bluuebunny/crossref_metadata_2025_split huggingface dataset:
320-OR: Axonal Swellings in Diabetic Patients With and Without Neuropathy
Authors: KARLSSON PALL , GYLFADOTTIR SANDRA SIF , TESFAYE SOLOMON , RICE ANDREW S. , NYENGAARD JENS RANDEL , JENSEN TROELS S. , BENNETT DAVID , THEMISTOCLEOUS ANDREAS 
Published: June 2019

Background: Up to 50% of patients with diabetes develop peripheral neuropathy (DPN). DPN is associated with low intraepidermal nerve fiber density (IENFD), and morphometric degenerative changes such as axonal swellings are also observed. The relationship of swellings to DPN status has not yet been delineated.
Methods: In total 207 patients with type 2 diabetes and 24 age- and gender-matched healthy controls were included in the study. Included in the analysis were participants whose IENFD was &gt;0.5 fiber/mm, thus allowing swelling ratio calculation (n=156). The patients underwent a rigorous DPN assessment, including a neurological examination, nerve conduction studies, skin biopsy and quantitative sensory testing. Patients were divided into three groups: without DPN (n=35), with painless DPN (n=72), and with painful DPN (n=100). Axonal swellings were defined as enlargements on nerve fibers exceeding 1.5 μm in diameter. Swelling ratio was obtained by dividing the number of swellings with IENFD.
Results: Median (IQR) IENFD was significantly different between the groups: without DPN: 6.15 (4.9;8.08) fibers/mm; painless DPN: 1.65 (1.07;2.73); painful DPN: 1.4 (0.80;2.12); controls: 5.8 (4.95;8.0), P&lt;0.01. Median swelling ratios were also significantly different between groups: without DPN: 0.34 (0.16;0.55); painless DPN: 0.14 (0;0.55); painful DPN: 0 (0;0.31); and controls: 0 (0;0.6), p&lt;0.01. This difference disappeared when only including patients with somewhat preserved IENFD (IENFD &gt;2) (P=0.4). Patients with diabetes and IENFD &gt;2 had higher swelling ratio compared with healthy controls, regardless of neuropathy status (P&lt;0.01). Swelling ratio did not correlate with BMI, diabetes duration, pain or Toronto Clinical Neuropathy score (P&gt;0.1), but did correlate negatively with HbA1c levels when only including all patients with IENFD &gt;0.5 (P=0.04).
Conclusions: Axonal swellings are present in most diabetic patients with preserved IENFD and may indicate morphological changes of nerve fibers.

Disclosure
P. Karlsson: Advisory Panel; Self; Grünenthal. S. Gylfadottir: None. S. Tesfaye: Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation, WÖRWAG Pharma. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., NAPP Pharmaceuticals Limited, Neurometrix, Novo Nordisk Inc., Pfizer Inc. Other Relationship; Self; Impeto Medical. A.S. Rice: Research Support; Self; Orion. Other Relationship; Self; Imperial College Consultants, Spinifex/Novartis. J.R. Nyengaard: None. T.S. Jensen: None. D. Bennett: Consultant; Self; Lilly Diabetes, Orion, Theranexus. A. Themistocleous: None.

Funding
Novo Nordisk Foundation (NNF14OC0011633); Danish Diabetes Academy (to P.K.)
33-LB: Nuclear Factor Erythroid 2 Related Factor 2 (Nrf2) Increases with Hyperbaric Oxygen Therapy and Promotes Wound Healing in Diabetic Foot Ulcers
Authors: UMAPATHY DHAMODHARAN , VIKRAMAN POOJA , ALLADI VAISHNAVI , ARUMUGAM SOMASUNDAR , DORNADULA SIREESH , AMIN KARAN , KESAVAN RAJESH , MOHANRAN RAMKUMAR KUNKA 
Published: June 2019

Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic foot ulcer (DFU) treatment and has been demonstrated to have antimicrobial effect, increased angiogenesis and enhanced collagen synthesis. In the present study, we investigated the molecular mechanism underlying HBO therapy particularly the role of Nrf2 in wound healing process. In addition, we have studied the levels of angiogenic markers in ulcer tissues and their correlation with Nrf2 during HBO therapy compared with a standard therapy (Non-HBO) for DFU. A total of 32 patients (16 males and 16 females) were recruited and randomized to standard wound care alone (n=17) or HBO therapy in combination with standard wound care (n=15). Our results showed that the tissue levels of Nrf2 along with the downstream targets showed significant increase in patients who underwent HBO therapy. It induces angiogenesis with significantly increasing the levels of angiogenesis markers such as EGF, VEGF, PDGF, FGF-2 and CXCL10 in the tissue samples. The HIF-1α expression showed a 4.9-fold and eNOS with a 4.5-fold among HBO therapy when compared to Day 0 subjects. HBO therapy sensitize macrophages to release FGF-2 and EGF thereby promotes angiogenesis. Further it increased the levels of CXCL-8, which is a potent neutrophil attractant thereby promote the release chemokine CCL2, a well-known mediator of neovascularization. The Spearman’s correlation showed that Nrf2 have a positive correlation with EGF, VEGF, PDGF and HIF-1α.
In conclusion, the findings of the present study suggest that HBO therapy promote wound healing by increasing oxygen dispersion to damaged tissues, stimulating angiogenesis, alleviating inflammation, and increasing the levels of NO. It is evidenced that elevated Nrf2 transiently regulates angiogenic gene expression in wound biopsies, which may enhance chronic wound healing.

Disclosure
D. Umapathy: None. P. Vikraman: None. V. Alladi: None. S. Arumugam: None. S. Dornadula: None. K. Amin: None. R. Kesavan: None. R. Kunka Mohanran: None.
341-LB: Chronic ER Calcium Depletion Resulting from Sarcoendoplasmic Reticulum Ca2+ Atpase 2b (SERCA2b) Deficiency Leads to Impaired Proinsulin Processing in the Pancreatic ß Cell
Authors: IIDA HITOSHI , KONO TATSUYOSHI , TONG XIN , LINDBERG IRIS , EVANS-MOLINA CARMELLA 
Published: June 2019

Reductions in pancreatic β cell endoplasmic reticulum (ER) Ca2+ levels are associated with the development of ER stress and impaired proinsulin processing in both type 1 and type 2 diabetes. The SERCA pump transports Ca2+ into the ER lumen in order to maintain a steep Ca2+ gradient between the ER and cytosol. SERCA2 activity and expression are reduced in diabetes, however, the relationship between SERCA2 and proinsulin processing remains incompletely understood. To this end, we developed mice with β cell specific deletion of SERCA2 (βS2KO mice) and S2KO INS1 cells. βS2KO mice exhibited glucose intolerance and reduced insulin secretion in response to glucose without evidence of impaired insulin sensitivity. Islets from βS2KO mice had significantly reduced ER Ca2+ levels and impaired glucose-induced Ca2+ oscillations, while serum proinsulin/insulin (PI/I) ratios and whole pancreas PI/I content were elevated. Immunoblot analysis of βS2KO islets and S2KO INS-1 cells revealed reduced total levels of the proinsulin processing enzymes, PC1/3, PC2 and CPE, and increased levels of proPC2. Restoration of SERCA2b via adenoviral transduction in S2KO INS1 cells was sufficient to restore PC1/3 and PC2 maturation and enzyme activity. Brefeldin A treatment in INS1 cells recapitulated the impairments in PC1/3 and PC2 maturation observed in S2KO INS1 cells, suggesting a disturbance in protein trafficking between the ER and Golgi. Trafficking assays were next performed using a vesicular stomatitis virus G (VSVG) protein construct and revealed a significantly slower rate of VSVG movement from the ER to the Golgi in S2KO INS1 cells. Taken together, these data indicate that loss of SERCA2 activity and impairments in ER Ca2+ lead to reduced proinsulin processing via altered protein trafficking through the β cell secretory pathway.

Disclosure
H. Iida: None. T. Kono: None. X. Tong: None. I. Lindberg: None. C. Evans-Molina: None.
343-LB: The Type 2 Diabetes-Associated Lipid Binding Protein STARD10 Controls Insulin Secretory Granule Biogenesis
Authors: CARRAT GAELLE , HAYTHORNE ELIZABETH , HAATAJA LEENA , ARVAN PETER , TOMAS ALEJANDRA , PIUNTI ALEXANDRA , PULLEN TIMOTHY J. , GEORGIADOU ELENI , STYLIANIDES THEODOROS , SALEM VICTORIA , DISTASO WALTER , CAKEBREAD ANDREW , HODSON DAVID , FUNG ANNIE C. , SESSIONS RICHARD B. , ALPY FABIEN , KONG ALICE P. , LECLERC ISABELLE , RUTTER GUY A. 
Published: June 2019

Aim: Risk alleles for type 2 diabetes (T2D) in the STARD10 locus, impair insulin secretion and are associated with decreased proinsulin:insulin ratios. We have shown that the T2D risk associated with variation at this locus is likely to be mediated through lowered STARD10 expression in the β cell. Here, we investigate the mechanisms by which STARD10 may regulate insulin secretion.
Materials and Methods: A 3-dimensional model of STARD10 was constructed from the structure of STARD2, using the modelling tools Chimera and Modeller. Islets were isolated from StarD10fl/fl-Ins1Cre male mice (βStarD10KO). Electron Microscopy (EM) images were obtained from isolated islets after chemical fixation. Total zinc content was measured by inductively coupled plasma mass spectrometry. Pulse-chase analysis of proinsulin processing was performed using 35S-labelled amino acids. RNA-Seq was done on polyadenylated transcripts selected during the preparation of paired-end, directional RNAseq libraries, sequenced on an Illumina HiSeq 4000 machine.
Results: Molecular modelling indicated that STARD10 binds either phosphatidylcholine or phosphatidylethanolamine. EM analysis of islets from βStarD10KO mice revealed a markedly altered dense core granule appearance, with a dramatic increase (Fold change = 4.3; p&lt;0.001) in "rod like" dense cores, and a ∼2-fold increase in total islet zinc content. Unexpectedly, pulse-chase studies revealed enhanced basal secretion of newly-synthesised proinsulin from βStarD10KO islets. Whilst RNA sequencing identified several dysregulated genes in βStarD10KO islets, STARD10 deletion did not affect prohormone convertase (Pcsk1, Pcsk2), or ZnT8 (Slc30a8) expression.
Conclusion: We identify STARD10 as a critical regulator of insulin granule biogenesis and β cell zinc homeostasis. Our data also suggest that increased β cell Zn2+ secretion in risk allele carriers may decrease the clearance of mature insulin to lower plasma proinsulin:insulin ratio.

Disclosure
G. Carrat: None. E. Haythorne: None. L. Haataja: None. P. Arvan: None. A. Tomas: None. A. Piunti: None. T.J. Pullen: None. E. Georgiadou: None. T. Stylianides: None. V. Salem: None. W. Distaso: None. A. Cakebread: None. D. Hodson: None. A.C. Fung: None. R.B. Sessions: None. F. Alpy: None. A.P. Kong: Advisory Panel; Self; Lilly Diabetes. Research Support; Self; AstraZeneca, Lilly Diabetes. Speaker's Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. I. Leclerc: None. G.A. Rutter: Consultant; Self; Sun Pharma.

Funding
Medical Research Council UK; UK Wellcome Trust; Royal Society; Societe Francophone du Diabete
379-P: Changes in Diabetes Management after a Hospital Visit for Severe Hypoglycemia
Authors: VIJAYAKUMAR PAVITHRA , LIU SHULING , KAHN PETER A. , MCCOY ROZALINA G. , KARTER ANDREW J. , LIPSKA KASIA J. 
Published: June 2019

Clinical guidelines recommend reevaluation of glucose-lowering medications and relaxation of HbA1c targets in patients with diabetes after a severe hypoglycemic event. We compared diabetes management before and after hypoglycemia requiring emergency department (ED) visit or hospital admission.
Using data from OptumLabs® Data Warehouse, we identified privately insured and Medicare Advantage enrollees 18+ years with pharmacologically-treated type 2 diabetes and an ED visit or hospitalization for hypoglycemia between July 1, 2013 and June 30, 2014. We assessed the differences in the number of physician office visits, glucometer test strips filled, continuous glucose monitor (CGM) use, diabetes medication fills, and HbA1c levels (available for 1582 [27.7%]), within 6 months prior to and 6 months after hypoglycemia.
Among 5721 patients with type 2 diabetes and severe hypoglycemia, mean age was 67.8 (SD 12.3), 51% women, 63% white, and 68% used insulin. Changes in management are summarized in Table 1. After an event, the proportion of patients filling insulin increased, but the proportion filling sulfonylureas declined. Less than one third of patients with a baseline HbA1c &lt;7% had a substantially higher post-event HbA1c.
Few of the recommended changes in diabetes management occur after a severe hypoglycemic event. These findings suggest the need for better post-event care to improve the safety of glucose-lowering therapy.

Disclosure
P. Vijayakumar: None. S. Liu: None. P.A. Kahn: None. R.G. McCoy: None. A.J. Karter: None. K.J. Lipska: Consultant; Self; Health Services Advisory Group (HSAG). Research Support; Self; National Institute on Aging. Other Relationship; Self; Centers for Medicare and Medicaid Services.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (T35DK104689); National Institute on Aging; American Federation for Aging Research; National Institutes of Health (K23AG048359)
384-P: An Integrated Summary of Safety and Efficacy of a Ready-to-Use Liquid Glucagon Rescue Pen for the Treatment of Severe Hypoglycemia in Adults
Authors: CHRISTIANSEN MARK P. , CUMMINS MARTIN J. , PRESTRELSKI STEVEN J. , JUNAIDI MOHAMMED K. 
Published: June 2019

Objective: To prevent medical complications of severe hypoglycemic emergencies, prompt and reliable rescue intervention is critically important. A ready-to-use stable liquid Glucagon Rescue Pen (GRP; Xeris Pharmaceuticals) auto-injector was evaluated for the rescue treatment of severe hypoglycemia.
Method: Two Phase 3 randomized, controlled, blinded, crossover studies were conducted in 161 adults with T1D to compare 1 mg doses of GRP versus Glucagon Emergency Kit (GEK; Eli Lilly) for the treatment of insulin-induced severe hypoglycemia. Efficacy was evaluated as either a return of plasma glucose (PG) to &gt;70 mg/dL or increase in PG ≥20 mg/dL from a baseline PG &lt;50 mg/dL, within 30 min of dosing.
Result: Subjects treated with GRP (98.7%) achieved successful PG recovery within 30 minutes, and (99.4%) had a PG &gt; 70 mg/dL or neuroglycopenic symptom relief within 30 minutes, both comparable to GEK. From glucagon dosing, the mean time to achieve PG &gt;70 mg/dL or increase in PG ≥20 mg/dL was 13.8±5.6 min for GRP and 10.0±3.6 min for GEK. This mean time does not account for the significantly shorter (p&lt;0.0001) drug preparation and administration time for GRP (27.3±19.7 seconds) vs. GEK (97.2±45.1 seconds). The GRP was similar to GEK in terms of glucose Cmax, Tmax, and AUC(0-90min). The overall incidence of treatment emergent adverse events (TEAEs) was comparable in both groups; the most commonly reported TEAEs were nausea (GRP 29.9%, GEK 22.9%) and vomiting (GRP 16.1%, GEK 9.6%). One SAE was reported in these studies (GEK).
Conclusion: A ready-to-use, easy two-step administration GRP achieved plasma glucose recovery reliably, was therapeutically equivalent to GEK, and had an incidence of nausea and vomiting comparable to GEK. There was a significant difference in drug preparation time in favor of the GRP. These results demonstrate that GRP is an effective, safe, and well tolerated rescue treatment for severe hypoglycemia and is a viable alternative to GEK.

Disclosure
M.P. Christiansen: Research Support; Self; Abbott, Biolinq, Dexcom, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk A/S, Sanofi-Aventis, Xeris Pharmaceuticals, Inc. M.J. Cummins: Employee; Self; Xeris Pharmaceuticals, Inc. S.J. Prestrelski: Employee; Self; Xeris Pharmaceuticals, Inc. M.K. Junaidi: None.
39-LB: Individualised Screening for Diabetic Retinopathy: The ISDR Study—A Randomised Controlled Trial of Safety, Efficacy, and Cost-Effectiveness
Authors: BROADBENT DEBORAH MARY , WANG AMU , CHEYNE CHRISTOPHER P. , LATHE JAMES G. , STRATTON IRENE M. , VORA JITEN , GARCIA-FINANA MARTA , JAMES MARILYN , HARDING SIMON P. 
Published: June 2019

Background: Varying the intervals in retinopathy screening informed by personal risk offers reallocation of resources to better target high risk groups and address the increasing prevalence of diabetes. However, safety data especially on extended intervals is minimal.
Aim: To evaluate the safety, efficacy and cost effectiveness (CE) of individualized variable-interval risk-based screening in a population setting compared to usual care.
Methods: Masked 2 arm, parallel assignment, equivalence RCT (largest to date in screening) with independent trials unit monitoring in people with diabetes aged ≥12 years attending screening in a single English program. Randomization was 1:1 to individualized screening (active group; 6, 12 or 24 months for high, medium and low risk) determined by a risk calculation engine using real-time local demographic, retinal and clinical data, compared with annual screening (control). CE analysis measuring NHS and societal costs took a 2-year time horizon.
Findings: 4534 participants entered the study - after withdrawals/loss to follow-up: active 2097; control 2224. Attendance rates at first follow-up visit (primary outcome, safety) were equivalent (per protocol analysis, 5% margin): active 83.6% control 84.7% (difference 1.0, 90% CI -0.8, 2.9). STDR detection rates were non-inferior (1.5% margin): active 1.43% control 1.71% (difference -0.28, CI -0.93, 0.36). Quality of life (EQ5D5L, HUI3) was not significantly different between the groups. Incremental cost saving per person was £18.75 (NHS cost) rising to £49.96 with societal costs. A 39.3% reduction in number of appointments was seen.
Conclusions: All parties involved in diabetes care can be reassured that extended and personalized screening intervals can safely be introduced in established screening program. Scale-up with further validation outside a research setting is recommended. Views expressed are solely those of the authors.

Disclosure
D.M. Broadbent: None. A. Wang: None. C.P. Cheyne: None. J.G. Lathe: None. I.M. Stratton: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Bayer AG, Boehringer Ingelheim International GmbH. J. Vora: None. M. Garcia-Finana: None. M. James: None. S.P. Harding: None.

Funding
UK National Institute for Health Research
395-P: Hypoglycemia and Cardiovascular Outcomes among Older Adults: The Atherosclerosis Risk in Communities Study
Authors: ECHOUFFO TCHEUGUI JUSTIN B. , DAYA NATALIE R. , LEE ALEXANDRA K. , TANG OLIVE , WINDHAM B. GWEN , SHAH AMIL , SELVIN ELIZABETH 
Published: June 2019

Background: There is limited community-based data on the association of hypoglycemia with cardiovascular events among older individuals, who are particularly susceptible to hypoglycemia.
Methods: We conducted a prospective cohort analysis of adults with diabetes aged ≥70 years from the Atherosclerosis Risk in Communities (ARIC) Study (baseline visit 5, 2011-2013). History of severe hypoglycemia was defined using first position ICD-9 codes from prior hospitalizations, emergency department visits, and ambulance calls through June 1, 2011. We evaluated the rate of cardiovascular events (myocardial infarction, fatal coronary heart disease, stroke or heart failure) and mortality (follow-up through December 31, 2017), using negative binomial and Cox proportional hazards regression models.
Results: Among 2,194 participants with diabetes (mean age: 75 years [SD: 5], 57% female, 32% blacks), 79 had a history of severe hypoglycemia. During a median follow-up of 5.4 years, a history of severe hypoglycemia was strongly associated with cardiovascular disease (incident and recurrent) and death (Table).
Conclusions: Our findings suggest potential cardiovascular benefits of severe hypoglycemia prevention among older individuals and provide strong evidence for relaxing the targets of blood glucose control among older individuals.

Disclosure
J.B. Echouffo Tcheugui: None. N.R. Daya: None. O. Tang: None. B. Windham: None. A. Shah: Advisory Panel; Self; Philips Ultrasound. Consultant; Self; Bellerophon. Other Relationship; Self; Novartis Pharmaceuticals Corporation. E. Selvin: None.
398-P: Prediction of Five-Year Severe Hypoglycemia Risk in Adult Patients with Type 2 Diabetes
Authors: KO SEUNG-HYUN , YUN JAE-SEUNG , HAN KYUNGDO , KWON HYUK-SANG , SONG KI-HO , AHN YU-BAE 
Published: June 2019

Objective: There is a scarcity of long-term prediction models for severe hypoglycemia (SH) in subjects with type 2 diabetes. A model was developed and validated to predict the risk of SH in adult patients with type 2 diabetes (T2DM).
Research Design and Methods: Baseline and follow-up data from patients with T2DM who received health evaluations from January 1, 2009, to December 31, 2010 (n = 1,676,885), were analyzed as development (n = 1,173,820) and validation (n = 503,065) cohorts using the National Health Insurance Database (DB) in Korea. New SH episodes were identified using ICD-10 codes until December 31, 2015. A Cox proportional hazards regression model and Cox model coefficients were used to derive a risk scoring system, and 14 predictive variables were selected. A risk score nomogram based on the risk prediction model was created to estimate the five-year risk of SH.
Results: In the development cohort, a total of 34,955 (2.98%) patients experienced SH episodes during the follow-up period of 5.7 years (5.22/1,000 person-years). After multivariable adjustment, older age, being female sex, being a current smoker, drinking, having a low body mass index, lack of exercise, previous SH events, insulin or multiple oral hypoglycemic agent use, presence of hypertension or chronic kidney disease, longer duration of diabetes, low or high glucose level, and high Charlson Comorbidity Index score were found to be significant risk factors for the development of SH and were incorporated into the risk model. The concordance indices were 0.822 (95% confidence interval, 0.81-0.83). In patients in the top decile, the incidence rate of SH was estimated to be 25.6/1,000 person-years. The calibration plot showed a nearly 45° line, which indicates that this model is a good predictor of an absolute SH event.
Conclusion: This 14-variable prediction model for SH events may be a useful tool to identify high-risk patients and guide prevention of SH in adult patients with T2DM.

Disclosure
S. Ko: None. J. Yun: None. K. Han: None. H. Kwon: None. K. Song: None. Y. Ahn: None.