bluuebunny/crossref_metadata_2025_split huggingface dataset:
32-LB: Variations of Sole Images on Hard and Soft Floors Are Useful in the Prediction of Diabetic Peripheral Neuropathy and Diabetic Foot Diseases
Authors: CHOU SHENGPU , HARAGUCHI MIKIKO , KOMORI HIROYA , WATANABE KOUHEI , TSUICHIHARA SATOKI , NAKAMURA SUNAO , TAKEMURA HIROSHI 
Published: June 2019

Background: Diabetic peripheral neuropathy (DPN) is one of the major risks to diabetic foot diseases (DFD). Currently, there are few quantitative methods to assess progression of DFD if no obvious ulcerations, microtraumas, and other skin lesions are presented. We investigated the differences of sole images (SI) on hard and soft floors in patients with or without diabetes and evaluated the availability to predict DPN and severity of DFD.
Material and Methods: We prospectively recruited 104 patients from December 2017 to December 2018. Both SI on hard and soft floors were taken by the specific device with a camera underneath and were analyzed according to total area, shape, distal and proximal variations and bilateral differences. Severity of DFD was defined and calculated according to classical neurological and hemodynamic assessments.
Results: SI variations were significantly increased in diabetic patients with DPN compared with those without DPN (p&lt;0.01). A weak but positive correlation was presented significantly between diabetes duration and SI variations (r=0.247, p&lt;0.05). Moreover, SI variations also showed positive correlation with severity of DFD (r=0.462, p&lt;0.001). The area under the ROC (receiver operating characteristic) curve of SI variations for diagnosing probable DPN was 0.722 with the optimal cut-off value of 0.591. The sensitivity, specificity was 67.9% and 72.9%, respectively. Logistic regression analysis showed that SI variation was a significant factor to predict DPN.
Conclusion: Variations of SI on hard and soft floors increase along with diabetes duration and have significantly positive correlation with severity of DFD. Because of good sensitivity and specificity for screening of DPN, this approach may be effective and useful in daily practice to diabetic patients.

Disclosure
S. Chou: None. M. Haraguchi: None. H. Komori: None. K. Watanabe: None. S. Tsuichihara: None. S. Nakamura: None. H. Takemura: None.
324-LB: A Novel Link between Mig6 and PP2a in Beta-Cell Apoptosis
Authors: REZAEIZADEH ALIREZA , BAUER BRANDON M. , FUEGER PATRICK T. 
Published: June 2019

Hyperglycemia in both type 1 and 2 diabetes is toxic to pancreatic beta cells and exacerbates the decline in functional beta cell mass in both diseases. Thus, identifying the molecular mechanism for how this glucotoxicity negatively impacts beta cells is essential for identifying new therapeutic targets to treat both forms of diabetes. We identified that EGF receptor feedback inhibitor Mig6 is induced in islets cultured in glucotoxic conditions and that Mig6 promotes apoptosis in beta cells. To define how the adaptor protein Mig6 promotes apoptosis, we sought to identify its interacting partners. Following immunoprecipitation of flag-tagged Mig6 in Ins1-derived 832/13 cells cultured in normal and toxic conditions, mass spectrometric analysis revealed protein phosphatase 2A (PP2A). PP2A controls many cellular functions ranging from metabolism, cell cycle, DNA replication, growth and apoptosis, and PP2A can be exploited by tumor cells to promote cell survival. Thus, we hypothesized Mig6 interacts with PP2A to regulate beta cell apoptosis. We cultured 832/13 cells and mouse islets in low (5 mM) or high glucose (HG, 20 mM) for up to 48h and validated that glucotoxicity increased methylation and decreased phosphorylation of PP2A (indicating activation). HG also increased expression of Mig6, CHOP (ER stress), γH2AX (DNA damage response), and cleaved caspase 3 (CC3; apoptosis). Compared to controls, siRNA-mediated suppression of Mig6 in 832/13 cells increased methylated PP2A and decreased γH2AX and CC3, suggesting Mig6 antagonizes beta cell survival. We generated mice lacking Mig6 in beta cells (Mig6βKO) by crossing Mig6-floxed mice (Mig6fl/fl) with RIP-Cre mice. Beta cell mass and glucose homeostasis were similar between Mig6βKO and control Mig6fl/fl littermates. Islets from Mig6βKO mice had increased methylated PP2A during HG compared to controls. We speculate the Mig6-PP2A interaction limits PP2A activation; hence, disrupting Mig6-PP2A or inhibiting Mig6 could promote compensatory beta cell survival by activating PP2A.

Disclosure
A. Rezaeizadeh: None. B.M. Bauer: None. P.T. Fueger: None.
332-LB: Mir-132 Controls Pancreatic Beta-Cell Proliferation and Survival through the Pten/Akt/Foxo3 Signaling
Authors: KERSTING STEPHAN , MZIAUT HASSAN 
Published: June 2019

Aim and Hypothesis: microRNAs (miRNAs) play an integral role in maintaining beta cell function and identity. We aimed to identify miRNAs and their downstream targets involved in regeneration of islet beta cells following partial pancreatectomy (pP) in mice.
Methods: RNA from laser capture microdissected islets of pP and sham-operated mice were profiled with microarrays to identify miRNAs implicated in control of beta cell regeneration. Altered expression of selected miRNAs, including miR-132, was verified by RT-PCR. Potential targets of miR-132 were selected through bioinformatic data mining. Predicted miR-132 targets were validated for their changed RNA and protein expression levels and signaling upon miR-132 knockdown and overexpression in mouse MIN6 cells and human EndoC-βH1 insulinoma cells. The ability of miR-132 to foster beta cell proliferation in vivo was further assessed in pP miR-132-/-and control mice.
Results: pP significantly increased the number of BrdU+/insulin+ positive islet cells. Microarray profiling revealed 14 miRNAs, including miR-132, to be significantly upregulated in LCM islets of partially pancreatectomized mice and confirmed by RT-PCR. Downregulation of miR-132 in MIN6 cells reduced proliferation while enhancing the levels of pro-apoptotic cleaved caspase-9. Microarray profiling, RT-PCR and immunoblotting revealed downregulated expression of Pten, with concomitant increased levels of pro-proliferative factors as well as inactivation of pro-apoptotic Foxo3. Overexpression of miR-132 in human insulinoma cells EndoC-βH1 validated the findings. In vivo regeneration of beta cells was reduced in pP miR-132-/- mice compared to control mice.
Conclusions: Our study provides compelling evidence for miR-132 being critical for regeneration of mouse islet beta cells in vivo through downregulation of its target Pten. Hence, the miR-132/Pten/Akt/Foxo3 signaling pathway may represent a suitable target to enhance beta cell regeneration.

Disclosure
S. Kersting: None. H. Mziaut: None.

Funding
German Center for Diabetes Research (to S.K.)
333-LB: Impact of Aging on Mitochondrial Respiratory Chain Expression and Pancreatic Islet Cell Composition by Using a Mitochondrial DNA Mutator Mouse Model
Authors: YU XUEFEI , ARDEN CATHERINE , CHEN CHUN , BRADSHAW CARLA , WHITEHALL JULIA , WHITE MICHAEL G. , ANDERSON SCOTT J. , SHAW JAMES A. , TURNBULL DOUG , GREAVES LAURA , WALKER MARK 
Published: June 2019

Introduction: Age-related cumulative mitochondrial mutations can cause mitochondrial dysfunction. The mitochondrial DNA mutator mouse (PolgAmut/mut) is a model of premature ageing and has been previously shown to develop impaired insulin secretion with age.
Methods: Immunofluorescence was used to study mitochondrial respiratory chain protein expression (complex I and IV) and the cell composition in islets. Experiments were conducted on pancreas tissue from PolgAmut/mut mice and age-matched wild type (WT) mice at two ages: 12 weeks (young) and 44 weeks (old).
Results: (1) Comparing young WT mice versus old WT mice, there was no difference in islet complex I expression, while islet size and beta cell number increased with age (both P&lt;0.01). (2) Comparing young PolgA mut/mut mice versus young WT mice, complex I expression was significantly lower (P&lt;0.01) in islets from young PolgA mut/mut mice. However, there were no significant differences in islet size and cell composition between young PolgA mut/mut and young WT mice. (3) Comparing old PolgA mut/mut mice versus old WT mice, complex I expression was significantly lower (P&lt;0.01) and complex IV expression was significantly higher (P&lt;0.01) in islets from the old PolgA mut/mut mice. Old PolgA mut/mut islets had a lower beta cell percentage (mean ± SEM; 71.8 ± 4 % vs. 89.3 ± 4% P&lt;0.01) but a higher alpha cell percentage (mean ± SEM; 29.6 ± 4 % vs. 12.5 ± 5%; P&lt;0.01) versus old WT mice (both P&lt;0.01).
Conclusions: In PolgA mut/mut mice, complex I deficiency was already present in the islets of young mice and persisted with age. This was associated with a proportional increase in alpha cells and decrease in beta cells in islets from old PolgA mut/mut versus the old WT mice. We conclude that complex I deficiency in PolgA mut/mut mice is linked to altered islet cell composition with increasing age.

Disclosure
X. Yu: None. C. Arden: None. C. Chen: None. C. Bradshaw: None. J. Whitehall: None. M.G. White: None. S.J. Anderson: None. J.A. Shaw: Advisory Panel; Self; Sanofi. Other Relationship; Self; Novo Nordisk A/S. D. Turnbull: None. L. Greaves: None. M. Walker: None.
334-LB: Dapagliflozin, a SGLT2 Inhibitor, Therapy Improves ß-Cell Function in Neonatal Diabetes by Reducing Oxidative and ER Stress, and Loss of ß-Cell Identity
Authors: YAN ZIHAN , SHYR ZEENAT A. , REMEDI MARIA S. 
Published: June 2019

Loss of pancreatic β-cell identity, rather than β-cell death, has been recently demonstrated in both neonatal and type-2 diabetes. However, the underlying mechanisms and temporal progression remains elusive. By using an insulin secretory-deficient KATP-GOF mouse model of human neonatal diabetes, we demonstrate normal insulin content at day 7 despite severe diabetes, but a dramatic decrease (55%) in content at day 15 of diabetes. Loss of content was accompanied by a marked increase in proinsulin protein, a striking increase in oxidative- and ER-stress markers such as ROS, TXNIP, sXBP1 and ATF6, distended ER and decreased number of insulin granules. These changes lead to later loss of β-cell identity and increased α-cell identity (ARX increased 50%), glucagon content and secretion. We hypothesized that lowering blood glucose alone will be sufficient to reverse this process and improve β-cell function. Therefore, diabetic KATP-GOF mice were treated with dapagliflozin (DAPA), a sodium-glucose transporter-2 (SGLT2) inhibitor clinically used to reduce blood glucose by preventing renal glucose reabsorption. As expected, DAPA therapy significantly reduced blood glucose without changing circulating insulin levels. Ten days DAPA therapy markedly improved insulin content, reduced proinsulin/insulin ratio and enhanced β-cell function by reducing oxidative and ER stress and preventing loss of β-cell identity. Together, we clearly demonstrate that loss of insulin content, increased oxidative and ER stress, and changes in calcium dynamics underlie later loss of β-cell identity in diabetes, and that these features can be prevented/reversed by normalization of blood glucose alone with SGLT2 inhibitors. From the therapeutic perspective, these results have important implications indicating that early alleviation of β-cell stress may prevent loss of β-cell mass and preserve islet-cell identity, architecture and function.

Disclosure
Z. Yan: None. Z.A. Shyr: None. M.S. Remedi: None.

Funding
National Institutes of Health (DK098584 to M.S.R.), (T32DK108742 to Z.A.S.)
335-LB: Towards Generating Spatiotemporal Multiscale Models of Pancreatic ß Cells
Authors: WHITE KATE L. , SINGLA JITIN , STEVENS RAYMOND C. 
Published: June 2019

To characterize biology, we must consider how molecular machines and organelles within a cell interact and traffic, similar to the importance of understanding traffic patterns in major cities. We use an imaging across scales approach to understand architectural changes that occur in pancreatic β-cells during insulin secretion. β-cells produce and release insulin in response to glucose and are therefore a target for diabetes therapies. Diabetes is a worldwide problem affecting hundreds of millions of people with increasing patient numbers every year. To acquire cellular architectural information, we are integrating data from cryo-electron tomography, soft x-ray tomography (SXT), and fluorescence microscopy. We used multiple glucose and GPCR agonist concentrations to investigate the cellular organization changes induced during insulin vesicle biogenesis and trafficking. The SXT method allows for investigating the 3D cellular architecture and is an ideal method for investigating cell-to-cell variabilities. Additionally, we are using machine learning methods for image analysis and autosegmentation which increased the number of conditions and samples we can analyze rapidly. Furthermore, we can use the information from cryo-ET and SXT along with with live cell imaging to assemble a data-driven, dynamic model of insulin granules within pancreatic β-cells. Furthermore, the SXT method provides a unique opportunity for comparing cell-to-cell heterogeneity and will be a useful technique for comparing differences between rodent and human primary cell architectures. The integration of data from different time and spatial scales represents a sophisticated convergence of our understanding of cellular structure and function, which will revolutionize biological discovery, open new dimensions of research, and accelerate advancements in healthcare.

Disclosure
K.L. White: None. J. Singla: None. R.C. Stevens: Board Member; Self; BirdRock Bio, Danaher Corp.

Funding
University of Southern California
337-OR: Injection Technique (IT) Training in Subjects Injecting into Lipohypertrophy (LH)—The Tianjin Randomized Controlled Trial (RCT)
Authors: CHEN LIMING , XING QIULING , LI JING , ZHOU JIANXIN , YUAN YI , XU HAIYAN , WAN YING , PFLUG BRIAN K. , STRAUSS KENNETH , HIRSCH LAURENCE 
Published: June 2019

Rationale: LH is a common local complication of insulin injection. We conducted a 6-month prospective RCT to assess effects of intensive IT training vs. usual care on HbA1c, TDD insulin, LH lesions, injection behavior and BG variability.
Methods: Adult subjects injecting into LH lesions were randomized to usual care (N=104), or intensive IT training (N=106): stop LH injections, lower TDD insulin 10-20%, properly rotate injections within and between sites, and reduce needle reuse. The 2 groups saw different study staff to avoid injection practice contamination in Controls.
Results: Subjects were well matched for (mean ± SD) insulin injection duration (7.0 ± 5.0 years); HbA1c (8.5 ± 1.1%); TDD insulin (46.2 ± 21.2 IU); LH lesion count (1.9 ± 0.4), strict correct site rotation (2.9%), and factors such as age, BMI, needle reuse (% and frequency), daily number and sites of injections. Subjects did not perform adequate SBGM to assess BG variability. Due to protocol non-adherence (not lowering TDD in initial IT subjects), and injection behavior contamination in 63 Controls, both ITT and Per Protocol (PP) results are shown.
Conclusion: Intensive IT training in subjects who inject into LH lesions can safely lower HbA1c even as TDD insulin is reduced. Conduct of LH RCTs with behavioral education is difficult for both investigators and subjects. Control contamination is likely multi-factorial.

Disclosure
L. Chen: Research Support; Self; Becton, Dickinson and Company. Q. Xing: Research Support; Self; Becton, Dickinson and Company. J. Li: Research Support; Self; Becton, Dickinson and Company. J. Zhou: Research Support; Self; Becton, Dickinson and Company. Y. Yuan: Employee; Self; Becton, Dickinson and Company. H. Xu: Employee; Self; Becton, Dickinson and Company. Y. Wan: Employee; Self; Becton, Dickinson and Company. B.K. Pflug: Employee; Self; Becton, Dickinson and Company. K. Strauss: Employee; Self; Becton, Dickinson and Company. L. Hirsch: Employee; Self; Becton, Dickinson and Company. Stock/Shareholder; Self; Merck & Co., Inc.

Funding
Becton, Dickinson and Company
338-OR: Leveraging the Project ECHO Model for Type 1 Diabetes (T1D) in California and Florida: Democratizing Knowledge in Underserved T1D Communities
Authors: CUTTRISS NICOLAS , ANEZ-ZABALA CLAUDIA , BAER LINDA G. , BERNIER ANGELINA , BASINA MARINA , FILIPP STEPHANIE L. , HOOD KOREY K. , GURKA MATTHEW J. , LAL RAYHAN , HALLER MICHAEL J. , MAAHS DAVID M. , HU HUI , TOWN MARISSA , SHEEHAN ELENI , WANG C. JASON , YABUT KATARINA , WALKER ASHBY F. ,   FOR THE ECHO T1D STUDY GROUP
Published: June 2019

T1D care for many patients in both the pediatric and adult populations in the U.S. falls on primary care providers (PCPs). Persistently suboptimal outcomes for people with T1D and a lack of access to subspecialty care mandates the development of innovative healthcare delivery models. Using the Project ECHO (Extension for Community Healthcare Outcomes) model, Stanford University and the University of Florida partnered to develop and pilot a “ECHO T1D” teleECHOTM clinic. The goal of the pilot was to demonstrate the feasibility of an ECHO model for T1D and improve the ability of PCPs to manage patients with T1D. Utilizing a “Hub-and-Spoke” model, we recruited and partnered with PCPs at non-specialty diabetes practices across Florida and California and held weekly hour teleECHO sessions consisting of didactic presentations and case reviews. Precision recruitment methods to target clinics in remote and medically underserved regions included: (1) geocoding to identify high-need areas, (2) claims data to identify PCPs treating T1D, (3) survey data from PCPs. The 18-month pilot program is ongoing and enrollment demonstrated extremely high interest amongst PCPs as the pilot program filled beyond capacity. In California, 11 Spoke sites enrolled with 37 clinics serving roughly 900 adult and pediatric patients with T1D who do not receive specialty T1D care. In Florida, 12 Spoke sites enrolled with 67 clinics who serve roughly 1,300 patients with T1D. PCPs and their clinic staff have become local experts in T1D, providing a more informed level of care for the many patients who lack access to endocrinologists. Project ECHO T1D is an innovative healthcare delivery model which appears capable of building capacity for diabetes management education in the medically underserved. Having demonstrated proof-of-concept for ECHO T1D, future efforts will focus on replicating the model and on designing studies to demonstrate improvements in patient level outcomes.

Disclosure
N. Cuttriss: None. C. Anez-Zabala: None. L.G. Baer: None. A. Bernier: None. M. Basina: None. S.L. Filipp: None. K.K. Hood: Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc. Speaker's Bureau; Self; Johnson & Johnson Diabetes Institute. M.J. Gurka: None. R. Lal: Consultant; Self; Abbott. M.J. Haller: Advisory Panel; Self; Pancreum, SAB Biotherapeutics. D.M. Maahs: Advisory Panel; Self; Novo Nordisk Inc. Consultant; Self; Abbott, Sanofi. Research Support; Self; Dexcom, Inc., Tandem Diabetes Care. H. Hu: None. M. Town: None. E. Sheehan: None. C. Wang: None. K. Yabut: None. A.F. Walker: None.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust
340-OR: Supports for Using Retail Pharmacists in Delivering Diabetes Education in Saudi Arabia
Authors: KHAN YASMIN , TURKISTANI SARAH , BAYOUMI ALY H. , MCNAMARA MAURA J. , LEBLANC JENNIFER , POBER DAVID M. , HSU WILLIAM C. 
Published: June 2019

The aim of this program evaluation was to assess the effectiveness of retail pharmacists in providing diabetes education in Saudi Arabia. Following an earlier pilot showing feasibility, the program was expanded to 50 community pharmacies. Joslin Diabetes Center collaborated with Nahdi Medical Company that operates a large network of retail pharmacy chains in Saudi Arabia to offer a diabetes program called “Let’s Talk About Diabetes” (LTAD). Pharmacists identified potential participants as having diabetes by the medication and supplies they purchased and then invited them to join the LTAD program. LTAD consists of four 1:1 educational sessions on topics such as medications, lab results, glucose monitoring, and doctor visits. Each session lasts approximately 20 minutes each, scheduled over a 2-4 month period. The entire program spanned approximately a 4-year period including the pilot. Among the 2066 participants who had paired results at baseline and follow-up, HbA1c improved from 8.5 ±1.6 to 7.6 ±1.5%. This change remained significant (p&lt;0.001) after adjustment for change in diabetes distress, age, gender, diabetes duration, insulin treatment, baseline awareness of HbA1c baseline HbA1c result, and number of sessions participated in. This change was associated with a shift in the proportion of individuals meeting target HbA1c &lt;7.0 from 22% at baseline to 37% at follow (p&lt;0.0001 by McNemar’s test). There were additional significant improvements in exercise, diet, medication adherence, and other diabetes self-care behaviors, attitudes and beliefs, suggesting that retail pharmacists were effective in delivering diabetes education programs in Saudi Arabia.

Disclosure
Y.Khan: None. S.Turkistani: Employee; Self; Nahdi Medical Company. A.H.Bayoumi: Employee; Self; Al Nahdi Pharmacy. M.J.Mcnamara: None. J.Leblanc: None. D.M.Pober: None. W.C.Hsu: Consultant; Self; Onduo LLC.
343-OR: Trends in A1C and Lipid Testing, Antilipid Therapy, and Target Attainment following First-Time Glucose-Lowering Drug Treatment in Type 2 Diabetes, Denmark, 2000-2017
Authors: KNUDSEN JAKOB S. , WITTE DANIEL R. , HULMAN ADAM , RØNN PERNILLE F. , LAURITZEN TORSTEN , SÔRENSEN HENRIK T. , THOMSEN REIMAR W. 
Published: June 2019

Objective: To examine 18-year trends in early A1C and lipid control among patients initiating first-time glucose-lowering drug therapy (GLD) for type 2 diabetes.
Materials and Methods: Population-based sequential cross-sectional study using healthcare databases covering Northern Denmark (∼1.8 million persons). For all 94,175 GLD initiators during 2000-2017, we examined likelihood of A1C and lipid testing, antilipid therapy, and 1-year glycemic and LDL cholesterol target achievement.
Results: The proportion of patients with at least one A1C test increased from 53% in 2000 to 95% in 2017 (Figure, Panel A). Lipid testing increased from 82% to 98% and lipid lowering therapy initiation quintupled from 12% to 61%. Mean pre-treatment A1C declined substantially, from 9.2% (77 mmol/mol) to 7.3% (56 mmol/mol) in 2011, then rose to 7.9% (63 mmol/mol) in 2017 (Panel B). Post-treatment A1C decreased less; pre- and post-treatment LDL cholesterol declined similarly. The proportion of patients achieving glycemic and cholesterol targets increased substantially over time (Panel C).
Conclusion: Monitoring and treatment of A1C and cholesterol in early type 2 diabetes have improved considerably over the past 18 years, while quality improvement was somewhat flat after the 2011 change in diagnostic criteria.

Disclosure
J.S. Knudsen: None. D.R. Witte: None. A. Hulman: None. P.F. Rønn: Research Support; Self; Amgen AB. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Lauritzen: Advisory Panel; Self; AstraZeneca. Board Member; Self; Novo Nordisk A/S. H.T. Sôrensen: None. R.W. Thomsen: None.

Funding
Aarhus University