bluuebunny/crossref_metadata_2025_split huggingface dataset:
291-LB: Long Noncoding RNA H19 Improves Insulin Resistance in Skeletal Muscle by Regulating Heterogeneous Nuclear Ribonucleoprotein A1
Authors: LIN XIHUA , GUI WEIWEI , LI HONG 
Published: June 2019

Skeletal muscles play a pivotal role in glucose and lipid metabolism, and it has become a consensus that impaired lipid metabolism leads to ectopic lipid accumulation in skeletal muscles, which ultimately causes systematic insulin resistant. Previous reports have shown that down-regulation of long non-coding RNA(lncRNA) H19 in skeletal muscle impairs glucose metabolism. To better understand the impact of H19 on insulin resistance, here we focused on the relationships between H19 and fatty acid metabolism in skeletal muscle. In our research, decreased H19 expression was found in skeletal muscle of db/db mice compared with db/m mice. In vivo overexpression of H19 via injection of recombinant H19-adenovirus by tail-vein in db/db mice significantly improved glucose tolerance, lowered serum insulin, TG and skeletal muscle TG levels, which were consistent with improved skeletal muscle H&E and oil red staining contrast to vehicle-treated db/db mice, indicating that overexpression of H19 in db/db mice ameliorated ectopic lipid accumulation in skeletal muscle. As expected, similar effects were observed in vitro. Overexpression of H19 in muscle cells treated with palmitate acid reduced lipid contents,promoted mitochondrial synthesis and ATP productions,and increased the expression of fatty acid oxidation related genes and mitochondrial respiratory chain complexes.Finally, it was drawn from RNA pull-down and RIP that heterogeneous nuclear ribonucleoprotein A1(hnRNPA1)is the target gene of H19, whose function in mitochondria has not been reported yet. Furthermore, we identified PGC1a and CPT1b were among the target genes of hnRNPA1 by searching widely used bioinformatics databases and preliminary RIP validation. Based on these results, we put forth our hypothesis that lncRNA H19 could improve insulin resistance by promoting mitochondrial biosynthesis and fatty acid oxidation in skeletal muscle, through regulating hnRNPA1.

Disclosure
X. Lin: None. W. Gui: None. H. Li: None.

Funding
National Natural Science Foundation of China (81873653)
306-OR: Gene-Environment Interactions for Type 2 Diabetes in UK Biobank
Authors: NAG ABHISHEK , MAHAJAN ANUBHA , MCCARTHY MARK 
Published: June 2019

Diet and lifestyle-related obesogenic environmental factors influence type 2 diabetes (T2D) risk, but there is little evidence that gene-environment (GxE) interactions underlie T2D susceptibility. We investigated whether obesogenic environmental factors (which, of course, are themselves partly genetic) interact with T2D-associated genetic variants to accentuate T2D risk using 375,736 unrelated European subjects from UK Biobank (16,430 T2D cases, 359,306 controls). We captured individual genetic risk of T2D with a weighted genetic risk score (T2D-GRS) based on 403 established T2D-associated variants from European-ancestry GWAS. We also constructed six distinct partitioned GRSs by classifying T2D-associated variants based on their likely pathophysiological mechanism (related to e.g., adiposity (T2D-GRSadiposity), beta-cell function, insulin action, mixed features). A logistic regression model was fitted to test for interactions between each GRS and environmental factor (duration and frequency of moderate/vigorous physical activity, sedentary lifestyle, MET, alcohol intake, dietary fat content, Townsend deprivation index (TDI), daytime nap and depression) on T2D, adjusted for age, sex, genotyping array and ethnic background (10 principal components). There was no evidence of statistically-significant interaction between any of the environmental factors and either the combined or partitioned T2D-GRS (p&gt;0.0006, Bonferroni for 77 independent tests). There was suggestive interaction between frequency of alcohol intake and T2D-GRSadiposity on T2D risk (betainteraction=0.08 [95% CI=0.02-0.14]; pinteraction=0.008). These findings stand in contrast with strong interactions between the same environmental factors and T2D-GRSadiposity when using BMI as the outcome (e.g., for TDI, pinteraction=10-17). Our study finds little evidence of substantial interaction between individual T2D genetic risk profiles and obesogenic environmental factors with respect to T2D as the outcome.

Disclosure
A. Nag: None. A. Mahajan: None. M. McCarthy: Advisory Panel; Self; European Association for the Study of Diabetes, Pfizer Inc. Consultant; Self; Eli Lilly and Company, Merck & Co., Inc. Consultant; Spouse/Partner; Merck & Co., Inc. Research Support; Self; AbbVie Inc., Boehringer Ingelheim International GmbH. Research Support; Spouse/Partner; Diabetes UK. Research Support; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., National Institutes of Health. Research Support; Spouse/Partner; National Institutes of Health. Research Support; Self; Novo Nordisk A/S. Research Support; Spouse/Partner; Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation, Roche Pharma, Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited.
31-LB: Identification of Repurposable Drug Candidate for Diabetic Peripheral Neuropathy Using High-Throughput Drug-Perturbation Data
Authors: GUO KAI , FELDMAN EVA L. , HUR JUNGUK 
Published: June 2019

Diabetic peripheral neuropathy (DPN) is a common complication of prediabetes and type 2 diabetes (T2D) for which there are limited treatment options. We recently demonstrated that dietary reversal (DR) corrects the DPN phenotype using mouse models of prediabetes and T2D. However, it is still important to develop therapeutic agents for treating DPN in addition to life style changes such as DR. In this study, we employed an in silico omics-based systems approach to identify small-molecule drugs with a high potential of reversing or halting DPN. The NIH Library of Integrated Network-based Cellular Signatures (LINCS) drug-perturbation transcriptomic data were obtained, which measured gene expression changes after treatment of 83 human cells with over 20,000 small-molecule compounds using the L1000 assay platform. Gene expression signature of DPN, consisting of highly up- or down-regulated genes, was defined based on the dysregulated genes, identified from sciatic nerves RNA-Seq data of C57BL/6J mice fed with high-fat diet (60% kcal fat for 19 weeks). This DPN signature was compared against the LINCS perturbation data using the CLUE Query app from the Broad Institute and our in-house analysis pipeline. The top small-molecule drugs, demonstrating opposite expression profiles of the DPN signature, included various protein synthesis inhibitors, calcium channel blockers, and adrenergic receptor antagonists such as cephaeline, levetiracetam, and esmolol, respectively. Although the anti-DPN effects of these drugs need to be systematically examined, our systems approach provides a list of drugs with a potential for being used to treat DPN.

Disclosure
K. Guo: None. E.L. Feldman: None. J. Hur: None.

Funding
National Institutes of Health (R24DK082841); University of Michigan
315-LB: Intervention Program on Lifestyle Changes and Weight Reduction for Workers in Remote Areas, Based on Therapeutic Education and Telemedicine Coordination
Authors: MOCIULSKY JULIANA , RUIZ PABLO , ZARATE PABLO C. , CURA LEILA , GANDUGLIA CAZABAN MERCEDES M. 
Published: June 2019

Introduction: Overweight and obesity are frequently found risk factors in oil industry workers in Argentinian Patagonia with limited access to health care system.
Objective: Implement an intervention program based on lifestyle changes for weight reduction among oil industry workers of Patagonia; coordinated by telemedicine from the City of Buenos Aires and carried out by local nurses.
Materials and Methods: Nurses in 10 different oil fields, were trained in motivational interviewing, nutrition and physical activity fundamentals. Employees were invited to a 3 months structured program, including workshops on healthy nutrition habits, and weekly consultations to infirmaries for weight control and brief motivational interviews. Participants received a health notebook for self-record of: food intake, physical activity, weight progress and therapeutic objectives. Coordinators monitored the program through video and teleconferences, plus 3 on-site visits.
Results: Of 220 participants, 178 (94% males) were included for data analysis, excluding those with BMI&lt;25 kg/m2. Initial data showed 41% overweight, 59% obesity (36.5% grade I, 17.4% grade II and 5.1% grade III) and 93,3% of dyslipidemia among participants. Adherence, measured by assistance to consultations, was 48,9 % high, 37,6% satisfactory and 13,5% low. Median weight loss was 2.5 kg (IQR 1.2 - 4.8) and 2.7% of initial weight (IQR 1.4 - 4.8). High adherence group had an average weight reduction of 4,8kg (95% CI 4.1 - 5.6). Overall, 24% of population lost more than 5% of initial weight, and 7 participants weight loss was greater than 10%.
Conclusions: A structured intervention program in remote areas, coordinated by telemedicine can be a successful tool for weight loss and reduction of cardiometabolic risk factors.

Disclosure
J. Mociulsky: None. P. Ruiz: None. P.C. Zarate: None. L. Cura: None. M.M. Ganduglia Cazaban: Consultant; Self; AstraZeneca. Speaker’s Bureau; Self; Merck & Co., Inc.
316-LB: Medically Reproducing Bariatric Surgery (MRB): A Proof-of-Concept Study
Authors: DAR MOAHAD , SMYTHE KEVIN F. , LEGGETT-FRAZIER NANCY K. , YANCY WILLIAM S. 
Published: June 2019

Introduction: Roux-en-Y gastric bypass (RYGB) leads to durable type 2 diabetes (DM2) remission. Increased glucagon-like peptide-1 (GLP-1) levels and caloric restriction are known sequela of RYGB and independently improve DM2 control.
Hypothesis: Since Liraglutide increases GLP-1 levels and the OPTIFAST program induces caloric restriction, we hypothesize that Liraglutide + OPTIFAST will medically reproduce RYGB and lead to DM2 remission, weight loss, decreased medication intensity and improved health related quality of life (HRQL).
Methods: The Medically Reproducing Bariatric surgery (MRB) study is a pilot study that tested whether poorly controlled DM2 subjects on Liraglutide ± other diabetic medicines experienced DM2 remission after completing the 24 week OPTIFAST program. Primary outcome: glycemic control. Secondary outcome: weight, medication intensity and HRQL measured by Problem Areas In Diabetes (PAID) score.
Results:

Conclusion: Responders (yellow) vis-a-vis Non-responders (plain) experienced significant improvements in glycemic control, weight, medication intensity and HRQL. Responders vis-a-vis Non-responders had much better compliance during the OPTIFAST weight loss phase (week 1-12) when 800 calories per day were being consumed. Non-responders still experienced modest improvement in weight loss and HRQL. No serious adverse events occurred. The MRB approach merits further study.

Disclosure
M. Dar: None. K.F. Smythe: None. N.K. Leggett-Frazier: None. W.S. Yancy: None.

Funding
Nestl?
376-P: Type 2 Diabetes Individuals Are at High Risk of Continuous Glucose Monitoring Detected Hypoglycemia Regardless of Degree of Metabolic Control
Authors: SZYMANSKA-GARBACZ ELEKTRA , BORKOWSKA ANNA , CZUPRYNIAK LESZEK 
Published: June 2019

Type 2 diabetes patients, especially those with poor metabolic control or treated with oral hypoglycemic agents (OHA) only are often regarded as being at lower risk of hypoglycemia than type 1 diabetes subjects. We used continuous glucose monitoring system (CGMS) in 69 type 2 diabetes individuals (mean [±SD] age 63±9 years, duration of diabetes 12±7 years, BMI 31.8±5.2 kg/m2, HbA1c 8.4±0.7%, 74% treated with insulin ± OHA, 26% - treated with OHA only, including sulfonylureas) to assess the hypoglycemia prevalence. Each patient underwent blinded CGMS (iPro2, Medtronic) for 5.8±0.8 days, duration of the time spent at blood glucose (BG) &lt;70 mg/dl was determined and expressed as a percentage of total CGMS use time (T hypo). Clinically statistical hypoglycemia (CSH) episodes defined as BG &lt;54 mg/dl lasting &gt;15 minutes were also recorded. Overall, hypoglycemia was detected in 28 (40.6%) patients, including five treated with OHA only. T hypo ranged from 1 to 15% (6.1±4.7%), and was twice as long in insulin treated individuals than in those on OHA only (8.8±5.1 vs. 4.2±3.6; p&lt;0.05). 57% of all patients experiencing hypoglycemia (including two treated with OHA only) had at least one episode of nocturnal CSH, with BG as low as 40 mg/dl, and none was symptomatic. To assess the relationship between hypoglycemia risk and degree of metabolic control the study subjects were divided into two subgroups: with good (n=29; HbA1c 7.2±0.6, range 6-8%) and poor (n=40; HbA1c 9.6±0.8, range 9-12%) metabolic control. Hypoglycemia was recorded in 37.9 and 42.5%, nocturnal hypoglycemia - in 54.5 and 58.8% of subjects from each group, and T hypo was 6.7±4.9 and 5.7±4.6%, respectively (p&gt;0.05).
In conclusion, 40% of type 2 diabetes individuals experience hypoglycemia when assessed with CGMS for 5-6 days, with majority having asymptomatic nighttime events. Importantly, the high prevalence of CGMS detected hypoglycemia was not related to the degree of metabolic control of diabetes.

Disclosure
E. Szymanska-Garbacz: None. A. Borkowska: None. L. Czupryniak: None.
416-P: The Ceramide-Based Coronary Event Risk Test (CERT) Predicts Cardiovascular Mortality in Cardiovascular Disease Patients with Type 2 Diabetes Mellitus as Well as in Those without Diabetes
Authors: LEIHERER ANDREAS , MUENDLEIN AXEL , SAELY CHRISTOPH H. , LAAKSONEN REJO , LAAPERI MITJA , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , BAUMGARTNER IRIS , FRAUNBERGER PETER , DREXEL HEINZ 
Published: June 2019

The recently introduced Coronary Event Risk Test (CERT) is a validated cardiovascular risk predictor that uses circulating ceramide concentrations to allocate patients into one of four risk categories. We here aimed at investigating the power of CERT to predict cardiovascular mortality in 1087 patients with established cardiovascular disease (CVD) including 360 patients with type 2 diabetes (T2DM). At baseline, the prevalence of T2DM increased through CERT categories (29.1, 31.1, 37.4, and 53.4%, respectively, ptrend&lt;0.001). Prospectively, we recorded 130 cardiovascular deaths during a mean follow-up time of 8.1±3.2 years. Overall, cardiovascular mortality increased with increasing CERT categories (Figure) and was higher in T2DM patients than in those who did not have diabetes (17.7 vs. 9.4%; p&lt;0.001). In Cox regression models, CERT categories predicted cardiovascular mortality in patients with T2DM (unadjusted HR 1.60 [1.28-2.01]; p&lt;0.001; HR adjusted for age, gender, BMI, smoking, LDL cholesterol, HDL cholesterol, hypertension, and statin use 1.65 [1.27-2.15]; p&lt;0.001) and in those without diabetes (unadjusted HR 1.43 [1.10-1.85]; p=0.008 and adjusted HR 1.41 [1.07-1.85]; p=0.015). We conclude that CERT predicts cardiovascular mortality in CVD patients with T2DM as well as in those without diabetes.

Disclosure
A. Leiherer: None. A. Muendlein: None. C.H. Saely: None. R. Laaksonen: None. M. Laaperi: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. I. Baumgartner: None. P. Fraunberger: None. H. Drexel: None.
502-P: Urinary Levels of Deoxyribonuclease-1 and Lysosomal Alpha-Glucosidase Were Associated with the Progression of Diabetic Nephropathy
Authors: KABURAGI YASUSHI , ITO EMI , UNOKI-KUBOTA HIROYUKI 
Published: June 2019

Recent reports showed early progressive renal function decline precedes the onset of microalbuminuria, indicating the need for new factors predicting diabetic nephropathy (DN) that work alone or as a complement to urinary albumin and eGFR. To identify urinary proteins associated with DN, we carried out a 2D-DIGE-based proteomic analysis using the urine obtained from healthy control subjects (H; n=8), type 2 diabetic patients without nephropathy (T2DM; n=16), and stage II DN patients (DN2; n=16). From the total 3034 protein spots detected, a total of 34 proteins were identified as the candidate protein differentially excreted in DN2 or T2DM. Thirty proteins out of 34 candidates were then validated by multiple reaction monitoring assay using an independent sample set (H: n=14, T2DM: n=13, DN2: n=14, stages III to IV DN: n=17), where 26 proteins were validated to be differentially excreted in DN. Among them, the levels of deoxyribonuclease-1 and lysosomal alpha-glucosidase were significantly correlated with both ACR and eGFR, and were also significantly lower in patients with an eGFR &lt; 60 compared with patients with an eGFR ≥ 60. We further analyzed gene expressions of DNase I and lysosomal alpha glucosidase in kidneys of DN patients using Nephroseq database (https://www.nephroseq.org), and found that DNase I gene was significantly downregulated in DN tubulointerstitum and glomeruli, and that lysosomal alpha glucosidase gene tend to decreased in DN tubulointerstitum. Finally, the urinary DNase I levels were found to be higher in patients who progressed to a more severe DN stage or had early renal decline than in patients who did not. These findings suggest a possible role for the identified proteins in the progression of DN, although further validation studies are required.

Disclosure
Y. Kaburagi: None. E. Ito: None. H. Unoki-Kubota: None.

Funding
Japan Society for the Promotion of Science
517-P: Communication from Tubular Epithelial Cells to Podocytes through Bim/NFAT2 Pathway
Authors: XU CHUNMEI , ZHOU XIAOJUN , SHEN XUE , JIANG SHAN , XIE TIANYUE , ZOU ZHIWEI , ZHANG QIAN , ZHANG RUI , XING YIQIAN , LIAO LIN , DONG JIANJUN 
Published: June 2019

Background: Our previous research revealed that the apoptosis of proximal tubular epithelial cells (PTECs) occupied a vital position in the early change of diabetic nephropathy (DN) and Bcl-interacting mediator (Bim) was the key factor to be involved in it. Whereas, Bim could also control T cell activation and play a specific regulatory role in other aspects besides inducing cell apoptosis. Changes of podocytes are classic hallmarks of the lesions of DN. Here, the study aims to investigate the specific influence of PTECs which have been damaged on the podocyte injury.
Methods: Bim expression in PTECs was modulated, and subsequently podocyte cytoskeleton was determined at different points of time (24, 48, 72 hours) by building transwell co-culture system under high glucose (40mmol/l HG).
Results: HG exposure for 48 hours induced the significant changes in podocyte cytoskeleton accompanied with high expression of Bim in PTECs. When co-cultured with PTECs, exacerbated filamentous actin (F-actin) rearrangement and markedly reduced synaptopodin level in podocytes were found compared with single cultured podocytes under HG. Gene knockdown of Bim in PTECs ameliorated above abnormalities in podocytes. Further screening for NFAT subtypes, the key downstream factors of Bim, found that NFAT2 level in PTECs was obviously decreased when suppressing Bim expression. Upregulating NFAT2 disrupted beneficial effects on podocyte F-actin arrangement which was achieved by inhibiting Bim in PTECs.
Conclusion: Our preliminary data have indicated that the apoptosis of PTECs mediates the early lesion of DN. It seemed corroborative that there exists crosstalk between PTECs and podocytes; Bim, the pivotal factor related to apoptosis of PTECs participates in the crosstalk by promoting NFAT2 activation, then contributes to injury of podocyte cytoskeleton, emphasizing the role of Bim/NFAT2 pathway in the control of early DN progression from tubular lesions to glomerular abnormalities.

Disclosure
C. Xu: None. X. Zhou: None. X. Shen: None. S. Jiang: None. T. Xie: None. Z. Zou: None. Q. Zhang: None. R. Zhang: None. Y. Xing: None. L. Liao: None. J. Dong: None.

Funding
National Natural Science Foundation of China (81570742, 81670757, 81770822, 81800732); Shandong Provincial Natural Science Foundation of China (ZR2017LH025); Shandong Provincial Medicine and Health Science and Technology Development Program (2017WS461)
582-P: Disambiguating the Nucleus Ambiguous with Single-Cell Transcriptomics
Authors: COVERDELL TATIANA , IVISON RACHAEL , TAO JENKANG , CAMPBELL JOHN 
Published: June 2019

The nucleus ambiguous (nAmb), a hindbrain region which degenerates in diabetes models, is the major parasympathetic input to the heart but also innervates the larynx and esophagus to control swallowing. These disparate functional roles are likely mediated by distinct nAmb neuron subtypes. Yet, the molecular identities of these subtypes are mostly unknown, limiting access to them for functional studies. Therefore, we classified mouse nAmb neurons using single-nuclei RNA-Seq (sNuc-Seq). First, we labeled nAmb neuron nuclei by injecting an adeno-associated viral (AAV) vector which Cre-dependently expresses a nuclear-localized mCherry protein into the nAmb of adult male Chat-IRES-Cre mice, in which all nAmb neurons (and few nearby ones) express Cre recombinase. We later dissected the nAmb, isolated its cell nuclei, and sorted the H2b-mCherry+ ones singly into microplate wells with fluorescence assisted cell sorting (FACS). We then used SmartSeq2 to generate cDNA sequencing libraries from the single-nuclei poly-adenylated RNA samples and deeply sequenced them to near-saturating depths for gene detection. Clustering the samples based on expression of their highly variable genes revealed six molecularly-distinct neuron subtypes, four of which localized to nAmb based on in situ detection of their marker transcripts. Comparing their gene expression revealed candidate transcriptional markers for each neuron subtype (Crhr2; Uts2; Vipr2; and Tbx3). In light of previous studies, three nAmb populations (Crhr2 neurons, Uts2 neurons, and Vipr2 neurons) are likely motor neurons innervating the larynx and esophagus, as they expressed high levels of CGRP (Calca) but little to no PACAP (Adcyap1). The opposite was true for the fourth subtype, Tbx3 neurons, raising the possibility that they are the cardiovagal nAmb neurons. Additional studies are underway to identify (1) tissues innervated by each marker-defined nAmb neuron type and (2) their role in controlling heart rate, laryngeal or esophageal muscle tone.

Disclosure
T. Coverdell: None. R. Ivison: None. J. Tao: None. J. Campbell: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-18-INI-14 to J.C.)