bluuebunny/crossref_metadata_2025_split huggingface dataset:
1056-P: Characterization of Multi-timescale Biological Rhythms in Individuals with Type 1 Diabetes
Authors: LEWIS DANA M. , GRANT AZURE D. 
Published: June 2019

Background: Longitudinal biological rhythms in glucose and insulin outputs have not been mapped in individuals with T1D. Physiologically based, within-individual predictions of ultradian (UR), circadian (CR) or longer timescale changes in glucose and insulin are not currently possible, in part due to a lack of understanding of population heterogeneity. This is the first longitudinal analysis of biological rhythms in T1D, compared to non-T1D individuals.
Methods: Frequency decomposition using the continuous morlet wavelet transformation were created to assess change in rhythmic composition of normalized blood glucose data from 5 non-T1D individuals, and anonymized, retrospective CGM data from 19 T1D individuals using a DIY closed loop APS in the OpenAPS Data Commons.
Results: T1D individuals showed a wide range of rhythmic power at the circadian and long-period ultradian timescales compared to individuals without T1D. There is not much UR power lower than 6-hour periodicity, likely due to insulin DIA effects.
Conclusion: Such analysis of biological rhythms should be further studied across a broader T1D population, including both APS and non-users, and knowledge of the rhythms could be used for improving personalization and prediction capabilities of APS.

Disclosure
D.M. Lewis: Consultant; Self; Diabeloop SA, Roche Diabetes Care. A.D. Grant: None.
106-LB: Correlation between CGM-Derived Mean Glycemia and Measured Hemoglobin A1c in the Real World
Authors: ANGELLOTTI EDITH , MUPPAVARAPU SANGEETHA , SIEGEL RICHARD , PITTAS ANASTASSIOS G. 
Published: June 2019

Objective: Continuous glucose monitoring (CGM) has emerged as a key component of diabetes care but there are issues with data synthesis and application. A published regression equation converts CGM-derived mean glycemia into an estimate of laboratory-measured HbA1c, termed glucose management indicator (GMI). How the GMI formula defers by CGM device is not known. We compared the GMI derived from published formula vs. GMI derived from FreeStyle Libre specific regression equation.
Research Design and Methods: We conducted an observational study using EHR data from a single academic endocrinology practice (Tufts Medical Center, Boston, MA). We included data from patients with diabetes and a minimum of 10-days of sensor data collected with FreeStyle Libre Pro or Personal, immediately prior to measurement of HbA1c. We plotted HbA1c and Libre average glucose and derived a Libre specific regression equation. We compared the GMI derived from the published formula (GMIp) with the Libre-specific GMI (GMIL).
Results: Data were available from 59 patients (age 62 [range 22-90], 36% women, BMI 29 Kg/m2; 80% had type 2 diabetes; 70% had diabetes ≥10 years disease; HbA1c 8.1% (range 4.8-13.7). The mean number of days with CGM data was 28 (range 10-90). The Libre specific regression equation formula was GMI (%) = 5.04 + 0.0173*(mean glucose in mg/dL)]. Mean GMIp was 8.1% (SD 0.9) and mean GMIL was 7.6% (SD 1.3)(p=0.004).
Conclusion: The GMI derived from a device-specific regression equation differs from the published GMI. The development of a device specific GMI may be warranted.

Disclosure
E. Angellotti: None. S. Muppavarapu: None. R. Siegel: None. A.G. Pittas: None.
1066-P: Improvement in Time-in-Range (TIR) with Real-Life Use of Hybrid Closed-Loop System in Patients with Type 1 Diabetes (T1D)
Authors: AKTURK HALIS K. , GIORDANO DOMINIQUE A. , JOSEPH HAL , GARG SATISH K. , SNELL-BERGEON JANET K. 
Published: June 2019

Newer metrics like TIR are gaining momentum for measurement of glycemic control. The Medtronic 670G is the first commercial hybrid closed-loop (HCL) system for the management of T1D. We conducted a single-center retrospective chart review to compare continuous glucose monitor (CGM) metrics before and after initiation of 670G system in patients with T1D. Of 408 adult T1D patients who initiated 670G system during the study period, 139 patients were using an insulin pump with CGM for at least 3 months before the initiation of 670G system and had 6 months follow-up. Mean baseline age was 41±12, (60% women) with HbA1c of 7.6±0.9%. We analyzed the change in CGM data: % TIR (70-180 mg/dl), time-below-range (&lt;70 mg/dl) and time-above-ranges (&gt;180 mg/dl and &gt;250 mg/dl) at 3 and 6 months of 670G system use. Use of 670G system significantly increased TIR (p&lt;0.0001) and decreased time-below-range (p&lt;0.0001) and time-above-range (p&lt;0.0001) at 3 and 6 months compared to baseline (Figure). The mean percent time in auto-mode was 71% and 73% at 3 months and 6 months respectively. We conclude that HCL use in real-life significantly improves TIR and decreases hypo- and hyperglycemia.

Disclosure
H.K. Akturk: Advisory Panel; Self; Sanofi. Research Support; Self; Eli Lilly and Company, MannKind Corporation, REMD Biotherapeutics. Speaker's Bureau; Self; MannKind Corporation. D.A. Giordano: None. H. Joseph: None. S.K. Garg: Advisory Panel; Self; Eli Lilly and Company, Roche Pharma, Sanofi-Aventis, Zealand Pharma A/S. Research Support; Self; Eli Lilly and Company, WebMD. J.K. Snell-Bergeon: None.
107-OR: Profiling of Human Pancreatic Islets by Single Cell Transcriptomics Reveals α- and ß-Cell Subpopulations
Authors: SHRESTHA SHRISTI , SAUNDERS DIANE C. , WALKER JOHN T. , HALIYUR RACHANA , POFFENBERGER GREG , ARAMANDLA RADHIKA , JONES ANGELA , PRASAD NRIPESH , LEVY SHAWN E. , POWERS ALVIN C. , BRISSOVA MARCELA 
Published: June 2019

Single cell RNA-sequencing (scRNA-seq) approaches are continuously improving at the point of data collection and analysis to simultaneously profile all cell types within islet microorgans to better understand heterogeneity and phenotype-function relationships and how these change with aging and disease. To better understand the advantages and limitations of scRNA-seq, we used the ChromiumTMplatform to profile human islets with a robust insulin and glucagon secretion by perifusion (5 nondiabetic donors, ages 14-66 years) and compared these results to scRNA-seq analysis of purified α and β cells. In context of the same donor (n=2), purified α and β cells (using NTPDase3 marker) showed high correlation (r=0.99) with the Seurat-identified α and β subsets originating from dispersed whole islets. Based on the analysis of a very large pool of single cells (79,881 cells; 2316 genes/cell), the Seurat-guided analysis identified cell types that segregated into eight different clusters (17% β, 66% α, 4% δ, 4% ductal, 4% mesenchymal, 2% acinar, 2% endothelial, and 1% immune). Interstingly, in this large single cell context, we did not identify the four β cell subsets previously reported on the basis of alternative cell surface markers, but found a β cell cluster with highly expressed ER stress-associated genes and an α cell cluster with higher cell cycle regulation marker expression. We concurrently investigated expression of functionally important MAFA and MAFB genes, which are expressed only in a fraction of β cells by histological analysis, and found that PERK-mediated UPR transcripts were enriched in the MAFB-expressing β cells, while the MAFA-expressing β cells differentially expressed genes associated with β cell function. Overall, our study indicates high fidelity of α and β cell clustering in dispersed and sorted islet cells and points to a different pattern of β cell heterogeneity when β cells are purified using NTPDase3 expression compared to other cell surface markers.

Disclosure
S. Shrestha: None. D.C. Saunders: None. J.T. Walker: None. R. Haliyur: None. G. Poffenberger: None. R. Aramandla: None. A. Jones: None. N. Prasad: None. S.E. Levy: None. A.C. Powers: None. M. Brissova: None.
1075-P: Safety and Efficacy of Medtronic MiniMed 670G Hybrid Closed-Loop System in the Diabetes Camp Setting: Comparison of Auto Mode (AM) vs. Manual Mode (MM)
Authors: CHAN SOPHIA H. , CHANG ERICA W. , TANG JONATHAN K. , SCHMELTZ LOWELL 
Published: June 2019

Introduction: The Medtronic MiniMed 670G insulin pump is the first FDA approved commercial hybrid closed-loop system for pediatric patients with type 1 diabetes (T1D). Clinical trials have shown that the pump’s Auto Mode system effectively maintains blood glucose (BG) levels in target ranges for longer periods of time. Campers may have different insulin requirements than they are accustomed to at home due to the different foods and activity levels at camp. In this retrospective quality review, Medtronic MiniMed 670G pump data from campers attending 2018 ADA Camp MIDICHA were analyzed to investigate the safety and efficacy of campers in AM vs. MM.
Methods: We analyzed de-identified data from 34 campers (mean age 13.1 years [range 8-17]). There were 18 MM and 16 AM campers. BG levels, grams of carbohydrates consumed, and amount of insulin administered were recorded at every meal, evening snack, 12AM, and 2AM. The number of hypoglycemic events (&lt;70 mg/dL), hyperglycemic events (&gt;250 mg/dL), and events within the target BG range (70-250 mg/dL) were also noted.
Results: Our results showed improved glycemic control for campers in AM at breakfast (AM 166.56 mg/dL, MM 182.50 mg/dL), lunch (AM 156.08 mg/dL, MM 167.67 mg/dL), dinner (AM 191.83 mg/dL, MM 194.22 mg/dL), and evening snack (AM 164.13 mg/dL, MM 179.19 mg/dL). Average daily BG was lower for AM (AM 162.12 mg/dL, MM 173.54 mg/dL). The number of hypoglycemic events was 37 for AM and 38 for MM. The number of hyperglycemic events was 62 for AM and 80 for MM.
Discussion: Compared to MM, using the AM system allowed for a higher percentage of BG in the target range and decreased incidences of hypoglycemic and hyperglycemic events. This suggests that the AM system in the Medtronic MiniMed 670G insulin pump can safely and effectively maintain target BG levels for children with T1D in camp settings.

Disclosure
S.H. Chan: None. E.W. Chang: None. J.K. Tang: None. L. Schmeltz: Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc.
108-LB: Sustained Glucagon Effect on Blood Glucose and Improvements of Insulin Resistance Mediated by a Novel Long-Acting Glucagon Analog, HM15136, in Animal Models
Authors: CHOI JAEHYUK , LEE SEON MYEONG , KIM JUNG KUK , LEE JONGSOO , KIM YOUNG HOON , CHOI IN YOUNG 
Published: June 2019

HM15136 is a novel long-acting glucagon (GCG) analog conjugated with human IgG FC fragment via a short PEG linker. Previously, HM15136 treatment led to body weight loss (BWL) in obese animal models while showing transient effect on blood glucose (BG). Insulin resistance (IR) can lead to imbalances in BG homeostasis in obesity, representing a key risk factor for T2DM. Considering the potential benefit of BWL in IR improvement, HM15136 could be a novel therapeutic option for obesity treatment. To assess this concept, the present study evaluated the effect of HM15136 on BG as well as BW, and investigated the mechanism leading to IR improvement in vitro and in vivo. In DIO rats, 4 weeks treatment of HM15136 led to remarkable BWL (-17 ∼ -42% vs. Veh). BG monitoring showed that an initial BG elevation was rapidly normalized and maintained normal thereafter, with no HbA1c increase (3.4 and 3.7% for Veh and HM15136). Similar results were also observed in DIO mice, showing no abnormal glycemic control by HM15136. Interestingly, BWL effect were correlated with free-fatty acid (FFA) and HOMA-IR reduction. In vitro studies in 3T3-L1 adipocytes further confirmed the deteriorating effect of FFA on insulin signaling. These results suggested that improvements in the lipotoxic milieu explains, at least in part, the IR improvement seen with HM15136. To further explore additional mechanism, inflammatory markers and adipokines affecting insulin signaling were evaluated. HM15136 not only inhibited F4/80 expression, but also increased FGF-21 and adiponectin expression in white adipose tissue and 3T3-L1 adipocytes. Our results demonstrated that BWL under by HM15136 therapy is accompanied by the reduction of 1) lipotoxicity, 2) inflammatory biomarkers, and the expression of 3) insulin-sensitizing adipokines, eventually leading to IR reversal and normal BG maintenance. Human studies are needed to confirm whether these findings will translate into humans.

Disclosure
J. Choi: None. S. Lee: None. J. Kim: None. J. Lee: None. Y. Kim: None. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd.
108-OR: Inhibition of SerpinB13 Stimulates Beta-Cell Development via Notch Signaling Pathway
Authors: KRYVALAP YURY , HENDRICKSON COLE , CZYZYK JAN 
Published: June 2019

Methods for repopulating the pancreas with new insulin-producing cells have strong potential for therapy in diabetes. Recently, we have found that inhibition of serpinB13 - a protease inhibitor of cathepsin L (catL) - with mAb in mouse embryos leads to a robust increase in the number of pancreatic Ngn3+ progenitor cells, significant expansion of islet mass, and improved resistance to severe diabetes in adulthood. To unveil the molecular mechanism of the augmented Ngn3+ cell response following inhibition of serpinB13 during gestation, we focused on the Notch communication system - a critical signaling pathway for pancreatic development. We found that serpinB13 is expressed and secreted by epithelial cells in murine embryonic pancreases. Moreover, in vivo and in vitro inhibition of serpinB13 during embryogenesis caused protease-dependent cleavage of the extracellular domain of Notch1 receptor in the pancreas (p&lt;0.0001). This partial loss of the extracellular Notch was followed by decreased translocation to the nucleus of active Notch intracellular domain (aNICD), a fragment of Notch that is critical for restraining endocrine cell development. Finally, embryonic pancreases of mice with genetic deficiency of catL had significantly fewer Ngn3+ cells compared with wild type controls. Together, our data point to a novel function of serpinB13 in maintaining Notch receptor-mediated repression of pancreatic endocrine progenitors. Consequently, the perturbation of this effect of serpinB13 enables protease activity to partially dismantle Notch signaling, thereby allowing for more efficient development of Ngn3+ progenitors cells and a subsequent increase in islet mass.

Disclosure
Y. Kryvalap: None. C. Hendrickson: None. J. Czyzyk: None.

Funding
American Diabetes Association (1-17-ICTS-083 to J.C.)
1080-P: A Prospective, Multicenter, Randomized, Open-Label, Parallel-Group Clinical Trial Comparing Patient Satisfaction and Compliance with a Needle-Free Insulin Injector vs. Conventional Insulin Pen Injections in Chinese Patients with Type 2 Diabetes Mellitus
Authors: WANG YANGANG , JI LINONG , GUO LIXIN , RAN XINGWU , CHEN LIMING , MA ZHONGSHU , SUN ZILIN , SHAN ZHONGYAN , XU XIANGJIN , WANG GUIXIA 
Published: June 2019

Background: The proportion of patients with type 2 diabetes (T2DM) using insulin is still very low and often is initiated relatively late. The needle-free insulin injector is designed for diabetic patients who fear injections or are reluctant to initiate insulin therapy when it is clearly indicated.
Objective: To evaluate patient satisfaction and compliance with a needle-free insulin injector versus conventional insulin pen injections in patients with T2DM treated for 16 weeks.
Methods: A total of 427 patients with T2DM were enrolled in a multicenter, prospective, randomized, open-label study, and were randomized 1:1 to receive basal insulin or premixed insulin via a needle-free injector or via conventional insulin pen injections. Patients’ quality-of-life (determined by the SF-36 questionnaire), the insulin dose administered, compliance with insulin therapy (as evaluated by missing injections), and patients’ satisfaction with their injection device (scored on a scale of 0 to 10) were evaluated.
Results: In the 412 patients who completed the study, mean SF-36 questionnaire scores were increased significantly in both the needle-free injector and conventional insulin pen groups (123.21 ± 16.64 vs. 122.11 ± 16.82, respectively), with no significant difference between the 2 groups. There was also no significant difference between the groups in compliance. However, subjects in the needle-free injector group showed significantly higher treatment satisfaction scores than those in the conventional insulin pen group after 16 weeks of treatment (mean scores, 8.17 ± 1.78 vs. 7.21 ± 2.22, respectively; P &lt; 0.0001).
Conclusions: The needle-free injector improved the quality-of-life of T2DM patients and significantly enhanced their satisfaction with insulin treatment compared with conventional insulin pen injections.

Disclosure
Y. Wang: None. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi. L. Guo: None. X. Ran: None. L. Chen: Research Support; Self; Becton, Dickinson and Company. Z. Ma: None. Z. Sun: None. Z. Shan: None. X. Xu: None. G. Wang: None.
1085-P: Dance 501 Inhaled Human Insulin (INH): Linear Dose Response, Earlier Onset of Action, and Higher Early Effect than s.c. Insulin Lispro (LIS)
Authors: ZIJLSTRA ERIC , PLUM-MOERSCHEL LEONA , ERMER MARCEL , KLEIN OLIVER , PORTER LISA , BUECHE BLAINE , KUO MEI-CHANG , LE TRUC , STEDMAN BENJAMIN J. , PATTON JOHN S. 
Published: June 2019

Dance 501 is a novel liquid formulation of human insulin for inhalation with the Dance 501 inhaler. This randomized, cross-over trial investigated the pharmacodynamic (PD) action and safety of INH in its final formulation vs. LIS during 10-hour glucose clamps in non-smoking subjects with T2D. LIS was injected s.c. at low (12 U), medium (24 U) and high (48 U) doses, INH was inhaled at equivalent doses, assuming a 13% relative biopotency. Twenty-two subjects completed all 6 single dose administrations. INH and LIS demonstrated a linear dose-response relationship and comparable total PD action (AUC_GIR0-10h). Median relative biopotency of INH was 12.3 to 13.0%. PD profiles (Figure) show a more rapid onset of action for equivalent doses of INH vs. LIS (median differences 6.5 to 20 min, p&lt;0.02) and greater action in the first hour after administration (median differences 19.7 to 48.2 mg/kg, p&lt;0.05). No safety issues and no cough were observed with any inhalation. These results nicely confirm and extend to higher doses the results of a previous PK/PD study in type 2 patients with an earlier version of the Dance 501 device and formulation (Zijlstra et al. Diabetes 2015; 64(Suppl 1): A248).
In conclusion, Dance 501 showed favorable glucodynamic properties vs. LIS and excellent tolerability and may therefore become a clinically meaningful alternative to rapid-acting insulin injectables.

Disclosure
E. Zijlstra: Speaker's Bureau; Self; Novo Nordisk A/S. L. Plum-Moerschel: None. M. Ermer: None. O. Klein: None. L. Porter: Other Relationship; Self; Dance Biopharm Holdings Inc., Eiger BioPharmaceuticals. B. Bueche: Employee; Self; Dance Biopharm Holdings Inc. M. Kuo: Employee; Self; Dance Biopharm Holdings Inc. T. Le: None. B.J. Stedman: None. J.S. Patton: Other Relationship; Self; Dance Biopharm Holdings Inc.

Funding
Dance Biopharm Holdings Inc.
1086-P: Preclinical Development of an Ultralong-Acting Insulin for Once-Weekly Dosing
Authors: HOWARD VICTOR G. , CHURCH CHRISTOPHER D. , OLDHAM STEPHANIE , HORNIGOLD DAVID C. , TREVASKIS JAMES , BAKER DAVID , RHODES CHRISTOPHER J. , ROSSI ALESSANDRA , NAYLOR JACQUELINE , DHILLON JATINDER , BUCHANAN ANDREW , LIANG LIHUAN 
Published: June 2019

Basal insulin analogues have been designed to mimic endogenous insulin secretion for maintaining normoglycaemia. Current insulin therapy for type 2 diabetes (T2D) requires at least daily dosing for patients. However, such daily injections can have poor patient compliance. An insulin analogue with longer duration requiring less frequent administration could improve compliance and maintain better glycaemic control. To achieve extended insulin action pharmacology, a panel of recombinant native single chain (SC) insulin molecules, consisting of B chain to A chain-linker variants, were fused to an antibody fragment crystallizable region (Fc). Characterization of the single chain insulin-Fc (SC-Insulin-Fc) variants were conducted in insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) luminescence-linked reporter assays, and with primary rodent and human hepatocyte assays for phosphorylated AKT. SC-Insulin-Fc-1 and -2 retained potency at the human IR within 6-fold of human insulin, without specificity over IGF1R binding, and induced Akt phosphorylation within a range of endogenous insulin. SC-Insulin-Fc variants lowered blood glucose levels in DIO and db/db mice by more than 50% vs. vehicle controls (p&lt;0.05) for 5 days following a single dose, significantly superior to a standard insulin bolus. Continuous glucose monitoring (CGM) telemetry to profile 24 h control of blood glucose in diabetic ZDF rats was also applied. CGM telemetry revealed enhanced basal and postprandial glucose control in both light and dark cycles (p&lt;0.05 vs. vehicle) up to 10 days following a single administration (90 nmol/kg). Repeat dosing of SC-Insulin-Fc variants (10/30/60 nmol/kg, Q1W) over 5 weeks resulted in dose-dependent improvements of glycaemic control (p≤0.05 vs. vehicle) with a long term readout towards decreasing %HbA1c. This dramatic shift in time spent away from hyperglycaemia toward normoglycaemia suggests once-weekly insulin as a novel viable option to treat human T2D.

Disclosure
V.G. Howard: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. C.D. Church: Employee; Self; AstraZeneca, MedImmune. S. Oldham: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. D.C. Hornigold: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Trevaskis: Employee; Self; Gilead Sciences, Inc., MedImmune. Stock/Shareholder; Self; AstraZeneca. D. Baker: Stock/Shareholder; Self; AstraZeneca. C.J. Rhodes: Employee; Self; AstraZeneca, MedImmune. A. Rossi: Employee; Self; MedImmune. J. Naylor: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. J. Dhillon: Employee; Self; MedImmune. A. Buchanan: Employee; Self; MedImmune. L. Liang: None.