bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of Islet-Infiltrating Lymphocytes in Type 1 Diabetes
Authors: FELTON JAMIE L. , BONAMI RACHEL H. , HULBERT CHRYS , THOMAS JAMES W. 
Published: June 2018

Type 1 diabetes (T1D) results in the immune-mediated destruction of insulin-producing beta cells in the pancreas. As such, immune intervention to prevent or delay T1D is an appealing therapeutic approach. Development of an antigen-specific intervention that targets the diabetogenic immune response without compromising systemic immunity is complicated by an expanding list of antigenic targets, including post-translationally modified peptides generated at the site of autoimmune attack in the islet. Thus, development of effective antigen-based therapy requires not only antigen identification, but also understanding of the unique antigen processing environment facilitated by the islet itself. Recently, cellular metabolism has emerged as a potent modulator of immune cell function. However, the metabolic state lymphocytic infiltrate in the islet, termed insulitis, is not known. Given the highly vascularized nature of the islet needed to accommodate the metabolic demand associated with insulin secretion, we sought to characterize the islet’s distinct metabolic environment and its influence on T-B cell interactions at the site of autoimmune attack. Using a transgenic mouse model that develops accelerated diabetes (VH125SD.NOD), we assessed the metabolic signature of islet-infiltrating lymphocytes compared to those in the spleen and pancreatic lymph nodes. We determined that islet-infiltrating lymphocytes are characterized by decreased glucose uptake in CD4 and CD8 T cell subsets. Mitochondrial mass and polarity were decreased in all subsets compared to secondary lymphoid organs, suggesting reduced metabolic fitness. These studies reveal a metabolic distinction between islet-infiltrating and secondary lymphoid organ lymphocytes and suggest that metabolic features that differentiate immune cells at the site of autoimmune attack are a potential target for selective therapeutic interventions in T1D.

Disclosure
J.L. Felton: None. R.H. Bonami: None. C. Hulbert: None. J.W. Thomas: None.
A Collaborative Approach to Health Promotion Targeting People with Mental Illness at Risk of Diabetes—A Process Evaluation
Authors: HEMPLER NANA F. , LEVISEN VINIE H. , PALS REGITZE S. , KROGH NAJA RAMSKOV , LAURSEN RIKKE H. 
Published: June 2018

People with mental illness (users) have a notable higher risk of developing type 2 diabetes than the general population. Recent studies show that traditional lifestyle interventions focusing solely on exercise and diet targeting users have small effect. Studies suggest that collaborative approaches as a starting point for health behavior change is more beneficial, but implementation into practice is a challenge. Using the Medical Research Council’s guidance for process evaluation, we explored implementation of a collaborative approach in health promotion activities targeting users at risk of diabetes. The collaborative approach focused on involvement of users in the agenda setting and reflection about readiness to change health behavior and was supported by dialogue tools (e.g., quotes and games), developed in collaboration with users. Educators received three days of training in applying the approach. Collected data included questionnaires for users (n=154) and educators (n=158), interviews with users (n=14) and educators (n=10) and observations of health activities (n=37). Data were analyzed using descriptive statistics and systematic text condensation. The majority of educators tested the approach in their practice and tried at least one tool (96%). Users expressed that the approach supported them in expressing their thoughts regarding their health and directed focus on their needs rather than the agenda of the educator. Most users strongly agreed that educators were open-minded and responsive (93%). However, observations showed that some educators overlooked cues from users regarding motivation for health behavior change. Furthermore, educators pointed to lack of involvement from their managers as a barrier for implementation. Implementation of a collaborative approach was feasible in practice. However, training of educators in active listening and involvement of managers prior to implementation should be prioritized further.

Disclosure
N.F. Hempler: None. V.H. Levisen: None. R.S. Pals: None. N. Ramskov Krogh: None. R.H. Laursen: None.
Effectiveness and Tolerability of Vildagliptin plus Metformin Compared with Other Oral Dual Antidiabetes Agents in Patients with Type 2 Diabetes—A Real-World Study (China PDS)
Authors: HAN YING , CHEN LIXIAN , HU DAQING , JIN HUI , YANG NAILONG , SHI XIAOYUN , LI QUANMIN , LIANG LINLANG , ZANG LI , LIU MINGMING , HE JAMES , MU YIMING 
Published: June 2018

Background and Aims: This real-world study aimed to assess the effectiveness and safety of vildagliptin plus metformin (VM) vs. other oral dual antidiabetes agents (OD) in type 2 diabetes mellitus (T2DM) patients in China.
Materials and Methods: This prospective, 1-year, real-world study was conducted in 52 sites in patients inadequately controlled by monotherapy. Eligible patients were assigned either vildagliptin dual therapy or other OD according to local physician’s decision. The primary outcome was the proportion of patients with HbA1c&lt;7%, without tolerability events (hypoglycemia, weight gain, or discontinuation due to gastrointestinal event) at 12th month. Secondary outcomes included subgroup analysis and tolerability.
Results: Totally 604 patients received VM and 670 patients received OD. After propensity score-matched, baseline HbA1c and BMI were similar in both groups. After 12-month treatment, 55.4% patients in VM and 36.2% in OD reached primary outcome (P&lt;0.001; OR, 1.88; 95% CI 1.47-2.40). In all subgroups, VM significantly benefited the primary outcome (Figure 1). Numerically, less tolerability events occurred in VM vs. OD (5.8% vs. 14.8%).
Conclusion: China PDS demonstrates that in a real-life setting, vildagliptin plus metformin is effective in glycemic control and is well tolerated.

Disclosure
Y. Han: None. L. Chen: None. D. Hu: None. H. Jin: None. N. Yang: None. X. Shi: None. Q. Li: None. L. Liang: None. L. Zang: None. M. Liu: None. J. He: None. Y. Mu: None.
Predictors of Preferences for Use of MK-1293 Pens among Patients with Diabetes—Findings from a Multinational Study in the U.S., Canada, and U.K.
Authors: ALEMAYEHU BERHANU , NGUYEN ALLISON M. , DIBONAVENTURA MARCO , SHAH-MANEK BIJAL , KARKI CHITRA , CRUTCHLOW MICHAEL 
Published: June 2018

This study examines the predictors of preferences of pen devices used with originator insulin glargine and MK-1293, a recently approved biosimilar insulin glargine (referred to as “Pen X”), among patients with diabetes. Adult patients with type 1/type 2 diabetes were recruited from commercial panels in the U.S., Canada, and the UK for one hour study visits. Respondents rated several attributes of each pen along with overall preferences for each of the two insulin pens. Non-inferiority analyses were conducted to compare ratings of the originator insulin glargine pen with Pen X. Logistic regression modeling was conducted to identify predictors of overall preference. A total of N=177 patients completed the study: mean age of 53.2 years, 56% males, with 73% type 2 diabetes. Overall, 63.2% preferred Pen X, 22.3% preferred originator insulin glargine pen and 14.5% had no preference. Except for employment, demographics were not significantly associated with overall preference, however the ease of pushing the injection button, instruction booklet and overall quality of the pen were predictive of an overall preference of Pen X (Table 1).The current study suggests that &gt;60% of patients preferred Pen X and that overall, functional use and individual pen characteristics were the strongest predictors of preference, after adjusting for other pen characteristics.

Disclosure
B. Alemayehu: Employee; Self; Merck & Co., Inc. A.M. Nguyen: Employee; Self; Merck & Co., Inc. M. DiBonaventura: Employee; Self; Pfizer Inc.. Consultant; Self; Merck & Co., Inc.. B. Shah-Manek: None. C. Karki: None. M. Crutchlow: Employee; Self; Merck & Co., Inc.. Consultant; Spouse/Partner; Novo Nordisk Inc., Zealand Pharma A/S, XOMA Corporation.
Clinical Outcomes of Patients with Type 2 Diabetes Treated with Multiple Daily Injection (MDI) of Insulin—A Retrospective Cohort Analysis
Authors: LUDDEN THOMAS , ERMAKOVA ANASTASIA , XIONG YAN , SIERADZAN RAY , SACKS NAOMI C. , CYR PHILIP L. , PHILLIPS SHAY , TAYLOR STEPHANIE D. 
Published: June 2018

Objective: We retrospectively analyzed clinical outcomes in type 2 diabetes mellitus (T2DM) multiple daily injections (MDI) insulin therapy patients compared with non-MDI insulin therapy patients. MDI was defined as patients having at least one basal and one prandial/bolus insulin prescription during a one year period starting October 2015.
Methods: We compared a cohort of patients with an ICD-10 code of E11, 18 years of age and older, not pregnant, with a minimum of one office visit between October 2015 and April 2016. Data such as HbA1c, LDL, Body Mass Index (BMI), cardiovascular and renal disease were pooled from one hospital EMR system in the southeastern United States for MDI (n=11742) and non-MDI (n=56025) patients. T-tests were conducted.
Results: All mean differences were significant (p&lt;0.001). Overall, the average patient population in the MDI group was 2.4 years younger with a slightly larger proportion of female gender in the MDI group. Patients in the MDI group had an average HbA1c of 8.3% (SD=1.9) vs. 7.2% (SD=1.4) in the non-MDI group, but average proportion of patients with glycemic control (HbA1c &lt;7%) was 23.9% vs. 54.8% respectively. The rate of cardiovascular disease in the MDI group was 37.8% vs. 21.8% in the non-MDI group. The rates of renal disease in the MDI group at 30.8% far exceeded the rates in the non-MDI group at 13.5%. Average BMI of 33.9 kg/m2 (SD=8.4) in the MDI group was greater than the non-MDI group at 32.9 kg/m2 (SD=8.6). The percentage of patients with blood pressure less than 140/90 mmHg was 78.3% in the MDI group vs. 81.4% in the non-MDI group, but the average LDL was 87.4 mg/dL (SD=37.4) vs. 88.7 mg/dL (SD=32.2) respectively.
Conclusion: These results suggest MDI insulin therapy patients have poorer glycemic control and greater rates of macro and micro vascular complications compared with non-MDI insulin therapy patients within a large healthcare system.

Disclosure
T. Ludden: None. A. Ermakova: Employee; Self; Becton, Dickinson and Company. Y. Xiong: Employee; Self; Becton, Dickinson and Company. R. Sieradzan: Employee; Self; Becton, Dickinson and Company. N.C. Sacks: Consultant; Self; Becton, Dickinson and Company. P.L. Cyr: Consultant; Self; Becton, Dickinson and Company. S. Phillips: None. S.D. Taylor: Employee; Self; Becton, Dickinson and Company.
Quality of Life in Patients Treated with Insulin Pump Compared with MDI in Croatia
Authors: BILIC-CURCIC INES , VUKOJEVIC VALENTINA , GRADISER MARINA , BERKOVIC MAJA CIGROVSKI 
Published: June 2018

Introduction: The aim of this study was to investigate parameters of glycemic control (HbA1c and incidence of hypoglycemia), and quality of life in patients treated with insulin pump compared to those treated with multiple daily injections (MDI).
Methods: Out of 104 diabetes type 1 patients included in the study, 52 were treated with an insulin pump and the other 52 were treated with MDI. All participants filled out questionnaires containing sociodemographic data, data related to their disease, quality of life (WHOQoL-BREF) and depression and anxiety questionnaires.
Results: Average age of patients was 26 years (interquartile range 22 to 35 years) without difference between groups. Patients treated with insulin pumps compared to those treated with MDI were more likely to visit diabetologist, majority of them were regularly counting carbohydrate units, however frequency of ketoacidosis was increased (p &lt;0.01 for all). Patients treated with MDI had higher level of HbA1c and were more likely to experience hypoglycemia. Also, insulin pump group of patients had significantly lower values ​​of HbA1c and decreased number of hypoglycemia after initiating pump therapy (p &lt;0.01 for all). Both groups of patients controlled glycemia on average 3-5 times per day, most common complication was glycemic variability which was also the most common reason for initiating pump therapy while majority considered insulin pump treatment more advantageous compared to MDI. Insulin pump treated patients had better quality of life (p &lt;0.01) including physical health, mental health and environmental parameters. Regarding depression and anxiety there were no differences between groups.
Conclusion: Our results are supporting the fact that the insulin pump therapy is one of the most successful diabetes treatments today which not only improves glycemic control but also significantly affects the quality of life. This fact should encourage authorities to provide greater access to insulin pump treatment for type 1 diabetes patients.

Disclosure
I. Bilic-Curcic: None. V. Vukojevic: None. M. Gradiser: None. M. Cigrovski Berkovic: None.
Maternal Diabetes Induces Congenital Heart Defects by Suppressing Mitochondrial Fusion through the miR-140 Mitofusin 1 Circuit
Authors: CHEN XI , SHEN WEI-BIN , YANG PEIXIN 
Published: June 2018

Pregestational maternal diabetes is a significant risk factor for congenital heart defects (CHDs) in the offspring. Increased apoptosis is implicated in CHD formation, yet the underlying mechanism is still unclear. Mitochondrial fusion and fission dynamics play a key role in the regulation of cell viability. Embryonic cardiomyocytes exposed to maternal diabetes display impaired fusion and enhanced fission, suggesting that maternal diabetes represses mitofusion gene expression. Here, we demonstrated that maternal diabetes in vivo and high glucose in vitro significantly increased microRNA-140 (miR140) expression whereas down-regulated its putative target gene Mitofusin 1 (Mfn1) expression in cardiomyocytes. We found that miR140 bound to the 3’ untranslated region of Mfn1 mRNA, leading to Mfn1 mRNA degradation. A miR140 mimic induced mitochondrial fragmentation, Mfn1 reduction and cell apoptosis, whereas a miR-140 inhibitor abrogated high glucose-repressed Mfn1 expression and mitochondrial fusion. Deletion of the miR140 gene in vivo reversed diabetes-suppressed Mfn1 expression, restored mitochondrial fusion, blocked cardiac cell apoptosis leading to a significant reduction of CHDs in diabetic pregnancy. Analysis of the miR-140 gene promoter revealed several putative binding sites of the transcription factor, c-Jun, which is downstream of JNK2. Deletion of the Jnk2 (c-Jun NH2-terminal kinase 2) gene using the JNK2-/- mice mimicked the effect of miR-140 deficiency in suppressing diabetes-induced CHDs. JNK2 deletion abolished the increase of miR-140 and restored Mnf1 expression and mitochondrial fusion. Our findings support the hypothesis that the JNK2-miR140-Mfn1 circuit is critically involved in maternal diabetes-induced mitochondrial fusion impairment and CHD formation.

Disclosure
X. Chen: None. W. Shen: None. P. Yang: None.
The Study on the Clinical Efficacy of Insulin Degludec/Insulin Aspart (IDegAsp)
Authors: KUSAMA MINORU 
Published: June 2018

Aim: Insulin degludec and aspart (IDegAsp) is the first soluble insulin preparation to combine two different types of insulin analogs in one pen. However, there are few reports describing the long-term use of IDegAsp in clinical practice.
Method: 140 outpatients received IDegAsp during the period between Feb 2016 and Dec 2017 and were retrospectively analyzed for HbA1c, body weight, and units of insulin used (mean follow-up period, 8.2 months). Also, a questionnaire survey was conducted 3 months after the introduction of IDegAsp, to assess patient satisfaction (Q1, device usability; Q2, glycemic control; Q3, frequency of hypoglycemia; Q4, formulation not requiring suspension procedure). The subjects were 69 men and 71 women with a mean age of 64 years, HbA1c of 8.8 %, and body weight of 59.0 kg. Treatment before IDegAsp introduction included no previous insulin therapy (group A) in 46 patients, once daily injection of long-acting insulin in 28 patients, twice daily injection of premixed insulin in 20 patients, once daily injection of premixed insulin in 13 patients, and intensive insulin therapy in 33 patients.
Results: The changes in HbA1c after the introduction of IDegAsp in the subjects overall were 8.1% (1 month [M]), and 7.3% (6 M), showing significant improvement as compared with the values before introduction. The body weights were 57.5 kg (1 M), and 57.6 kg (6 M), showing no significant changes. The changes in HbA1c, according to prior treatment, were 10.3% (0 M), 8.7% (1 M), and 7.0% (6 M) in group A, with each value showing significant improvement as compared with the baseline. In the patient survey on the use of IDegAsp, the percentages of patients responding "very good" or "good" to Q1, Q2, Q3, and Q4 were 31%, 85%, 91%, and 43%, respectively.
Discussion: The introduction of IDegAsp consistently improved glucose metabolism. Also, the patient questionnaire showed mostly favorable results with use of IDegAsp. We plan to conduct a further study and report the results including a detailed assessment of each group.

Disclosure
M. Kusama: None.
Therapy Optimization with Once Daily Glargine Gla-300–Based Therapy in Patients Insufficiently Controlled on Premixed Insulins or Twice Daily Basal Regimens—Real-Life Data
Authors: KOMEL JANA , FABCIC DEJAN , VUKELIC KATARINA 
Published: June 2018

Introduction: In Slovenia, as in many Central Europe countries, there is a high share of patients with T2D treated with human basal and premixed insulins. Many of them are often sub optimally controlled. One barrier to the achievement of optimal glycaemic control is the risk of hypoglycaemia, a common side effect of insulin therapy. Gla-300 is a new formulation of insulin glargine delivering the same amount of insulin as insulin glargine 100 units/mL (Gla-100) in a 1/3 volume. Pharmacokinetic and pharmacodynamic action profiles of Gla-300 are more constant and prolonged compared with Gla-100, due to a more gradual and extended release of glargine from the subcutaneous depot which allows continued blood glucose control beyond 24 hours.
Study Design: We performed a retrospective, observational study. We have obtained data from medical charts of T2D and T1D patients, who initiated Gla-300 in the period from May 1st, 2016 to June 1st, 2017. The primary objective was to evaluate a real-life efficacy of once daily Gla-300 basal insulin therapy in patients insufficiently controlled on premixed insulins or twice- daily basal regimens, defined as the mean change in HbA1c value 3 or 6 months after the switch. The secondary objective was relationship between the occurrence of hypoglycaemia before and after the switch.
Results: Data from 107 patients on Gla-300 have been analysed. Switching to insulin Gla-300 significantly reduced HbA1c (∆ -1.0%, p=0.000), FPG (∆ - 1.7mmol/l, p=0.000) and PPG (∆ -2.8mmol/l, p=0.000). More patients achieved target HbA1c concentrations (≤ 7%) after the switch to Gla-300 (8.4% before vs. 32% after the switch). 90.2% of subjects reported reduced number of hypoglycaemic events after switching to Gla-300.
Conclusion: Switching to insulin Gla-300 proved to be safe and effective for patients with both, T1D and T2D.

Disclosure
J. Komel: Research Support; Self; Novo Nordisk Inc.. Other Relationship; Self; Sanofi, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. D. Fabcic: None. K. Vukelic: None.
Survivin from Flk1+ Endothelial Progenitor Cells in the Developing Embryo Ameliorates Maternal Diabetes–Induced Neural Tube Defects through Exosome
Authors: CAO SONGYING , SHEN WEI-BIN , YANG PEIXIN 
Published: June 2018

Neural tube defects (NTDs) are among the most common and severe structural birth defects and maternal diabetes induces NTDs. During mouse embryonic development, blood vessel formation initially occurs in the yolk sac, preceding neurulation which takes place from embryonic day 8 (E8) to E10.5. Our previous studies have demonstrated that maternal diabetes induces embryonic vasculopathy at early embryonic developmental stage. We hypothesize that early vasculopathy accounts for late failed neural tube closure in diabetic pregnancy. To test this hypothesis, we created the Flk1 promoter driven survivin (the cell cycle-regulated apoptosis inhibitor) transgenic mice. Maternal diabetes induced the loss of Flk1+ progenitors, impaired blood island formation and reduced blood vessel densities. Expression of survivin in the Flk1+ progenitors ameliorated diabetes-induced NTDs. Under nondiabetic conditions, survivin overexpression did not affect embryonic development. Overexpression of survivin significantly reduced diabetes-induced NTDs. Flk1+ progenitors produced survivin-containing exosomes. Immunocytochemistry staining indicated that survivin-containing exosomes were transported and incorporated into cells of the developing neuroepithelium, leading to blockage of neuroepithelial cell apoptosis induced by maternal diabetes. Furthermore, we isolated exosomes from Flk1+ progenitors derived from E7.5 embryos. In utero delivery of the survivin-containing exosomes by microinjection into the amniotic cavity of diabetic mice at E9 significantly inhibited maternal diabetes-induced neuroepithelial cell apoptosis and reduced NTDs. Taken together, these data revealed that the cross-talk between the extra-embryonic structures and the developing neuroepithelium through the survivin-containing exosome plays a critical role for the proper neural tube closure.

Disclosure
S. Cao: None. W. Shen: None. P. Yang: None.