bluuebunny/crossref_metadata_2025_split huggingface dataset:
866-P: Quantitative Analysis of Metformin-Induced Glucose Excretion in the Intestine
Authors: HOSOKAWA YUSEI , SAKAGUCHI KAZUHIKO , ITO JUN , SUGAWARA KENJI , MORITA YASUKO , OGAWA WATARU 
Published: June 2023

The enhancement of the uptake of 18F-labeled fluorodeoxyglucose (FDG) during [18F]FDG PET is a recently found metformin action in the gut. Taking advantage of PET-MRI, which provides better tissue registration and soft-tissue contrast than conventional PET-CT, we revealed that metformin enhanced FDG accumulation in the intestinal lumen. We now quantitatively analyzed the phenomenon with a newly developed protocol of PET-MRI. We also analyzed the intestinal glucose dynamics using 13C-labeled glucose and mass spectrometry in mice.
We adopted imaging sequences of MR enterography to create 3D images of the intestinal tract, then superimposed the [18F]FDG PET images to obtain the 3D distribution of radioactivity. We conducted this test on type 2 diabetes subjects treated (N=5) or not (control, N=5) with metformin. Radioactivity was detected in the wall and lumen at similar extents in the control. However, in the metformin group, the radioactivity in the lumen, but not the wall, was three to four-fold greater than that in the control. We mathematically analyzed the data using a compartment model and calculated the glucose excretion rate (GER). GER of the control and metformin groups were 6.8 ± 1.2 mg/min and 26.1 ± 2.9 mg/min, respectively, the latter being comparable to glucose excretion into the urine induced by SGLT2 inhibitors.
For mouse experiments, we intravenously injected 13C-glucose into C57/B6 mice and analyzed the feces 1 hour after injection with a gas chromatography-quadrupole mass spectrometry. We could not detect 13C-glucose in the feces, possibly because gut microbiota metabolizes glucose in the intestine. However, the content of 13C in short-chain fatty acids (SCFAs) was increased by the injection of 13C-glucose, and metformin augmented the incorporation of 13C into SCFAs.
These results suggest that glucose in the circulation transfers to the intestinal lumen at a considerable rate and is metabolized by microbiota, at least partly, into SCFAs and that metformin augments the processes.

Disclosure
Y.Hosokawa: None. K.Sakaguchi: Research Support; Sumitomo Dainippon Pharma Co., Ltd. J.Ito: None. K.Sugawara: None. Y.Morita: None. W.Ogawa: Advisory Panel; Abbott Japan Co., Ltd., Research Support; Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Novo Nordisk, Teijin Pharma Limited, Kowa Company, Ltd., Sumitomo Dainippon Pharma Co., Ltd., Abbott Japan Co., Ltd., Speaker's Bureau; Sumitomo Dainippon Pharma Co., Ltd.

Funding
Japan Society for the Promotion of Science (21K08578, 22K18393)
89-OR: Immunoprivileged Hydrogels Extend Functionality of Islets in Immunocompetent Animals
Authors: STOVER HARALD 
Published: June 2023

Background: Despite the promise of current islet cell transplantation, the need for systemic immune suppression significantly limits its utility for patients with diabetes. Until safe and immune-evasive cells are realized, physical immuno-protection offers an alternate route to allogeneic islet implants. Our proprietary synthetic hydrogels provide shape-agnostic, robust and retrievable Islet environments with anti-fouling and non-fibrotic properties.
Methods: Rat and human donor islets were encapsulated and implanted in the peritoneal space of streptozotocin (STZ)-induced diabetic immunocompetent mice and pigs to assess islet functionality over time through measurement of blood glucose, C-peptide, and HbA1c. Next generation shape-agnostic hydrogels were also tested for in-vitro and in-vivo function.
Results: Our hydrogels enabled rapid and persistent blood glucose control for 140+ days in immunocompetent mice with marginal loads of 1000 rat IEQ/mouse. Human donor islet function in mice was extended to day 45 (~8x longer than free human islets), with C-peptide detected at day 50, and corresponding HbA1c decreases. Our hydrogels showed minimal fibrosis when explanted after 45 days and showed robustness and integrity at day 340 post-implant in immunocompetent mice. Next-gen shape-agnostic hydrogels successfully excluded immune components including IgG and maintained good islet function in vitro. Our data also demonstrate function of human donor islets in immunocompetent pigs, based on C-peptide and cell viability data.
Conclusion: Our proprietary synthetic and retrievable hydrogels show strong immune protection in xenogenic transplants of donor islets into immune-competent animals. We are currently scaling to therapeutic doses in large animals, in pursuit of a curative therapy based on an optimal balance of Islet protection and functionality, without immunosuppression.

Disclosure
H.Stover: Employee; Allarta Life Science Inc.
90-OR: 3D Bioprinting of a Bionic Pancreas with a Vascular System—Results of Transplantation in Large Animals
Authors: WSZOLA MICHAL , BERMAN ANDRZEJ , KLAK MARTA , DOBRZANSKI TOMASZ , JANOWSKA OLIWIA , DOMANSKI SYLWESTER , PIATEK DOMINIKA , WEJMAN JAROSLAW , SZKOPEK DOMINIKA , ROSZKOWICZ-OSTROWSKA KATARZYNA I. , KOWNACKI LUKASZ , WOLINSKI JAROSLAW , DOBRZYN AGNIESZKA , KAMINSKI ARTUR 
Published: June 2023

The transplantation of the pancreas is recommended in diabetes with complications. The combination of cell biology and 3D-bioprinting can create organs with vasculature which should be functional. There are issues to be solved: leakage, thrombosis, enhancement against high pressure, connecting organ to the recipient. The purpose of this study was to demonstrate 3D-bioprinting of bionic organs with use of dECM-derived biomaterials with stable flow through the organ in vitro and in large animal studies.
Materials and methods: Mathematical analysis in the designed bionic pancreas was performed. The bionic pancreas was 3D bioprinted with 2 types of bioinks. The first tests were carried out in a bioreactor then organs were subjected to magnetic resonance and X-ray with contrast. Pressure endurance tests were performed. 14 pigs received 3D-bioprinted bionic pancreas transplantation. DCL-VESS-Group (n=5) received decellularized vessels as anastomosis. 9 pigs received bionic pancreas with vascular prosthesis as anastomosis - Prosthesis-Group. Pigs were observed up to 14 days. Hist-pat analysis of removed pancreas was performed.
Results: The tests carried out in the bioreactor showed the stability of the bionic organ and vascular system in MRI and X-ray examination for 5 days. No leaks beyond the bionic pancreas were observed up to 400 mmHg. In all 14 cases of transplantation there was stable flow throughout the organ after release of vascular clamp. DCL-VESS-Group - In all cases vascular cloth was observed. Prosthesis-Group - In 5 cases there were no complications influencing blood flow through the organ. 4 died to postoperative complications. Stable flow within a transplanted bionic organ was observed till 2 weeks post - surgery within ultrasound examination and radiology intervention. Histopatological showed the presence of CD31 / PECAM-1 (new blood formation).
Conclusion: It is feasible to 3Dbioprint and transplant bionic organ in big animal model.

Disclosure
M.Wszola: Board Member; Polbionica Ltd., Stock/Shareholder; Polbionica Ltd.. K.I.Roszkowicz-ostrowska: None. L.Kownacki: None. J.Wolinski: None. A.Dobrzyn: None. A.Kaminski: None. A.Berman: Board Member; Polbionica Ltd., Stock/Shareholder; Polbionica Ltd. M.Klak: Employee; Polbionica Sp. z o.o., Stock/Shareholder; Polbionica Sp. z o.o. T.Dobrzanski: Employee; Polbionica. O.Janowska: Employee; POLBIONICA Sp. z o.o. S.Domanski: Employee; Polbionica. D.Piatek: None. J.Wejman: None. D.Szkopek: None.
92-LB: Safety, Tolerability, and Clinical Effects of ZP8396, a Novel Long-Acting Amylin Analog—A Single Ascending Dose Trial
Authors: OLSEN MINNA B. , HÖVELMANN ULRIKE , GRIFFIN JON , KNUDSEN KIM M. , JOHANSEN THUE , KENDALL DAVID , HEISE TIM 
Published: June 2023

ZP8396 is an amylin analog designed for once weekly dosing that has demonstrated the potential to reduce body weight and improve glycemia in animal models of obesity and diabetes. We performed a randomized, double-blind, placebo-controlled trial to assess safety, pharmacokinetics, and pharmacodynamics of a single subcutaneous injection of ZP8396 in healthy lean and overweight male subjects. A total of 56 subjects (mean age was 38.1 years; mean BMI of 25.6 kg/m2) were randomized to ZP8396 or placebo (6:2) within seven dose cohorts ranging from 0.04 mg to 2.4 mg. The mean half-life of ZP8396 was approximately 10 days. After 1 week of observation, mean body weight decreased by -0.6%, 2.6%, 3.6%, and 4.2% from baseline following a single dose of placebo, 0.7 mg, 1.4 mg and 2.4 mg, respectively (Figure 1). ZP8396 was well tolerated, with no serious or severe adverse events (AEs) and no withdrawals. The most frequent related AEs were decreased appetite, nausea and vomiting, most events were mild and transient. No anti-drug antibodies were detected.
In conclusion, administration of a single dose of ZP8396 resulted in dose-dependent and consistent reductions in body weight supporting the potential of ZP8396 as a treatment for obesity. Additional clinical studies of longer duration will be necessary to fully assess the clinical potential of ZP8396.

Disclosure
M. B. Olsen: Stock/Shareholder; Novo Nordisk A/S, Zealand Pharma A/S. U. Hövelmann: None. J. Griffin: Employee; Zealand Pharma A/S. K. M. Knudsen: Employee; Zealand Pharma A/S. T. Johansen: Employee; Zealand Pharma A/S. D. Kendall: Employee; Zealand Pharma A/S. Stock/Shareholder; Zealand Pharma A/S, MannKind Corporation. T. Heise: Research Support; Adocia, AstraZeneca, Biocon, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Consultant; Gan & Lee Pharmaceuticals. Research Support; Genova. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Research Support; Sanofi, Zealand Pharma A/S.
928-P: The Use of a Novel CGM-Informed Insulin Bolus Calculator Mobile Application by People with Type 1 and Type 2 Diabetes Improves Time in Range
Authors: SHOMALI MANSUR , KELLY COLLEEN , IYER ANAND K. , PARK JEAN Y. , ALEPPO GRAZIA 
Published: June 2023

Background and Aims: People with diabetes on basal-bolus insulin regimens face challenges calculating bolus doses. Continuous glucose monitoring (CGM) systems can assist users with bolus dosing optimization through trend arrows. The purpose of this study was to demonstrate the safety and effectiveness of a CGM-informed insulin bolus calculator (IBC, Welldoc, Inc., Columbia, MD, U.S.A.) integrated into a mobile application that applies trend arrow and exercise adjustments to the bolus insulin dose recommendation. This investigational software also provided real-time coaching on CGM data to assist users in improving their time in range (TIR).
Methods: Fifty-four participants with diabetes using CGM (Dexcom G6, San Diego, CA, U.S.A.) were enrolled in a 30-day prospective study conducted at two research sites. Participants were asked to use the mobile application to monitor their CGM data and calculate their insulin doses. TIR during the prospective 30-day period was compared to that from 30 days of baseline data. Three populations were defined: 1) the intention-to-treat (ITT) group consisted of all enrolled subjects; 2) the complete cases (CC) group had ≥90% sensor wear time; and 3) the per-protocol (PP) group used the IBC at least 30 times during the study period.
Results: In the ITT group, the TIR improved from 68.4% to 71.8% (N=54, P=0.013). In the CC group, the TIR improved from 69.1% to 73.0% (N=49, P=0.005). In the PP group, the TIR improved from 69.2% to 73.0% (N=39, P=0.017). There was no increase in time with low glucose (&lt;70 mg/dL) in all three populations. In a subgroup analysis, TIR increased from 74.7% to 81.4% in those with type 2 diabetes and from 64.4% to 65.2% in those with type 1 diabetes.
Conclusions: Use of a novel CGM-informed insulin bolus calculator with trend arrow and exercise dose adjustment by individuals with type 1 and type 2 diabetes was associated with significant improvement in TIR.

Disclosure
M.Shomali: Employee; WellDoc. C.Kelly: Consultant; WellDoc, Caladrius Biosciences, Inc., Epigenomics AG, Luna, Nevro Corp., Presidio Medical, Hitachi, Ltd., Resmed, Inc., Seaspine Hldgs, Inc., ViaCyte, Inc. A.K.Iyer: Employee; WellDoc. J.Y.Park: None. G.Aleppo: Advisory Panel; Medscape, Consultant; Bayer Inc., Insulet Corporation, Research Support; Dexcom, Inc., Eli Lilly and Company, Emmes, Insulet Corporation, Fractyl Health, Inc., WellDoc, Speaker's Bureau; Dexcom, Inc.

Funding
Welldoc Inc.
940-P: Real-World Concordance between Point-of-Care and Continuous Glucose Monitoring among Hospitalized Patients with Diabetes
Authors: SPIERLING BAGSIC SAMANTHA R. , FORTMANN ADDIE L. , BELASCO REBEKAH , RITKO ANNA , LOHNES SUZANNE , SANDOVAL HALEY , CHICHMARENKO MARIYA , SORIANO EMILY , BASTIAN ALESSANDRA , TALAVERA LAURA , PHILIS-TSIMIKAS ATHENA 
Published: June 2023

Concordance between continuous glucose monitoring (CGM) and point-of-care testing (POCT) in research studies has been promising; however, the accuracy of using CGM for glucose management in real-world settings requires evaluation. Amid the COVID-19 pandemic, the CGM as “standard of care” (CGM as SOC) program was implemented at Scripps Mercy Hospital in San Diego, CA. In this real-world setting, concordance between the Dexcom G6 CGM system and POCT was evaluated among hospitalized adult patients with diabetes requiring insulin from May 2020-July 2022. For N=880 admissions, CGM readings over the first 24 hours of wear were analyzed relative to POCT conducted within 5 minutes. Patients had a median of 3 CGM-POCT data pairs, and the first CGM-POCT pair occurred a median of 2.75 hours after CGM device placement. Mean absolute relative difference (MARD) decreased over the first 24 hours of wear (B= -0.09%, p=0.0005; Figure 1A). Following the %20/20 rule, 62% of CGM readings were concordant upon the first measured POCT; 15.8% did not meet criteria at all during the first 24-hours. Using the Clarke Error Grid to describe concordance between CGM-POCT pairs (n=3015), only 0.7% (n=22) of CGM readings would have led to incorrect treatment decisions indicated by zones D/E (Figure 1B). These findings provide support for the accuracy of CGM for glucose management in the hospital.

Disclosure
S.R.Spierling bagsic: None. L.Talavera: None. A.Philis-tsimikas: Advisory Panel; Dexcom, Inc., Novo Nordisk A/S, Sanofi, Other Relationship; Medtronic, Research Support; Novo Nordisk A/S, Lilly, Viking Therapeutics, NIH - National Institutes of Health. A.L.Fortmann: Employee; Dexcom, Inc. R.Belasco: None. A.Ritko: None. S.Lohnes: Consultant; Dexcom, Inc. H.Sandoval: None. M.Chichmarenko: None. E.Soriano: None. A.Bastian: None.
946-P: Impacts of MAGE and SD on the Relationship between TIR and Glucose Management Indicator in T2D Patients
Authors: CHEN DANRUI , LIU ZHIGU , LIN BEISI , YANG DAIZHI , YAN JINHUA , YANG YANLING , XU WEN 
Published: June 2023

Aims: Previous studies proved that glucose coefficient of variation (CV), an index of glycemic variability (GV), affected the relationship between TIR and glucose management indicator (GMI) in patients with diabetes. This study aimed to explore whether other GV indexes, including MAGE and SD of glucose, affect the relationship between TIR and GMI in T2D patients.
Methods: Data were collected from T2D patients who received 48-h to 72-h CGM with iPro2 between January 2018 and October 2019. GV indexes, TIR, and GMI were derived from iPro2. A linear regression equation was generated with values of TIR and GMI. Patients were then divided into 3 subgroups according to the values of MAGE or SD. Predicted TIR in given GMI was calculated via the linear regression equations in the respective tertiles groups of MAGE or SD.
Results: A total of 118 T2D patients who were 57.2±11.6 years old, with a median diabetes duration of 6.0 years, HbA1c of 6.9±1.2%, and TIR of 87.5±12.9% were included. There was a strong negative correlation between TIR and GMI (r=-0.762, P&lt;0.001). The linear regression equation was TIR%=-21.2× GMI%+224.6. Multiple linear regression analysis showed that both MAGE and SD have impacts on the relationship between TIR and GMI (P&lt;0.001). The predicted TIR decreased when MAGE or SD increased with different given GMI (Table 1).
Conclusions: MAGE and SD influenced the relationship between TIR and GMI in T2D patients.

Disclosure
D.Chen: None. Z.Liu: None. B.Lin: None. D.Yang: None. J.Yan: None. Y.Yang: None. W.Xu: None.
95-LB: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Novel Oral Small Molecule GLP-1 Receptor Agonist (HRS-7535) in Healthy Subjects —A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Dose Study
Authors: WU JINGYING , HU WEI , DU YIJUN , ZHANG QIAN , ZHOU RENPENG , ZHANG QIN , QIN HUILING , YE ZI , XU YIMEI , FENG SHENG , SHU CHANG , SHEN YU , FAN YANG 
Published: June 2023

Background: HRS-7535, a novel, oral small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, has demonstrated no strict food restriction, and has been found to obviously improve glucose tolerance, promote insulin secretion, and reduce food consumption in preclinical studies. This study aimed to assess the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single and multiple ascending doses (SAD and MAD) of HRS-7535 in healthy subjects.
Methods: This was a randomized, double-blind, multi-part, phase 1 trial (NCT05347758). Overtly healthy adults 18-55 yrs were eligible, with the body mass index of 19.0-28.0 kg/m2 and the HbA1c of &lt;6.2%. In the SAD, healthy subjects were randomized (6:2) to receive HRS-7535 (15, 60, and 120 mg) or placebo. In the MAD, healthy subjects were randomized (18:6) to receive daily HRS-7535 (120 mg [30/60/90/120 mg titration scheme]) or matching placebo for 4 wks.
Results: 24 subjects participated in SAD and 24 participated in MAD, respectively. Most common treatment-emergent adverse events in both SAD and MAD were nausea and vomiting; all TEAEs were mild in severity. PKs were approximately proportional; In SAD, the median Tmax was 5.98-5.99 h and geometric mean t1/2 was 5.28-9.08 h across the HRS-7535 dosing range. In MAD, the median Tmax was 5.98-10.98 h and geometric mean t1/2 was 6.48-8.42 h on Day 28 across the HRS-7535 dosing range. In MAD, the mean reduction in body weight from baseline on Day 29 was 4.38 kg in subjects with HRS-7535.
Conclusion: Both SAD and MAD of HRS-7535 showed acceptable safety profile and favorable PKs/PDs. The obvious reductions in body weight could be observed in healthy subjects. These finding support further clinical exploration of HRS-7535 in patients with metabolic syndromes.

Disclosure
J. Wu: None. S. Feng: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. C. Shu: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y. Shen: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y. Fan: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. W. Hu: None. Y. Du: None. Q. Zhang: None. R. Zhou: None. Q. Zhang: None. H. Qin: None. Z. Ye: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y. Xu: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Funding
Jiangsu Hengrui Pharmaceuticals Co., Ltd.
950-P: Factors Associated with Hyper-/Hypoglycemia Unawareness in People with Type 2 Diabetes
Authors: SUZUKI YUKA 
Published: June 2023

Background: Hyper-/hypoglycemia unawareness harvours one of the major issues to hamper good clinical practice in people with type 2 diabetes (T2DM). To unveil risk factors of hyper-/hypoglycemia unawareness, we investigated its relationship with actual glucose variability in people with T2DM using continuous glucose monitoring (CGM).
Methods: Data were obtained from our prospective observational study comprising Japanese people with T2DM who underwent blinded professional CGM and the Diabetes Treatment Satisfaction Questionnaire (DTSQ). People with a time above range (TAR; &gt;180 mg/dL) ≥25% and those who answered 0 (“never”) or +1 (“almost never”) for the frequency of hyperglycemia in the DTSQ were defined as having hyperglycemia unawareness. People with a time below range (TBR; &lt;70 mg/dL) ≥4% with an answer of 0 or +1 for the frequency of hypoglycemia were labelled as having hypoglycemia unawareness. We extracted various clinical characteristics associated with the discrepancies between hyper-/hypoglycemia unawareness and TAR ≥25% / TBR ≥4% on a multivariate logistic regression analysis.
Results: This analysis included 284 subjects. In subjects with a TAR ≥25% (n=115), 27 had hyperglycemia unawareness. The analysis showed that each of no insulin use, older age, and a history of stroke was correlated with hyperglycemia unawareness. Among subjects with a TBR ≥4% (n=45), 28 were unaware of their hypoglycemia. A low eGFR was an independent risk of hypoglycemia unawareness.
Conclusions: We newly identified some clinical characteristics that were significantly associated with hyper-/hypoglycemia unawareness. In people with those characteristics, careful and intensive information sharing regarding asymptomatic hyper-/hypoglycemia using CGM may lead to better glucose management.

Disclosure
Y.Suzuki: None.
957-P: Continuous Glucose Monitoring in Patients with End-Stage Kidney Disease and Burnt-Out Diabetes
Authors: KAMINSKI CANDICE , GALINDO RODOLFO J. , ZABALA ZOHYRA E. , MOAZZAMI BOBAK , GERGES AMANY Y.G. , MCCOY ROZALINA G. , PENG LIMIN , UMPIERREZ GUILLERMO 
Published: June 2023

Patients with long-standing type 2 diabetes and end-stage kidney disease (ESKD) on dialysis may experience resolution of their hyperglycemia, as defined by an HbA1c &lt; 6.5%, without antidiabetic therapy. This phenomenon is known as “burnt-out diabetes”. Because HbA1c may be falsely low in patients with ESKD/dialysis therapy, we conducted a prospective study to compare glycemic control as measured by Dexcom G6 CGM in patients with ESKD and burnt-out diabetes and those without history of diabetes. We hypothesize that the use of CGM may provide better assessment of glycemic control than HbA1c (standard-of-care) in these patients and clarify the glycemic characteristics of burnt-out diabetes. We included adults with ESKD on dialysis, with (n=20) and without (n=10) a known history of diabetes, and with HbA1c &lt;6.5% without antidiabetic therapy for &gt; 6 months. All subjects wore a blinded Dexcom G6 CGM for 10 days. Their clinical characteristics and CGM metrics are shown in Table 1. Conclusion: CGM provides better assessment of glycemic excursions, compared to HbA1c, in patients with ESKD and diabetes. Most patients with burnt-out diabetes (HbA1c &lt;6.5%, off therapy) have frequent and significant hyperglycemic excursions as detected by CGM. Further research will need to examine whether these excursions require pharmacotherapy.

Disclosure
C.Kaminski: None. R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. Z.E.Zabala: None. B.Moazzami: None. A.Y.G.Gerges: None. R.G.Mccoy: Consultant; Emmi. L.Peng: None. G.Umpierrez: Research Support; Abbott, Dexcom, Inc., Baxter.

Funding
Jacob's Fund for Education