differences in the incidence of advanced retinopathies. To clarify this, we utilized ICD-and medical treatment codes from a nationwide claims database that finally included 13,721 type 2 diabetes patients (mean age 50 y, HbA1c 7.0%, mean follow-up period 5.8 y, 10,962 men) . During the study period, 388 patients developed vision-threatening treatment-required diabetic eye diseases (4.9/1000 person-years) . Multivariate Cox analysis demonstrated that a serum uric acid ≥7.1 mg/dl was significantly positively associated in men with future occurrence of treatment-required diabetic eye diseases, but not in women. Hazard ratios for those with serum uric acid ≥7.1 mg/dl for incident treatment-required diabetic eye diseases were 1.36 (95% confidence interval, 1.01-1.85) in men and 2. (0.71-6.08) in women, compared with the reference group (&lt;7.1 mg/dl) after adjusting for covariates. This finding suggested that the effect of high serum uric acid on the development of vision-threatening retinopathy in individuals with type 2 diabetes differed between men and women. Although estrogen-induced effects, decreased antioxidant activity, and increased oxidative stress may partially explain the differences in results between men and women, further investigation is needed.

Disclosure
M. Yamamoto: None. K. Fujihara: None. H. Ishiguro: None. M. Ishizawa: None. M.H. Yamada: None. T. Osawa: None. M. Kitazawa: None. M. Kaneko: None. M. Iwanaga: None. T. Yamada: None. S. Kodama: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited.

Funding
The Japan Society for the Promotion of Science and the Ministry of Health, Labor and Welfare, Japan. (18K17897)
474-P: Efficacy of Saroglitazar on Diabetes Dyslipidemia with Higher Triglyceride
Authors: SINHA AJAY 
Published: May 2022

Objectives: Diabetes and diabetic dyslipidemia with high triglycerides (TGs) are commonly associated. Saroglitazar is the first dual PPAR α/γ agonist which has been approved in India for diabetes dyslipidemia management. This study aimed at evaluation of the efficacy and long-term safety of Saroglitazar on diabetic dyslipidemia with very high triglyceride (&gt;500 mg/dl) in real-world clinical practice.
Methods: This investigation took up the form of a real-world retrospective observational study. In this retrospective study, we identified 150 patients with diabetic dyslipidemia with triglycerides &gt;500 mg/dL at baseline) . They were treated with Saroglitazar once daily.
Results: Significant reduction of TG and LDL-cholesterol was observed from baseline to 12th weeks 669.93±81.22 to 268.72±82.32 mg/dl and from 167.68±10. to 118.88±12 mg/dl. This study showed that in addition to statins, Saroglitazar paved the way for significant improvement in all the lipid parameters. At 52 weeks, a reduction in values of TG of 66.9%, LDL-C of 38.47%, total cholesterol of 44.84 %, and non- HDL-C of 52.62 % was evident. Adding Saroglitazar in patients on existing antidiabetic medications had highlighted a crucial 0.8% absolute reduction in HbA1c. Significant amounts of improvements in postprandial plasma glucose and fasting have also been seen.
Conclusion: This study concludes that there are no adverse alterations in serum creatinine and edema. Saroglitazar can be considered as an effective therapeutic option in diabetic dyslipidemia with very high triglycerides levels. It is very safe for long-term use.

Disclosure
A.Sinha: None.
477-P: Vagal GLP-1–Mediated Reductions in Postprandial Lipids Are Sensitive to Fructose Feeding
Authors: HOFFMAN SIMON S. , ALVARES DANIELLE C. , ADELI KHOSROW 
Published: May 2022

Dyslipidemia is a common co-morbidity of insulin resistance, where chronic elevations in hepatic and intestinal lipoproteins are linked to cardiovascular disease. Postprandial production is regulated in-part by gut-derived hormones such as glucagon-like peptide (GLP) -1. Although degradation-resistant analogs of GLP-1 continue to work in diabetic individuals, none have examined whether GLP-1s endogenous neuroendocrine signalling pathways are affected by diet-induced dyslipidemia. Thus, we sought to test whether native GLP-1 could modulate postprandial lipids in a fructose-fed hamster model.Hamsters were fed either a chow or fructose-enriched (FF) diet for 14 days, then received a portal vein injection of either GLP-1 (7-36) or vehicle control to examine if they remained responsive to portal GLP-1. Separately, in hamsters fed either chow or a fat/fructose/cholesterol enriched (FFC) diet we performed nodose ganglia (NG) injections with GLP-1 (7-36) or vehicle. To recapitulate the loss of vagal GLP-1R signalling in the absence of dietary intervention we selectively deafferented GLP-1R containing NG neurons via injection of the cytotoxin saporin conjugated to exendin-4. After treatment, animals received a gavage of olive oil and an intraperitoneal injection of poloxamer to prevent lipoprotein clearance. Postprandial triglyceride-rich lipoproteins isolated via density ultracentrifugation were assessed via blood draws over a 6-hour period.Chow-fed hamsters saw significant reductions in post-prandial lipids after portal GLP-1 injection, whereas FF-fed hamsters were unaffected. Chow-fed hamsters were similarly responsive to GLP-1 (7-36) injection into the NG, displaying reduced postprandial lipids; however, FFC-fed hamsters showed no reduction in plasma lipids. Finally, selective deafferentation of NG GLP-1R-containing neurons caused significant rises in postprandial TG and TRL, underscoring the importance of GLP-1R insensitivity in states of metabolic disease.

Disclosure
S.S.Hoffman: None. D.C.Alvares: None. K.Adeli: None.

Funding
CIHR Foundation Grant
489-P: Flap Reconstructions for Gangrenous COVID Toes
Authors: SWERDLOW MARK , KRESS GAVIN T. , SHIN LAURA 
Published: May 2022

Objective: Describe the clinical courses of and reconstructive methods utilized for two patients with diabetes who presented with gangrenous feet following Covid-and required partial foot amputations.
Background: Covid-produces mainly respiratory symptoms but has a variety of atypical presentations and sequelae. Serious complications are increased in patients with underlying medical conditions such as diabetes mellitus. By generating a prothrombotic milieu, SARS-CoV-2 increases the risk for arterial and venous thromboses. Inflammatory damage and micro-thromboses are thought to contribute to acro-ischemia, colloquially known as “Covid Toes,” which presents cutaneously as chilblain-like lesions.
Case Report: (1) A 57 year old female presented to vascular clinic with pedal gangrene one month after developing painful discoloration in her right toes. After angioplasty restored pedal blood flow, she received a TMA with a local fillet flap. (2) A 41 year old female presented to vascular clinic with extensive pedal gangrene three months after hospitalization for Covid-19. After arteriotomy improved pedal blood flow, she underwent a Lisfranc amputation followed by SCIP flap reconstruction.
Conclusion: Sufficient evidence suggests that Covid-impairs microcirculatory function and can be especially detrimental in diabetic patients. Reconstructive techniques in patients with severe Covid Toes help patients regain functionality.

Disclosure
M.Swerdlow: None. G.T.Kress: None. L.Shin: None.
49-LB: Use of Financial Incentives to Promote Adolescent Type 1 Diabetes Self-Management—A Pilot Randomized Controlled Trial
Authors: MALIK FAISAL , CHEN TOM , MANZUETA MARIA , YI-FRAZIER JOYCE , PIHOKER CATHERINE , LEBLANC JESSICA L. , SHAH SEEMA K. , WRIGHT DAVENE 
Published: May 2022

Background: Providing individuals with immediate, consistent inducements for health behaviors that do not provide proximal tangible benefits may promote adherence to diabetes self-management behaviors.
Objective: To evaluate whether financial incentives lead to improvement in glycemic control and self-management behaviors in adolescents with type 1 diabetes.
Methods: We conducted a randomized controlled crossover study with 12-18 year olds with type 1 diabetes. Adolescents self-selected target self-management behaviors (e.g., increase continuous glucose monitor [CGM] sensor wear time) and outcome goals (e.g., improve time in range [TIR]) and could earn up to $180 in each 3-month intervention cycle. Adolescents cycled through 3 study arms every 3 months: gain-framed payment where adolescents earned money for meeting behavioral goals, loss-framed payment where adolescents lost a portion of a weekly payment for not meeting behavioral goals, and usual care. Adolescents earned or lost $1.75 per day in the financial incentives arms, and a $2.75 weekly bonus for meeting their outcome-based goal. Goals were modeled against study arms with generalized linear mixed models to account for the longitudinal nature of the crossover design.
Results: Out of 39 participants (mean age 16.1 years, 54% male, mean baseline HbA1c 9.42%, 38% insulin pump use, 95% CGM use) , 34 completed the trial. Mean HbA1c aggregated over all interventions was lower compared to baseline at 9.07% (p=0.13) and there was no difference in HbA1c among the 3 arms. Compared to the mean TIR for those under usual care of 39%, mean TIR under gain- and loss-frames were 45% (p&lt;0.01) and 43% (p&lt;0.01) , respectively. Compared to a mean 41% behavioral goal attainment within usual care, mean behavioral goal attainment under gain- and loss-frames were 50% (p&lt;0.01) and 45% (p&lt;0.01) , respectively.
Conclusions: Financial incentives can improve adolescent self-management behaviors and time in range in the short term and merits further longitudinal study to evaluate the effects on glycemic control and health care utilization.

Disclosure
F. Malik: n/a. T. Chen: None. M. Manzueta: None. J. Yi-frazier: None. C. Pihoker: None. J. L. Leblanc: None. S. K. Shah: None. D. Wright: None.

Funding
American Diabetes Association (1-18-ICTS-100)