bluuebunny/crossref_metadata_2025_split huggingface dataset:
2197-P: SEL1L-HRD1 Endoplasmic Reticulum-Associated Degradation Is Required for Maintaining Glucagon Production in Pancreatic Alpha Cells
Authors: REINERT RACHEL B. , SHRESTHA NEHA , JI YEWEI , QI LING 
Published: June 2019

Endoplasmic reticulum-associated degradation (ERAD) is a key component of cellular protein quality control, an essential process for pancreatic islet endocrine cells, which synthesize peptide prohormones in high quantities. Two highly conserved ER membrane proteins comprise the core ERAD machinery: HRD1, a ubiquitin ligase that retrotranslocates and ubiquitinates misfolded proteins for proteasomal degradation, and SEL1L, an adaptor protein that identifies ERAD target proteins and is required for HRD1 stability and function. Pancreatic alpha cells, intestinal L-cells, and certain neurons synthesize and differentially cleave proglucagon into tissue-specific hormones, including glucagon and glucagon-like peptide 1 (GLP-1). To investigate the role of ERAD in these cells, we targeted SEL1L deletion with the Cre-lox system, using mice expressing Cre recombinase under the proglucagon promoter. We found that Sel1LGcg mice showed normal growth and glucose homeostasis in vivo. Oral glucose tolerance was equally impaired by administration of the GLP-1 receptor antagonist exendin 9-39 in both Sel1LGcg and control mice, suggesting intact GLP-1 signaling in Sel1LGcg mice. Glucagon secretion in vivo was not significantly different following a 24 hour fast or insulin-induced hypoglycemia. Interestingly, pancreatic glucagon content was reduced by half in Sel1LGcg mice, despite unchanged pancreatic weight. By immunofluorescence, pancreatic islet morphology in Sel1LGcg mice was normal, though α-cells demonstrated increased expression of the ER chaperone BiP and ERAD-associated proteins OS9 and XTP3-B. By transmission electron microscopy, a large subset of α-cells showed significant ER dilation and fewer, smaller glucagon granules. Our data demonstrate that SEL1L-HRD1 ERAD is required for maintaining normal glucagon expression and ER morphology in pancreatic α-cells but does not entirely disrupt proglucagon signaling in vivo.

Disclosure
R.B. Reinert: None. N. Shrestha: None. Y. Ji: None. L. Qi: None.

Funding
National Institutes of Health (5T32DK007245)
2213-PUB: Management Practices in Indian Type 2 Diabetes Mellitus (T2DM) Participants With or Without Comorbidities in Real-World LEADD (Learnings with Experts to Advance Diabetic Dyslipidemia Management) Study
Authors: UNNIKRISHNAN AMBIKA GOPALAKRISHNAN , DAS ASHOK KUMAR , SABOO BANSHI D. , KALRA SANJAY 
Published: June 2019

Background: Diabetes is India’s major health concern due to its high disease burden.
Objective: Evaluate management practices in Indian T2DM participants with/without co-morbidities and risk factors based on ADA/AACE guidelines.
Methods: A real world, prospective, cross sectional, observational LEADD study in T2DM participants conducted at 226 sites. Participants with informed consent, were enrolled. Demographics, disease family history, comorbidities, lab data, and treatment as available was analyzed with descriptive statistics. “n” signifies number of participants analyzed for each parameter.
Results: A total of 4002 participant’s records were evaluated. Mean age was 55.7 ± 11.5 years (n=3822), 52.5% males (n=1697/3230) and 66.5% had BMI of ≥25 kg/m2 (n=1868/2808). Average duration of T2DM was 7.6± 6.0 years (n = 2855) with mean values of Hb1Ac 8.15± 1.7% (n=2577), LDL 117.7±37.6mg/dl (n = 2545) and serum creatinine 1.34 ± 2.5 mEq/L (n= 2086). LDL-C levels (≥100mg/dl), 69.3% (n = 1764/2545), non-HDL C high (≥ 160mg/dl) in 42.6% (n= 1039/2438) was analyzed. Most common comorbidities were: Hypertension (68.3%, n = 1826/2673), dyslipidemia (52.3%, n = 1399/2673). Rosuvastatin was given in 87% (n=2419/2757) participants. Hb1Ac ≧7% was in 77.7% (n=2003/2577), blood pressure &gt;140/90mmHg (n = 596/1826) in 32.6% participants. In ≥80% participants with ASCVD/ASCVD risk factors were not prescribed antihyperlipidemic drugs per recommendation by AACE/ADA guidelines.
Conclusion: Significant participants with Diabetes had hypertension, hyperlipidemia as co-morbidities. T2DM participants have high ASCVD risk, many participants with co-morbidities were not optimally treated to goal. A need to strive for stringent control of Hb1Ac, hypertension and hyperlipidemia, as per AACE/ADA guidelines, is desired for better patient outcome.

Disclosure
A. Unnikrishnan: Other Relationship; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Dr. Reddys Laboratories, Eli Lilly and Company, Eris Pharmaceuticals, Ipca Laboratories Ltd., MSD, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi. A.K. Das: None. B.D. Saboo: None. S. Kalra: None.

Funding
Dr. Reddy's Laboratories; Diabetes Care India
2219-PUB: Antioxidant Protective Effect and Mechanism of Selenoprotein S in Diabetic Vascular Endothelium-Mimicking Microenvironment
Authors: YU SHANSHAN , ZHONG YINGSHUO , MEN LILI , YAO JUNJIE , DU JIANLING 
Published: June 2019

Endothelial dysfunction is an initiating key step for diabetic macrovascular complications, and it is closely related to the hemodynamic microenvironment in vivo. However, diabetic patients usually coexist with other cardiovascular risk factors, and the more powerful targeting strategy for protecting endothelium is still limited. Selenoprotein S (SelS) was found in our previous study that could increase vascular endothelial cells resistance to oxidative stress associated with protein kinase C α (PKCα). Thus, in this study, we constructed a diabetic vascular endothelial bionic microenvironment mimicking hyperglycemia and/or hyperlipidemia based on microfludic chip through modulating the concentration of medium glucose and oxidized low density lipoproteins. Our results showed that under diabetic vascular endothelial bionic microenvironment, the upregulation of SelS enhanced nitric oxide synthase (eNOS) expression and reduced endothelin-1 level in human aortic endothelial cells (HAECs), accompany with increase in cell viability and SOD1 and SOD2 activity, and decrease in ROS. Furthermore, SelS overexpression attenuated the activation of PKCα, which subsequently promoted the activation of PI3K/Akt/eNOS pathway. Conversely, the knockdown of SelS resulted in an enhancement of endothelial injury. These findings suggest that SelS could protect endothelial cells from oxidative stress injury under diabetic vascular endothelial bionic microenvironment through PKCα and PI3K/Akt/eNOS pathway. Our results offer a promising and biomimetic platform for investigation on endothelial protection, and provide evidence of SelS as potential novel target to treat diabetic macrovascular complications.

Disclosure
S. Yu: None. Y. Zhong: None. L. Men: None. J. Yao: None. J. Du: None.

Funding
National Natural Science Foundation of China (81570727)
222-OR: BETA-2 Calculated Based on Single Fasting Blood Sample Allows to Define and Discriminate between Optimal and Suboptimal Islet Allograft Function Prior to the Clinical Need for Insulin Support
Authors: BACHUL PIOTR J. , GOLEBIEWSKA JUSTYNA E. , ANTIC FILIP , PARA MONICA , BASTO LINDSAY , GOLAB KAROLINA , PEREA LAURENCIA , WANG LING-JIA , TIBUDAN MARTIN L. , THOMAS CELESTE C. , WITKOWSKI PIOTR 
Published: June 2019

Introduction: The goal of the study was using BETA-2 to define suboptimal islet allograft function, which precedes clinical need of the insulin support and to discriminate it from the optimal function which allows for persistent insulin independence after islet allotransplantation.
Material: Thirty five islet transplants were performed in 16 patients with T1DM. BETA-2 trends over the time were assessed in 3 transplant groups depending on the clinical outcome: Group 1 (N=9) persistent insulin independence; Group 2 (N=13) insulin independence loss preceded by the gradual islet graft decline; Group 3 (N=13) no insulin independence. Day 75 was a surrogate day of accomplished islet engraftment.
Results: None of the transplants with BETA-2 &lt; 17.4 on Day 75 resulted in persistent insulin independence (ROC AUC=17.4 for BETA-2 Group 1 vs. Group 2+ Group 3 with 100% sensitivity). Moreover, afterwards BETA-2 always oscillated above 17.4 and never dropped below after each transplant from Group 1 with up to 12 years follow-up. In contrast BETA-2 dropped below 17.4 in every case from Group 2, 9 months (3-24) prior to the loss of insulin independence (Kaplan-Meyer, p=0.03). Based on above, we defined that optimal islet function at any time point was represented by BETA-2 &gt;=17.4, whereas suboptimal when BETA-2 was below that. Once BETA-2 dropped below 17.4 at any time point, islet function never recovered, instead gradually deteriorated with subsequent need for insulin support in every patient from group 2. Optimal vs. suboptimal islet graft function could be also discriminated based on individual fasting glucose, c-peptide or A1c values but with lower sensitivity and specificity. BETA-2 values never reached 17.4 at any time point after each transplant from Group 3.
Conclusion: BETA-2 with cut off 17.4 allowed to define and discriminate optimal vs. suboptimal islet allograft function before need for insulin support.

Disclosure
P.J. Bachul: None. J.E. Golebiewska: None. F. Antic: None. M. Para: None. L. Basto: None. K. Golab: None. L. Perea: None. L. Wang: None. M.L. Tibudan: None. C.C. Thomas: None. P. Witkowski: None.

Funding
State of Illinois; Dompé
2223-PUB: Association of Vitamin D Metabolites with Type 2 Diabetes Complications in Qatar
Authors: ATKIN STEPHEN , BUTLER ALEXANDRA E. 
Published: June 2019

Aims: Vitamin D deficiency is a major issue worldwide, and particularly in Middle Eastern countries where full body coverage is standard cultural practice. Epidemiology studies have suggested that vitamin D deficiency is associated with the development of type 2 diabetes. The relationship between diabetes complications and 1,25-dihydroxyvitamin D (1,25(OH)2D3), 25-hydroxyvitamin D3 (25(OH)D3), 24,25-dihydroxyvitamin D (24,25(OH)2D3) and 25-hydroxy-3epi-Vitamin D3 (3epi25(OH)D3) is unclear.
Methods: 750 Qatari subjects, 460 (61.3%) with type 2 diabetes and 290 (38.7%) nondiabetic, participated in the study. Plasma levels of vitamin D and its metabolites were measured by LC-MS/MS analysis.
Results: The type 2 diabetic subjects had lower levels of all vitamin D metabolites except 3epi25(OH)D3. Males had higher levels of all vitamin D metabolites (p &lt; 0.001) versus females. In the type 2 diabetic subjects. 1,25OHD3 deficiency was associated with hypertension, diabetic retinopathy and coronary artery disease (p&lt;0.01), whilst 25OHD3 and (24,25(OH)2D3) levels were only associated with dyslipidemia (p&lt;0.005); 3epi25(OH)D3 was not associated with diabetic complications.
Conclusions: The active 1,25OHD3 correlated to diabetic complications, but 25OHD3 levels did not, other than for dyslipidemia. Vitamin D3 metabolites were lower in type 2 diabetic subjects in this Qatari population, where full body coverage is standard, particularly in Qatari females. The role of 24,25(OH)2D3 in dyslipidemia requires clarification, but 3epi25(OH)D3 appears not to be associated with diabetes complications.

Disclosure
S. Atkin: None. A.E. Butler: None.
223-OR: Pioglitazone Discontinuation in Patients with Nonalcoholic Steatohepatitis (NASH) Is Associated with Disease Recurrence
Authors: BRIL FERNANDO , LOMONACO ROMINA , KALAVALAPALLI SRILAXMI , LAI JINPING , CUSI KENNETH 
Published: June 2019

Pioglitazone (PIO) therapy results in a ∼60% resolution of NASH in patients with prediabetes or T2DM. However, the effects of treatment discontinuation have not been carefully examined. To this end, we assessed plasma aminotransferases (LFTs) after study drug discontinuation among patients who had completed 36 months (n=63) of our randomized, controlled trial (RCT) of PIO for NASH (Cusi, et al. Ann Intern Med 2016). This was an 18 month RCT of PIO 45mg QD vs. placebo (and dietary counseling in all), followed by 18 months of open label PIO. We retrospectively assessed LFTs for 18 months following study discontinuation. PIO normalized plasma ALT, an indicator of hepatocyte injury in NASH, within 3 months of therapy initiation (from 61±5 to 35±2 U/L; p&lt;0.001) and for the duration of treatment (Figure 1).
However, PIO discontinuation resulted in a rapid rebound of LFTs after 3 months (from 30±2 to 42±7 U/L, p=0.02), and continued to increase over time, reaching the highest levels 18 months after discontinuation (59±12 U/L, p&lt;0.001 vs. end of the trial). Plasma AST followed a similar pattern during treatment and after discontinuation.
Conclusion: PIO rapidly normalizes LFTs in NASH and improves liver histology, but its discontinuation results in an abrupt increase in LFTs, likely reflecting NASH recurrence. Therefore, PIO therapy for NASH should be considered as a long-term management approach.

Disclosure
F. Bril: None. R. Lomonaco: None. S. Kalavalapalli: None. J. Lai: None. K. Cusi: Consultant; Self; Allergan, AstraZeneca, Genentech, Inc., Novo Nordisk Inc., Poxel SA, ProSciento. Research Support; Self; Cirius Therapeutics, Echosens, Eli Lilly and Company, Inventiva Pharma, Janssen Research & Development, Novartis AG, Novo Nordisk Inc.

Funding
American Diabetes Association (1-08-CR-08 to K.C.); Burroughs Wellcome Fund; National Center for Research Resources (M01-RR-01346); University of Texas Health Science Center at San Antonio; U.S. Department of Veterans Affairs
2230-PUB: The Role of Baseline Urine ACR and Estimated GFR in the Development of Advanced CKD after 8.4 Years of Follow-Up in Type 2 Diabetic Patients
Authors: AN LINGWANG , HSU HUI-CHUN , CHANG YU HUNG , LEE TAO-CHUN 
Published: June 2019

Background: There is discordance between the presence of albuminuria and the decline in renal function. This study aimed to assess the role of baseline Urine Albumin-to-Creatinine Ratio (UACR) and the estimated glomerular filtration rate (eGFR) in the development of advanced chronic kidney disease (CKD; GFR &lt; 60 mL/minute per 1.73 m2) in type 2 diabetic patients.
Methods: A total of 2424 patients who had participated in a comprehensive diabetic care program were studied and were stratified into progressor (n=578) and non-progressor groups (n=1846) according to the status of progression to advanced CKD during the mean 8.4 years follow-up period.
Results: By Cox regression analysis, the risk of CKD progression [hazard ratio, HR (95% CI)] for patients with microalbuminuria and eGFR &gt;90, non-albuminuria and eGFR 60~89 or microalbuminuria and eGFR 60~89 were 2.215 (1.592~3.081), 3.091 (2.354~4.059) and 4.351 (3.253~5.820), respectively (P&lt;0.001 for all). By Kaplan-Meier survival curve, the progression rates were 9.4% in patients with non-albuminuria and eGFR &gt;90, 25.6% in patients with microalbuminuria and eGFR &gt;90, 28.0% in patients with non-albuminuria and eGFR 60~89 and 38.5% in patients with microalbuminuria and eGFR 60~89.
Conclusions: Our study demonstrated that type 2 diabetic patients with microalbuminuria and eGFR &gt;90 or patients with non-albuminuria and eGFR level of 60~89 were associated with similar risk of progression to advanced CKD.

Disclosure
L. An: None. H. Hsu: None. Y. Chang: None. T. Lee: None.
2244-PUB: Role of B Vitamins (B1, B6, B12) in Managing Diabetic Peripheral Neuropathy (DPN): A Systematic Review
Authors: LIEW JASS , BARLOW ASHLEY , LIM LEE-LING , SUASTIKA KETUT , YASAHARDJA YOSKA , CHAN SIEW PHENG , SOH ABEL , LI LEONARD S.W. , TAN ALEXANDER T. 
Published: June 2019

Introduction: DPN affects approximately 50% of diabetic individuals worldwide1. B Vits are used in DPN management although evidence supporting treatment outcomes vary.
Objective: Evaluate the evidence supporting B Vits usage in DPN.
Methods: Literature search: Medical Subject Headings and text words in Pubmed/EMBASE identified 226 clinical trials published between 1978 - Nov 2018. Using PRISMA guidelines, data was extracted from eligible studies and risk of bias assessed was assessed by 2 authors.
Main Results: Fifty-one studies involving 4621 patients were selected [40 RCTs (Placebo-controlled: 7; Active-control: 34) and 10 single-arm study]. Results from placebo-control studies involving daily B vitamin(vit) monotherapy [benfotiamine 300- 600mg OR methylcobalamin 1500μg (MC)] OR Superoxide Dismutase (SOD), Alpha Lipoic Acid (ALA), Acetyl L-Carnitine (AC) and Vit B12 combination showed significant improvement in neuropathy-related scores/symptoms vs. control. One study (150mg pyridoxine daily) showed no improvement in nerve conduction was noted vs. placebo. Vit B6 80mg + 800mg ALA/day showed no inflammatory marker improvement.
When Mono- or combination B Vits was compared to active controls[e.g.: micronutrients/herbs(ALA; ALC; Traditional Chinese Medicine), drugs (pregabalin; nortriptyline; venlafaxine) and lifestyle interventions (moxibustion; low-fat plant-based diet)], 29 studies showed improvements in DPN symptoms relative to control. Two studies showed less effectiveness compared to venlafaxine and cytidinie triphosphate. All single arm B Vit studies (IM MC 500μg 1/day OR 3/week OR benfotiamine/Vit B1/B12) showed improvement in nerve function.
Conclusion: B Vits had positive effect on neurophysiological symptoms and/or functions compared to baseline in 38 studies. RCTs evaluating the efficacy of B Vits in standardized combination/doses are limited. Further studies are required to elucidate optimum treatment combination/doses and duration.

Disclosure
J. Liew: None. A. Barlow: None. L. Lim: Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc. K. Suastika: None. Y. Yasahardja: None. S. Chan: None. A. Soh: None. L.S. Li: None. A.T. Tan: None.
2264-PUB: Status of Self-Monitoring of Blood Glucose and Its Influencing Factors among Patients with Diabetes in Shanghai
Authors: WEI LI , ZENG YUANYUAN , XIAO YUANYUAN , JI LINLIN , LIU MENGDAN 
Published: June 2019

Objective: To investigate the status of self-monitoring of blood glucose (SMBG) among patients with type 2 diabetes mellitus in Shanghai and analyze the factors affecting the frequency of SMBG.
Methods: A total of 987 Chinese subjects with type 2 diabetes mellitus aged 20 to 80 years old was included in the present study from August 2017 to December 2017. A standard questionnaire was completed. The frequency of SMBG and related factors of hyperglycemia were analyzed. The subjects were divided into two groups according to the frequency of SMBG. The relatively high frequency group (RHF) (more than twice a week) and the relatively low frequency group (RLF) (one and twice a week).
Results: Among all the subjects, 337 (34.2%) of them were in the RHF group, and 648 (65.8%) were in the RLF group. The number of patients who monitored blood glucose three times a day and more than three times a day was less (16 and 43, 1.6% and 4.4% respectively). Majority of patients adjusted their blood glucose levels through exercise (38.9%) and diet (38.1%), rather than drug (7.7%) after SMBG. Other methods (15.2%) were also used to alleviate hyperglycemia. Multivariate logistic regression analyses showed that age, duration of diabetic history, glycated hemoglobin, educational levels, insulin usage were factors influencing the frequency of SMBG in patients.
Conclusions: The current status of SMBG among diabetic patients in Shanghai is not optimistic, in which the frequency of SMBG is relatively low. It is of great importance to increase the frequency of SMBG in controlling blood glucose levels.

Disclosure
L. Wei: None. Y. Zeng: None. Y. Xiao: None. L. Ji: None. M. Liu: None.

Funding
National Natural Science Foundation of China (81570778)
2265-PUB: Education in T2D: What Else Can We Do to Improve Patients' Quality of Life?
Authors: MARTINS AMANDA , ABRÃO PAULA , SEGAWA JULIE , CAVALCANTI CATARINA , NITATORI MARCOS , CARIRI FRANCISCO ANDRE , BRITO ROBERTA , ABRUSIO FABIANA , LABA ISABELLA 
Published: June 2019

Brazil has more than 13 million people with diabetes, 4th place among top 10 countries for number of adults with diabetes. One of our main problems regarding T2D is lack of patients’ understanding about disease severity and its complications. Considering this, in 2017 we carried out a theater-experience for T2D education. There were 20 presentations for 1.400 patients all over the country, and a great result. Considering Brazil is huge and heterogeneous, in 2018 we decided to go beyond and listen what patients have to say, conducting Regional Patients Advisory Boards, so that we could understand the different scenarios of our 5 geographic regions and the main unmet needs, to design new effective educational programs for both patients and health care professionals. So, we had 5 meetings with patients from public and private health systems, and a local T2D leader conducting the discussion, to find out their journey, perceptions, treatment patterns and what is important for them. All patients and HCPs involved in this project were very impressed and satisfied with this action. Patients felt important and really the center of the discussion, and somebody was carrying about them. HCPs could learn a lot and think about what they are doing for patient’s education and to change this worrying scenario. Interestingly, they are now actively sharing this experience with other HCPs and spreading this way of bringing patients to the center of the decisions. The main Brazilian medical societies are interested in establishing partnerships to conduct educational and disease awareness actions. We have participated on the first T2D patients’ national conference, and have organized a big action in and also a symposium in 2 regions, impacting almost 2.000 people. Now we are preparing the next meetings addressing specific regional needs, also drafting a scientific manuscript for T2D awareness, and planning more actions together with medical societies to spread the importance of education for improving patients’ treatment and quality of life.

Disclosure
A. Martins: None. P. Abrão: None. J. Segawa: None. C. Cavalcanti: None. M. Nitatori: None. F.A. Cariri: None. R. Brito: None. F. Abrusio: None. I. Laba: Employee; Self; AstraZeneca.

Funding
AstraZeneca Brazil