bluuebunny/crossref_metadata_2025_split huggingface dataset:
319-OR: Renoprotective Effects of Glucagon and Incretin Agonist Combinations Mediated by Macula Densa Cells
Authors: GYARMATI GEORGINA , BECERRA CALDERON ALEJANDRA , IZUHARA AUDREY , KONKAR ANISH , DUFFIN KEVIN L. , DEY ASIM B. , PETI-PETERDI JANOS 
Published: June 2024

Introduction & Objective: Recent therapeutic advances in diabetic nephropathy (DN) including GLP-1 analogs are promising, however more efficient treatments are needed with improved mechanistic understanding of their mode of action. Glucagon (GCG), GLP-1 and GIP receptors (R) are expressed in the kidney. Macula densa (MD) cells play central roles in controlling renal hemodynamics and tissue remodeling. This study aimed to examine the renoprotective effects of GCG w/without incretin analogs.
Methods: Intravital multiphoton imaging (MPM) was used to detect acute or chronic effects of GCG (long-acting IUB288) w/wo GLP-1 and GIP on afferent (AA) and efferent arteriole (EA) blood flow, single nephron glomerular filtration rate (SNGFR), MD cell calcium, nitric oxide (NO, using DAF-FM diacetate iv), mitochondrial function (using MitoTracker Red iv) in wild-type or Sox2-GCaMP5, Ren1d or Cdh5-Confetti mice (for genetic cell fate tracking) in control and STZ model of type I DN, and in MD cells in vitro.
Results: MPM revealed intense, selective MD cell labeling with AF647-conjugated GCG injected iv. GCG induced acute, two-fold increases in cell calcium only in MD cells. GCGR was 7.64-fold enriched in MD vs control cell transcriptome. Acute GCG treatment significantly increased MD cell protein synthesis, NO production, mitochondrial metabolism, AA/EA blood flow, protected glomerular hemodynamics from vasoconstrictor challenge. These effects were preserved or augmented when given in combination with incretin analogs including the GCG/GLP-1/GIP triagonist TG208, in chronic treatments and DN. Chronic GCG treatment induced a trend towards augmented tissue remodeling by resident progenitor cells.
Conclusion: MD-specific functional expression of GCGR is linked to improved cell metabolism, vasodilation, renal hemodynamics and tissue repair. MD cell targeting is an important novel mode of action of GCG that may be combined with incretin analogs for greater therapeutic effect in DN.

Disclosure
G. Gyarmati: Research Support; Traveere Pharmaceuticals. Other Relationship; Macula Densa Cell LLC. A. Becerra Calderon: None. A. Izuhara: None. A. Konkar: None. K.L. Duffin: Employee; Eli Lilly and Company. A.B. Dey: Employee; Eli Lilly and Company. J. Peti-Peterdi: Research Support; Traveere Pharmaceuticals. Other Relationship; Macula Densa Cell LLC.

Funding
Eli Lilly and Company
324-OR: Characterization of Aqueous Retinol Binding Protein 3 Concentrations and Diabetic Retinopathy Progression in Type 1 and Type 2 Diabetes
Authors: CHOKSHI TANVI , FICKWEILER WARD , VISHVA TEJA JANGOLLA SURYA , WU I-HSIEN , SUN JENNIFER K. , AIELLO LLOYD P. , KING GEORGE L. 
Published: June 2024

Joslin Medalist Study identified Retinol Binding Protein 3 (RBP3) as a potential protective factor against advanced diabetic retinopathy (DR) in the vitreous and retina of people with type 1 diabetes for 50 years or longer. There is emerging interest in DR biomarker identification in aqueous due to its easier access compared to vitreous. Quantitive aqueous RBP3 concentration, in a pilot study, correlated inversely with DR severity, but positively with vitreous RBP3, suggesting it may be a clinically useful DR biomarker. This study measured RBP3 concentration in 153 aqueous samples from patients undergoing cataract surgery at the Joslin Beetham Eye Institute to characterize RBP3 concentrations in relation to DR progression. DR progression was defined as ≥2-step worsening on the Early Treatment Diabetic Retinopathy Study severity scale. At baseline, DR severity distribution was 36% no DR, 38% mild and 26% moderate DR. The average follow-up was 5.6±3.6yrs. Aqueous RBP3 concentration was highest in patients with no visible signs of DR (median 2.1nM) compared to mild and moderate DR (1.5nM, P=0.04). There was no significant difference between aqueous RBP3 concentration in those with type 1 or type 2 diabetes (P=0.55). DR progression was present in 28.1% (N=45). Elevated aqueous RBP3 concentration was associated with less frequent diabetic macular edema (Odd Ratio (OR) 0.20, 95% Confidence Interval (CI) 0.07;0.56, P=0.002). In unadjusted analyses, less DR progression was associated with older age (OR 0.87, CI 0.79;0.96, P=0.006), lower HbA1c (OR 1.88, 95% CI 1.01;3.49, P=0.05), and elevated RBP3 concentration (OR 0.51, 95% CI 0.28;0.93, P=0.029). The performance of an Area Under the Curve model including RBP3 was 0.69 for predicting DR progression. These findings indicate that elevated aqueous RBP3 concentration is associated with less DR progression, supporting its potential as a protective factor and retinal-specific DR biomarker.

Disclosure
T. Chokshi: None. W. Fickweiler: None. S. Jangolla: None. I. Wu: None. J.K. Sun: Research Support; Optovue, Boehringer-Ingelheim, Novo Nordisk, Roche Pharmaceuticals. Other Relationship; Roche Pharmaceuticals. Research Support; Physical Sciences, Inc, Boston Micromachines. L.P. Aiello: Advisory Panel; Novo Nordisk. Stock/Shareholder; Kalvista. Other Relationship; Optos. Consultant; Ceramedix. G.L. King: None.

Funding
American Diabetes Association (7-21-PDF-022); National Eye Institute (R01EYE26080-01), the National Institute of Diabetes and Digestive and Kidney Diseases and National Institutes of Health (DP3- DK-094333-01); JDRF (17-2013-310); the Dianne Nunnally Hoppes Fund; the Beatson Pledge Fund
33-OR: The Risk of Heart Failure Hospitalization after Initiation of SGLT2i, GLP-1RA, DPP-4i, or SUs in Patients with Type 2 Diabetes and Low-to-Moderate CV Risk
Authors: TESFAYE HELEN , PAIK JULIE M. , ALIX CAROLINE , JANE CROMER SARA , EVERETT BRENDAN M. , GLYNN ROBERT , WEXLER DEBORAH J. , PATORNO ELISABETTA 
Published: June 2024

Introduction & Objective: Patients with type 2 diabetes (T2D) are at increased risk of heart failure (HF). There is limited guidance on which diabetes medications clinicians should use in patients without established cardiovascular disease (CVD) to address this risk.
Methods: Using Medicare and 2 U.S. private health plans (2013-2023), we identified six pairwise cohorts of 1:1 propensity score-matched patients aged ≥18 years (≥66 years in Medicare) with T2D without established CVD (atherosclerotic CVD or HF) who initiated SGLT2i, GLP-1RA, DPP-4i, or SU (Table), and estimated HRs and 95% CIs for the risk of hospitalization for HF [using 2 definitions based on a HF discharge diagnosis in the primary position (HHF-primary), or in any position (HHF-any)] and a composite of HHF or mortality, adjusting for 156 covariatesResults: Over a mean follow-up of ~11 months, the risk of HHF (either definition) was lower among SGLT2i initiators compared to all other classes (risk reduction 16-56%). Compared to DPP4i or SU, initiators of GLP-1RA also had lower risk of HHF (risk reduction 27-40%) (Table). Results were consistent for the composite outcome, driven by a decreased risk of HHF.
Conclusion: This study suggests that in patients with T2D and without established CVD, initiation of SGLT2i or GLP-1RA is associated with lower risk of HHF compared to other diabetes medications.

Disclosure
H. Tesfaye: None. J.M. Paik: None. C. Alix: None. S. Cromer: Other Relationship; Johnson & Johnson Medical Devices Companies. Advisory Panel; Alexion Pharmaceuticals, Inc. Other Relationship; Wolters Kluwer Health. B.M. Everett: Consultant; Novo Nordisk. Research Support; Novo Nordisk. Consultant; Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Ipsen Pharmaceuticals, Provention Bio, Inc. R. Glynn: Research Support; Amarin Corporation, Kowa Pharmaceuticals America, Inc., Novartis AG, Pfizer Inc. D.J. Wexler: Other Relationship; Novo Nordisk. E. Patorno: Research Support; Boehringer-Ingelheim, Food and Drug Administration (FDA), National Institutes of Health, Patient-Centered Outcomes Research Institute.

Funding
PCORI
335-OR: Preliminary Results of Islet Survival in a Novel Biovascular Pancreas Implanted in Primates
Authors: KURAL MEHMET H. , NASH KEVIN M. , NAEGELI KALEB M. , QIAN HONG , WANG JUAN , KIRKTON ROBERT D. , NIKLASON LAURA E. 
Published: June 2024

Islet transplantation into the portal vein is currently regarded as the most promising therapeutic approach for reversing Type-1 diabetes. Nevertheless, islet loss due to inflammatory reaction, hypoxia, and peri-islet thrombosis, often hinders sustained insulin independence in most patients, despite the considerable number of islets utilized. In response to these constraints, we are focused on the development of an acellular biological vascular graft with an outer layer coated with an islet-populated hydrogel known as the Biovascular Pancreas or “BVP” (Fig. 1 A). When connected to arterial circulation, the BVP provides an oxygen-rich environment for the embedded islets due to blood flow through the BVP lumen. Previously, we demonstrated that the BVP can restore normoglycemia in diabetic rodent models with islet numbers as low as 1500 islet IEQ per rat. Recently, we generated BVPs made of 6-mm inner-diameter human acellular vessels (HAV) that are coated with a primate islet-populated fibrin layer and tested the islet engraftment in non-human primates. When implanted as an aortic bypass graft in a Cynomolgus macaque for two weeks, the BVP supported islet viability and insulin secretion (Fig. 1 B, C and D). Our results demonstrate the first primate implantation of the BVP and its potential to improve transplanted islet viability which will be evaluated via subsequent long-term in vivo studies.

Disclosure
M.H. Kural: None. K.M. Nash: Employee; Humacyte Inc. K.M. Naegeli: Employee; Humacyte Global, Inc. Stock/Shareholder; Humacyte Global, Inc. H. Qian: None. J. Wang: None. R.D. Kirkton: Employee; Humacyte, Inc. L.E. Niklason: None.

Funding
JDRF Industry Discovery and Development Partnership (IDDP) (3-IND-2023-1380-I-X)
35-OR: Lantidra, First FDA-Approved Cellular Therapy to Treat Type 1 Diabetes
Authors: RIOS PETER , MCGARRIGLE JAMES J. , LAMONICA GIOVANNA , LI YI , COOK JENNIFER , JOSHI IRA , GHANI SOFIA , COOK DAVID , LOPEZ DAISY , NASIR HAFSA , WANG YONG , OBERHOLZER JOSÉ 
Published: June 2024

Despite intensive insulin therapy and frequent blood sugar monitoring, a subset of patients with type 1 diabetes (T1D) still suffer from debilitating symptoms, including severe hypoglycemia and hypoglycemia unawareness, and are left susceptible to the secondary complications of T1D. For T1D patients unable to achieve target hemoglobin A1c (HbA1c) despite intensive diabetes management and education, Lantidra is a treatment option to restore glycemic control, eliminate hypoglycemia episodes, and reduce or eliminate exogenous insulin injections. Lantidra is an FDA-approved allogeneic cellular therapy derived from donor pancreatic islet cells. Compared to whole pancreas transplantation, administration of Lantidra (minimum dosage: 5,000 islet equivalent/kg body weight) into the hepatic portal vein via percutaneous or transvenous transhepatic access, presents a safer and more minimally invasive surgical procedure. The efficacy and safety of Lantidra were examined in two core clinical studies, UIH-001 (Phase 1/2) and UIH-002 (Phase 3), at a single center (Pooled Population; n=30). Patients were screened to ensure an appropriate benefit-risk profile and received 1 to 3 Lantidra administrations. 19/30 patients (63%) met the composite efficacy endpoint (i.e., HbA1c ≤6.5% and absence of severe hypoglycemic events (SHEs) through 1 year after last transplant) and 20/30 (67%) were insulin independent at 1 year after last transplant. Importantly, improvements in glycemic control persisted. Two-thirds of patients assessed exhibited good glycemic control after 6 years. Lantidra demonstrated a safety profile consistent with known risks of the transplant procedure and concomitant medication use, particularly long-term use of immunosuppressants. The benefits of Lantidra outweigh the risks in T1D patients who have failed state-of-the-art insulin therapy. Lantidra fills a significant medical need, is effective at restoring good glycemic control in patients, and improves patient quality of life.

Disclosure
P. Rios: Employee; CellTrans, Inc. Stock/Shareholder; CellTrans, Inc. Board Member; CellTrans, Inc. J.J. McGarrigle: Employee; CellTrans Inc. Stock/Shareholder; CellTrans Inc. Board Member; CellTrans Inc. G. LaMonica: Employee; CellTrans, Inc. Stock/Shareholder; CellTrans, Inc. Y. Li: Other Relationship; Moderna, Inc. Employee; Cytel Inc. J. Cook: Employee; CellTrans Inc. Stock/Shareholder; CellTrans Inc. I. Joshi: Employee; CellTrans, Inc. Stock/Shareholder; CellTrans, Inc. S. Ghani: Employee; CellTrans, Inc. Stock/Shareholder; CellTrans, Inc. D. Cook: Employee; CellTrans Inc. Stock/Shareholder; CellTrans Inc. D. Lopez: Employee; CellTrans, Inc. H. Nasir: Employee; CellTrans. Y. Wang: Board Member; CellTrans, Inc. Stock/Shareholder; CellTrans, Inc. J. Oberholzer: Board Member; CellTrans, Inc. Stock/Shareholder; CellTrans, Inc.
357-OR: Association between Continuous Glucose Monitoring and Diabetes-Related Complications in Children with Type 1 Diabetes—Nationwide Cohort Study
Authors: YOON KIM JI , KIM SEOHYUN , CHO SOHYUN , OH ROSA , HYEON KIM JAE 
Published: June 2024

Introduction & Objective: This study aimed to investigate the effect of continuous glucose monitoring (CGM) on diabetes-related complications in children with type 1 diabetes.
Methods: From the Korean Nationwide Cohort (2016-2022), we included children (aged &lt;19 years) with type 1 diabetes managed by intensive insulin therapy. The primary outcome included severe hypoglycemia and diabetic ketoacidosis (DKA). Adjusted hazard ratios (HRs) for primary outcomes were compared between CGM users and non-users by using Cox proportional hazard regression models. Additionally, among CGM users, the events of severe hypoglycemia and DKA were compared before and after CGM use by paired t-test.
Results: A total of 3,765 children (2,313 CGM users and 1,452 non-users) were included. During the follow-up period, CGM users showed a lower risk of severe hypoglycemia (adjusted HR: 0.48, 95% confidence interval (CI): 0.29-0.79) and DKA (adjusted HR: 0.44, 95% confidence interval (CI): 0.35-0.56). Among CGM users, the events of severe hypoglycemia and DKA significantly reduced after CGM use (p&lt;0.001 for both).
Conclusion: In this nationwide cohort study, the use of CGM reduced the risk of severe hypoglycemia and DKA in children with type 1 diabetes receiving intensive insulin therapy.

Disclosure
J. Kim: None. S. Kim: None. S. Cho: None. R. Oh: None. J. Kim: None.
359-OR: CGM in Primary Care—Practice Characteristics and Choice of CGM Implementation Strategy in PREPARE 4 CGM
Authors: OSER SEAN , WIGGINS KIMBERLY T. , HALL TRISTEN , MIRIAM DICKINSON L. , CRISPE KRISTIN , DICKINSON PERRY , OSER TAMARA 
Published: June 2024

Introduction & Objective: Most diabetes care occurs in primary care (PC). Continuous glucose monitoring (CGM) is associated with clinical and psychosocial benefits. While CGM uptake in PC is rising, understanding models to support CGM use in diverse PC practices is needed. The PREPARE 4 CGM study evaluates strategies to implement CGM in PC. We compared characteristics among practices choosing a practice-led, self-paced CGM implementation plan or referral to a virtual CGM implementation service.
Methods: Colorado PC practices interested in implementing CGM were recruited and chose to use the American Academy of Family Physicians CGM implementation modules or refer patients to a virtual CGM initiation and education service with dietitian, pharmacist, diabetes care and education specialist (DCES), and physician. Baseline practice characteristics (staffing, specialty, size, payer mix, etc) were compared across study arms using descriptive statistics (frequencies, means, SDs), chi-square tests, Fisher’s exact tests and independent two sample t-tests, using SAS 9.4 (Cary NC). Associations were considered significant at p&lt;0.05.
Results: Of 76 practices, 46 chose self-paced implementation, 16 of which (35%) had a DCES; 30 chose the virtual service, none (0%) of which had a DCES, X2(2, N=62)=11.05, p &lt;.001. Besides having a DCES, no differences in 50 other practice characteristics were seen between groups.
Conclusion: PC practices were eager to implement CGM. While other practice characteristics were not associated with implementation strategy choice, having a DCES was highly associated: all practices with a DCES chose to implement CGM on their own. DCESs may have potential as technology champions in PC practices. Referral to virtual CGM implementation service allowed access to a DCES and multidisciplinary team for practices without them. As many practices without a DCES also chose to implement CGM on their own, multiple models may be necessary to foster CGM implementation in PC.

Disclosure
S. Oser: Other Relationship; American Diabetes Association, Association of Diabetes Care & Education Specialists. Research Support; Abbott. Advisory Panel; Dexcom, Inc., Jaeb Center for Health Research. K.T. Wiggins: None. T. Hall: None. L. Dickinson: None. K. Crispe: None. P. Dickinson: None. T. Oser: Research Support; Abbott. Advisory Panel; Medscape. Consultant; Dexcom, Inc. Research Support; Insulet Corporation.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust (G-2204-05191)
37-OR: Effectiveness of Continuous Glucose Monitoring on Short-Term In-Hospital Mortality among Frail Critically Ill Patients with COVID-19—An Exploratory, Prospective, Randomized, Open-Label, Parallel, Single-Center, Randomized Clinical Trial
Authors: WANG WEI , SHEN YUN 
Published: June 2024

Objective: We aimed to investigate the effectiveness of CGM on intensive care unit (ICU) related outcomes among frail and critically ill patients with confirmed COVID-19.
Research Design and Methods: This was an exploratory, prospective, randomized, open-label, parallel, single-center clinical trial. A total of 124 patients was finally analyzed. The primary outcome was 28-day in-ICU mortality. The secondary outcome included the length of ICU stay, the occurrence of hypoglycemia and severe hypoglycemia events.
Results: The mean age was 78.3±11.5 years old. The mean fasting glucose level at baseline was 8.12±1.54 mmol/L. The mean HbA1c level was 7.2±0.8%. The percentage of participants with diabetes was 30.6%. The corresponding hazard ratio of the primary outcome in the isCGM group when compared with the POCT group was 0.18 (95%CI 0.04-0.79). The average length of ICU stay was 10.0±7.57 days in the isCGM group and 14.0±6.86 days in the POCT group (P &lt; 0.05). There were fewer events of both hypoglycemia and severe hypoglycemia observed in the isCGM group compared to POCT group.
Conclusions: We found a significant clinical benefit from the use of CGM among frail and critically ill patients with COVID-19. These findings support the use of CGM in ICU and might help with the extension of application in various in-hospital settings.

Disclosure
W. Wang: None. Y. Shen: None.
376-P: Novel Continuous Glucose Monitoring Marker, Shannon Entropy, Is Significantly Correlated with Incidence of Severe Hypoglycemia
Authors: ZHANG XIAOHUA D. , KUEI LIN YU , ZHANG RENA D. , FISHER SIMON J. 
Published: June 2024

Introduction & Objective: Detailed analysis of continuous glucose monitoring (CGM) data may identify novel risk markers for severe hypoglycemia (SH).
Methods: Correlations between established and novel CGM features (Table 1) derived from 30-day CGM data and the number of self-reported SH events in the previous 6 months were investigated in 163 adults with type 1 diabetes (T1DM).
Results: The number of SH events were significantly positively correlated with SD (p=0.0360), Mean (p=0.0446), TAR1 (p=0.0482), MODD (p=0.0448), 24-hour CONGA (p=0.0492), and significantly negatively correlated with TIR (p=0.0296), but was not significantly correlated with TBR2, TBR1, TAR2, CV, MAG, GVP nor MAGE (Table 1). The strongest CGM correlation with severe hypoglycemia was Shannon entropy (p=0.0161), a measure of randomness/disorder in the CGM data.
Conclusion: Surprisingly, the number of severe hypoglycemic event did not correlate with time below range. However, the novel CGM analytic feature of Shannon entropy had the strongest correlation with the number of SH events. These findings suggest that incorporation of CGM-derived Shannon entropy determinations may have clinical utility to identify T1DM adults at high risk for severe hypoglycemia.

Disclosure
X.D. Zhang: None. Y. Lin: None. R.D. Zhang: None. S.J. Fisher: None.

Funding
National Institutes of Health (UL1TR001998); National Institutes of Health (U01DK135111); National Institutes of Health (P30 DK020579); National Institutes of Health (OT2HL161847)
384-P: Comparative Efficacy of Irbesartan and Sotagliflozin in a Nonhuman Primate (NHP) Model of Diabetic Kidney Disease
Authors: DE VILLA FLORDELIZA P. , PEREZ ROSARIO M. , HUA ZHU Z. , YANG LICHUAN 
Published: June 2024

Introduction and Objective: Renin-angiotensin system (RAS) inhibition has become the standard of care but new agents have emerged in the treatment of diabetic kidney disease (DKD) and its complications. Thus, the efficacy of irbesartan (IB), a RAS inhibitor, and sotagliflozin (SG), a dual SGLT1/2 inhibitor, on renal functional markers was evaluated in the most relevant animal model that closely approximates the human DKD phenotype.
Methods:Male cynomolgus monkeys with DKD [fasting blood glucose 281±82 mg/dL; 24h urine albumin creatinine ratio (UACR) 589±340 mg/g; glomerular filtration rate (GFR) 49±20 mL/min/1.73m2] from the high-fat diet NHP colony were selected for the study. Animals were dosed daily by oral gavage for 4 weeks with either vehicle (VH, n=8), IB at 3 mg/kg (n=12), or SG (n=5) at weekly escalating doses of 10, 12 and 14 mg/kg. Serial UACR, GFR and blood pressure (BP) measurements were done.
Results:UACR reductions were recorded for both IB and SG groups compared to the VH. Percent changes (%) from baseline of UACR were higher with IB treatment (-34±31 &gt;-3±50 &gt;23±23%; IB&gt;SG&gt;VH) but minimal sustained reductions were noted at the end of the 4-week washout period with SG (-7±53 vs 22±42%; SG vs IB). Marked sustained improvement in GFR was recorded in the SG group (27±16&gt;16±93&gt;9±43 %; SG&gt;IB&gt;VH) at the end of the washout period. Decreases in systolic BP (SBP; -11±8 %) and mean arterial pressure (MAP; -2±14%) were noted with IB during dosing with return to baseline at the end of the washout period. Decreased SBP (-8±8%), diastolic BP (-9±14 %) and MAP (-9±10%) during dosing, which continued until the end of washout, were seen in the SG group.
Conclusion:Treatments with IB and SG resulted in improvements in albuminuria and GFR with BP reductions. Sustained effects in renal function were noted with SG implying enhanced renoprotection with SGLT1/2 inhibition in this NHP model which is considered a vital translational model for testing novel interventions for DKD.

Disclosure
F.P. De Villa: None. R.M. Perez: None. Z.Z. Hua: None. L. Yang: None.