bluuebunny/crossref_metadata_2025_split huggingface dataset:
1013-P: Effect of Upper Gastrointestinal Disease on the Pharmacokinetics of Oral Semaglutide in Subjects with Type 2 Diabetes
Authors: MEIER JURIS J. , GRANHALL CHARLOTTE , HOEVELMANN ULRIKE , NAVARRIA ANDREA , PLUM-MOERSCHEL LEONA , RAMESH CHETHANA , TANNAPFEL ANDREA , KAPITZA CHRISTOPH 
Published: June 2019

The GLP-1 analog semaglutide has been co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) to allow oral administration. Since oral semaglutide is absorbed in the stomach, the effect of upper gastrointestinal disease (UGD) on exposure to oral semaglutide has been investigated in an open-label, parallel-group trial (NCT02877355). Subjects aged 18-80 years with T2D and with UGD (N=36; chronic gastritis [n=5], gastroesophageal reflux disease [GERD; n=8] or both [n=23]) or without UGD (N=19) received oral semaglutide 3 mg once-daily for 5 days followed by 7 mg for 5 days. Key endpoints were area under the semaglutide plasma concentration-time curve (AUC) (primary) and maximum semaglutide plasma concentration (Cmax) from 0-24 h after the 10th dose. Semaglutide exposure was not statistically significantly different in subjects with vs. without UGD (Figure; estimated group ratios with/without UGD [95% CI] AUC: 1.18 [0.80; 1.75]and Cmax: 1.16 [0.77; 1.76]). Time to maximum plasma concentration and half-life of semaglutide were similar in subjects with vs. without UGD. Oral semaglutide was well tolerated. All adverse events (AEs) were mild or moderate with no withdrawals due to AEs.
In conclusion, no significant difference in exposure to oral semaglutide in subjects with vs. without UGD was found; hence, no dose adjustment is expected to be required.

Disclosure
J.J. Meier: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. C. Granhall: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. U. Hoevelmann: None. A. Navarria: Employee; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Novo Nordisk A/S. L. Plum-Moerschel: None. C. Ramesh: None. A. Tannapfel: None. C. Kapitza: Research Support; Self; ADOCIA, Biocon, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Mylan, Nestlé, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi-Aventis, Wockhardt, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S.

Funding
Novo Nordisk A/S
1021-P: Liraglutide Improves Periodontitis by the Anti-inflammatory Activities of GLP-1
Authors: SAWADA NORITAKA , NARUSE KEIKO , MATSUBARA TATSUAKI , NAKAMURA NOBUHISA , MIYABE MEGUMI , ITO MIZUHO , SUZUKI YUKI , ADACHI KEI , KOBAYASHI SHUICHIRO , KIKUCHI TAKESHI , MITANI AKIO , TORIUMI TAKU , MIZUTANI MAKOTO , HONDA MASAKI 
Published: June 2019

Periodontal disease which consists of gingivitis and periodontitis is one of the diabetic complications due to the high prevalence and the severity. Periodontitis is a chronic inflammation by the infection of Gram-negative bacteria in the periodontal pocket, following the destruction of periodontal tissue. On the other hand, many researches have shown extrapancreatic functions of glucagon-like peptide-1 (GLP-1), including the anti-inflammatory action and the suppression of indirectly bone resorption. In this study, we focused on the therapeutic effects of GLP-1 on periodontitis. Experimental periodontitis was induced by placing a nylon thread ligatureat the cervical portion of the maxillary second molar in Sprague-Dawley rats. Half of the rats were administered GLP-1 receptor agonist, Liraglutide (0.4mg/kg/day). Two weeks after the ligation, periodontitis was evaluated by histological examinations (H-E staining and the immunostaining) and mRNA expressions of inflammatory cytokines. Alveolar bone loss was evaluated by the distance at maximal bone resorption site from cement-enamel junction (CEJ) to the alveolar bone crest, and the bone micro-architecture parameters, using micro-CT and analytical software. We also investigated the anti-inflammatory effects of GLP-1 on monocytes using THP-1 cells. The mRNA expressions of TNF-α, iNOS and Mac1 in gingiva and alveolar bone resorption were significantly increased in the periodontitis rats. Liraglutide significantly suppressed the periodontitis-related inflammatory cytokine expressions and alveolar bone resorption. The part of the bone micro-architecture parameters in periodontitis rats deteriorate, which was not affected by Liraglutide. In vitro study revealed that GLP-1 significantly inhibited lipopolysaccharide-induced TNF-α mRNA expression in THP-1 cells in a dose-dependent manner.
In conclusion, GLP-1 may be effective in the treatment of periodontal disease mainly through the suppression of gingival inflammation.

Disclosure
N. Sawada: None. K. Naruse: None. T. Matsubara: None. N. Nakamura: None. M. Miyabe: None. M. Ito: None. Y. Suzuki: None. K. Adachi: None. S. Kobayashi: None. T. Kikuchi: None. A. Mitani: None. T. Toriumi: None. M. Mizutani: None. M. Honda: None.
103-LB: Intergenerational Improvements of Continuous Glucose Monitoring Systems in Youth
Authors: PUHR SARAH , CALHOUN PETER , WELSH JOHN , WALKER TOMAS C. , PRICE DAVID A. 
Published: June 2019

Standard methods and metrics to describe the accuracy of continuous glucose monitoring (CGM) systems in children and adolescents are subject to change. We reanalyzed data from youth ages 6-17 from clinical trials evaluating G4 PLATINUM (NCT01667185), G5 Mobile (NCT02280577), and G6 (NCT02880267) CGM systems (all from Dexcom, Inc., San Diego, CA). Subjects participated in 1-2 clinic sessions of varying duration, depending on their age, throughout the 7-day wear of G4 and G5 and 10-day wear of G6 for comparison of CGM values with temporally matched YSI measurements. Reference measurements were obtained every 15±5 minutes and paired with the CGM measurement that immediately followed (within 5 minutes). Percent accuracy was defined as the proportion of CGM values within ±20% of paired YSI values for CGM values &gt;100 mg/dL or within ±20 mg/dL of paired YSI values for CGM values ≤100 mg/dL. Accuracy was also evaluated using the mean absolute difference (MAD) and mean absolute relative difference (MARD) between CGM and YSI pairs, as well as the proportion of pairs in Clarke Error Grid (CEG) Zone A. Accuracy improved dramatically from G4 to G6, regardless of the metric evaluated (Table). Improved device performance may drive increased uptake and adherence, especially among children and adolescents.

Disclosure
S. Puhr: Employee; Self; Dexcom, Inc. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. J. Welsh: Employee; Self; Dexcom, Inc. T.C. Walker: Employee; Self; Dexcom, Inc. D.A. Price: Employee; Self; Dexcom, Inc. Stock/Shareholder; Self; Johnson & Johnson.
104-LB: Post-Market Surveillance of 18 Blood Glucose Monitoring Systems’ Accuracy Based on ISO 15197:2013
Authors: PLEUS STEFAN , BAUMSTARK ANNETTE , JENDRIKE NINA R. , MENDE JOCHEN , HAUG CORNELIA , FRECKMANN GUIDO 
Published: June 2019

High quality blood glucose monitoring systems are required for adequate self-monitoring of blood glucose (SMBG). In this study, system accuracy of 18 current-generation SMBG systems from different manufacturers was evaluated based on the international standard ISO 15197:2013 with 1 lot each against 2 comparison methods. Manufacturers were selected by their respective market share in Europe.
Each lot was tested on 100 capillary blood samples from different subjects and compliance with accuracy criterion A stipulated in ISO 15197 (at least 95% of results within ±15% or ±15 mg/dL of the comparison method’s results for BG concentrations above or below 100 mg/dL, respectively) was assessed. Glucose oxidase (GOD) and hexokinase (HK) were used as comparison methods (GOD: YSI 2300 STAT Plus, YSI Incorporated, OH, U.S.A.; HK: Cobas Integra® 400 plus, Roche Instrument Center, Switzerland).
In total, 14 of 18 systems had ≥95% of results within ±15% or ±15 mg/dL of the result obtained with the respective manufacturer’s measurement method. Individual systems showed 89 to 100% of results within these limits. Results within ±10% or ±10 mg/dL of the respective comparison method results ranged from 71 to 99.5% with 3 systems showing ≥95% of results within these more stringent limits.
In this evaluation, 14 out of 18 systems met the minimum system accuracy criterion A of ISO 15197 with the tested lot. Although only current-generation systems available on the market were used, more than 20% of systems did not meet ISO 15197 accuracy criteria.

Disclosure
S. Pleus: None. A. Baumstark: None. N.R. Jendrike: None. J. Mende: None. C. Haug: None. G. Freckmann: Advisory Panel; Self; Abbott, Novo Nordisk Pharma GmbH, Sensile Medical AG. Consultant; Self; Metronom Health Europe, Roche Diabetes Care, Sanofi. Speaker’s Bureau; Self; Ascensia Diabetes Care, Dexcom, Inc., Ypsomed AG.

Funding
AgaMatrix Europe Limited; Ascensia Diabetes Care GmbH; Beurer GmbH: i-SENS GmbH; LifeScan Scotland Limited; Roche Diabetes Care GmbH
104-OR: Glucoregulatory Effects of Hypothalamic Glucocorticoid Action In Vivo
Authors: BEAULIEU-BAYNE EMILIE , CARDOSO MIGUEL , KIM HYEJUN , YANG SHULING , YUE JESSICA T. 
Published: June 2019

Diabetes is characterized by dysregulated glucose homeostasis that leads to hyperglycemia, due in part to increased hepatic glucose production (GP) and insulin resistance. Excessive levels and/or action of glucocorticoids (GCs) are associated with obesity, insulin resistance, and hyperglycemia. We aim to delineate a mechanism of GC action in the mediobasal hypothalamus (MBH) that modulates GP in normal and pre-obese rodents.
Male SD rats underwent stereotaxic MBH bilateral cannulation and intravenous (iv) and intraarterial catheterization to enable simultaneous direct infusions into the MBH, iv infusions, and blood sampling, respectively. Mildly hyperinsulinemic-euglycemic clamps with tracer dilution methodology combined with MBH GC infusion ± GC receptor (GR) inhibition enables measurement of GP and utilization while assessing MBH GC interaction with its MBH receptors independent of changes in plasma insulin, glucagon, and glucose levels.
MBH GC infusion potently stimulates GP and lowers the requirement for exogenous glucose infusion without altering glucose utilization. This effect is mediated via GRs since co-infusion of GR antagonist mifepristone, or a HSP90 inhibitor, negates the ability of MBH GCs to increase GP. MBH GCs similarly increased glucose excursions during iv glucose tolerance tests, which was reversed with concomitant MBH mifepristone infusion. Rats fed with high fat diet (HFD) for 3 days had altered glucose kinetics and increased basal plasma corticosterone, insulin, and blood glucose levels without changes in body weight. Chronic MBH GR inhibition with MBH GR shRNA lowered GP compared to MBH mismatch control HFD rats with MBH vehicle infusions, suggesting that blocking excessive MBH GC action resulting from HFD-feeding attenuates GP to improve glucose homeostasis.
We provide novel evidence that MBH GC action modulates GP in healthy and pre-obese rats. Importantly, targeted inhibition of MBH GC action may help improve glucose regulation in obesity-related metabolic disease.

Disclosure
E. Beaulieu-Bayne: None. M. Cardoso: None. H. Kim: None. S. Yang: None. J.T. Yue: None.

Funding
Diabetes Canada; Natural Sciences and Engineering Research Council of Canada; Alberta Diabetes Institute; Canadian Institutes of Health Research
1064-P: Use of Temporary Target during the MiniMed™ 670G System Pivotal Trials
Authors: SHIN JOHN , CHEN XIAOXIAO , CORDERO TONI L. , LEE SCOTT W. , KAUFMAN FRANCINE R. 
Published: June 2019

Background: The MiniMed™ 670G system targets glucose levels to 120mg/dL (6.7mmol/L) and has a temporary target (TT) of 150mg/dL (8.3mmol/L) that can be set from 2-12 hours. An exploratory analysis of glycemic outcomes and TT use during the 3-month MiniMed™ 670G system pivotal trials was conducted.
Methods: Data from 151 children (n=46, 2-6 years and n=105, 7-13 years) and 124 adolescents and adults (n=30, 14-21 years and n=94, 22-75 years) during 2-week Manual Mode use (run-in), followed by 3-month Auto Mode use (study), were analyzed by percentage of TT use.
Results: The median (IQR) of TT use for those 2-6 years was 4.1% (0.6-16.3%); for 7-13 years was 0.4% (0-2.1%) and ≥14 years was 0.4% (0-1.2%). Glycemic outcomes for the 2-6 years are shown by percentage of TT use (&lt;4% or ≥4%). A trend in baseline data show that the ≥4% group had less hypoglycemia (3.0% vs. 4.3%) and more hyperglycemia (44.9% vs. 36.8%), suggesting preemptive hypoglycemia avoidance.
Conclusions: Improved glycemia was observed in the 2-6 years group regardless of TT use during study phase, compared to baseline run-in. The higher glucose target was used more often in the youngest cohort, suggesting the TT feature is important for young children with T1D using automated insulin delivery.

Disclosure
J. Shin: Employee; Self; Medtronic. X. Chen: None. T.L. Cordero: Employee; Self; Medtronic. S.W. Lee: Employee; Self; Medtronic. F.R. Kaufman: Employee; Self; Medtronic.
1065-P: The Effect of a Closed-Loop Insulin Delivery System on Glycemic Control in Type 1 Diabetes
Authors: KOUTSOVASILIS ANASTASIOS , SOTIROPOULOS ALEXIOS , ANTONIOU ANASTASIA , KORDINAS VASILIOS , PAPADAKI DESPINA , PEPPAS THEODOROS 
Published: June 2019

Background: Using a software, which creates a closed loop between the pump and the monitoring glucose sensor is considered to be a progress in controlling and using insulin pumps in type 1 diabetes patients (T1DM). OpenAPS is a system which completes and closes the pump-glucose sensor loop.
Aim: The aim of this study is to examine the effect of an independent closed-loop insulin system using the OpenAPS system on the glycemic control of T1DM patients.
Material and Methods: 24 T1DM patients with insulin pump were included in the study. 11 started using the OpenAPS closed-loop system and 13 continued using an insulin pump without OpenAPS. The effect on glycemic control (HbA1c, Fasting Blood Glucose (FBG), pre-meal, post-meal and before bedtime glucose) was recorded before the beginning of the study and on 12±1 and 24±1 weeks. Hypoglycemic episodes were also recorded.
Results: Patients using OpenAPS noted a significant reduction of HbA1c on the 3 and 6-month follow-up (7.70±1.14 vs. 6.85±1.17 vs. 6.63±1.05, p&lt;0.001). The reduction of HbA1c in the other group ws not significant (7.78±1.12 vs. 7.44±1.18 vs. 7.21±1.09, p=0.058). A significant reduction on FBG was noticed on the OpenAPS group (154.14±26.17 vs. 128.33±21.41 vs. 117.74±8.73, p=0.010), while the other group’s reduction was not found to be statistically significant (p= 0.112). Statistically lower pre-meal (p&lt; 0.001), post-meal (p&lt; 0.001) and before bedtime (p= 0.016) blood glucose levels were found on the OpenAPS group. Before the beginning of the study all of the participants had at least one hypoglycemic episode in the last month, while after 3 months of using OpenAPS, no patient showed hypoglycemia. The other group’s participants continued having such episodes.
Conclusions: Using a closed-loop in an insulin pump via OpenAPS system leads to a better glycemic control, less hypoglycemic episodes and lower daily blood glucose levels fluctuations compared to using an insulin pump with no closed-loop system.

Disclosure
A. Koutsovasilis: None. A. Sotiropoulos: None. A. Antoniou: None. V. Kordinas: None. D. Papadaki: None. T. Peppas: None.
107-LB: Variation of Measured Values Associated with Different Lots of Sensors for the Freestyle Libre
Authors: OKADA JUNICHI , OKADA SHUICHI , YAMADA MASANOBU 
Published: June 2019

The FreeStyle Libre Flash glucose monitoring system is a continuous glucose monitoring system that is used worldwide for improving plasma glucose control in patients with diabetes mellitus. Although we have used six different lots of the sensors, we recently and unexpectedly noted that one of the sensors for the FreeStyle Libre system showed completely different measured values. Herein, we designated these six lots as lot A through F. We observed that 53.4% and 54.6% of repeatedly measured interstitial glucose levels by Lot A were below 80 mg/dL (We tested two of Lot A on different day to confirm reproducibility.). On the other hand, the rest of 5 Lots (Lot B through F) showed that 0% of repeatedly measured interstitial glucose levels was below 80 mg/dL. However, unexpectedly, SMBG using a FS precision electrode with using the same reader of FreeStyle Libre system measured completely different values. Thus, Lot A consistently showed lower measured values compared to with those obtained using SMBG. As measured values using the FreeStyle Libre system are considered to be accurate as well as those obtained by SMBG, we decided to simultaneously test different lots of sensors, although the arm-attached sensor for B was on a different side than that for lot A. Lot A consistently showed measured values that were 20-30 mg/dL lower than those of Lot B. It is obvious that one of the six different lots showed inappropriately lower measured values and these discrepancies were critical. Therefore, it is possible that some lots of sensors for the FreeStyle Libre system do not work correctly, and may lead to false readings of hypoglycemia and a delayed response to true hyperglycemia, which requires a rapid response.
In summary, when changing of the lots of sensors for the FreeStyle Libre glucose monitoring system, we recommended that patients double check measured values using an alternative method, such as SMBG, as soon as possible to avoid incorrect blood glucose control.

Disclosure
J. Okada: None. S. Okada: None. M. Yamada: None.
1079-P: Glycemic Control and Change in Insulin Dose with Real-Life Use of Hybrid Closed-Loop System
Authors: GIORDANO DOMINIQUE A. , SNELL-BERGEON JANET K. , JOSEPH HAL , GARG SATISH K. , AKTURK HALIS K. 
Published: June 2019

Optimal glycemic control with minimal hypo- and hyperglycemia in type 1 diabetes (T1D) is difficult to achieve. New technologies such as hybrid closed loop (HCL-670G) system could help to improve glycemic control and prevent complications. We report a single-center 6-month experience regarding changes in metrics for glycemic control in adult patients with T1D on the Medtronic® 670G system. There were 139 patients (mean±SD age 41±12 years, 60% women) with T1D who were on a pump and CGM for at least 3 months prior to initiating 670G system, and who had at least six months of follow-up on 670G. We analyzed the changes in HbA1c, daily insulin dose, and BMI from baseline (just prior to initiating 670G system) at 3 and 6-months of 670G use. The mean percent time in auto-mode was 71% at 3 months and 73% at 6 months, with a range of 0-99% at both time points. Use of the 670G system significantly improved HbA1c with no change in BMI (Table). Percent time in auto-mode was significantly correlated to HbA1c at 3 (r=-0.26, p=0.009) and 6 months (r=-0.32, p=0.002). Daily bolus and total insulin dose increased at 3 months but were not significantly higher than pre-670G after 6 months of 670G use. We conclude that HCL use in real-life improves glucose control without increasing body weight or insulin dose.

Disclosure
D.A. Giordano: None. J.K. Snell-Bergeon: 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. H.K. Akturk: Advisory Panel; Self; Sanofi. Research Support; Self; Eli Lilly and Company, MannKind Corporation, REMD Biotherapeutics. Speaker's Bureau; Self; MannKind Corporation.
109-OR: Notch Signaling Controls Islet Architecture and ß-Cell Function in the Developed Pancreas
Authors: BARTOLOME ALBERTO , PAJVANI UTPAL 
Published: June 2019

Although β cell dysfunction is a well-appreciated contributor to type 2 diabetes (T2D) pathophysiology, determinants of β cell function are incompletely understood. For instance, disrupted islet architecture is associated with T2D progression in humans and rodent models, but the identity of the molecular elements that govern islet architecture remain mostly unknown. Nevertheless, data suggest that the spatial arrangement of the different cell types that form the endocrine islets influences cell-to-cell communication and β cell function.
The Notch pathway transduces signals between neighboring cells in pancreas development, then thought to be silenced in the developed endocrine islet. However, recent reports have uncovered a maladaptive Notch response in adult β cells in T2D patients and obese rodent models. To test the repercussions of Notch activity, we created β cell-specific gain-of-function mice that express a constitutively-active Notch intracellular domain (β-NICD). β-NICD mice show a profound disorganization of islet architecture, loss of β cell maturity and marked glucose intolerance. Importantly, we generated a second model that allows doxycycline-dependent expression of NICD (β-TetO-NICD), which recapitulates the phenotypes of β-NICD mice, even when NICD is induced in adulthood. Upon doxycycline withdrawal, β-TetO-NICD mice recover markers of β cell maturity, but disrupted islet architecture and glucose intolerance persist in β-TetO-NICD mice as compared to controls. To assess the molecular mechanisms of these findings, we performed unbiased transcriptomic screening of adult islets, which identified differentially expressed pathways that regulate cell-to-cell communication in different systems.
These studies uncover β cell Notch signaling as a novel determinant of islet architecture, and suggest that Notch inhibitors repurposed from oncology pipelines may have potential application to correct obesity-related β cell dysfunction in patients with T2D.

Disclosure
A. Bartolome: None. U. Pajvani: Research Support; Self; Sanofi.

Funding
American Diabetes Association (1-17-PMF-025 to A.B.)