bluuebunny/crossref_metadata_2025_split huggingface dataset:
1665-P: Analysis of Glucose Biomarkers in Phase I and Phase II Studies of Survodutide in People with Type 2 Diabetes or Living with Overweight/Obesity
Authors: EKINCI ELIF I. , ARRUBLA MARTINEZ JORGE , HENNIGE ANITA M. , SCHÖLCH CORINNA 
Published: June 2024

Introduction & Objective: Survodutide, a glucagon receptor/glucagon-like peptide-1 receptor (GCGR/GLP-1R) dual agonist, elicited greater HbA1c reduction up to -1.71% vs semaglutide 1 mg (-1.47%) in a Phase 2 trial in patients with type 2 diabetes. This analysis evaluated changes in insulin sensitivity, pancreatic islet cell function, and glucose biomarkers from three Phase I/II trials of survodutide.
Methods: Descriptive statistics were derived from a Phase 2 trial in patients living with obesity/overweight without diabetes (NCT04667377), a Phase 2 trial in patients with type 2 diabetes (NCT04153929), and a Phase 1 study in patients living with obesity/overweight (NCT03591718).
Results: High survodutide doses improved insulin sensitivity as reflected in a decrease in mean absolute HOMA-IR scores from baseline (BL) to the end of treatment (EOT), in contrast to no change or increase with placebo (PBO): NCT04667377, -1.1 (4.8 mg QW) vs -0.2 at Week 46; NCT04153929, -0.9 (1.8 mg twice weekly [BIW]) vs 0.9 at Week 17; and NCT03591718, -1.0 (2.4 mg BIW following up titration) vs 0.3 at Week 16. Survodutide improved HOMA-β, with mean percentage change from BL to EOT consistently higher vs PBO: NCT04667377, 8.6% vs -1.1%; NCT04153929, 88.0% vs 18.0%. In NCT04667377, change from BL to Week 46 in FPG with survodutide vs PBO was 0.4 vs 0.0 mmol/L. Change from BL in insulin and non-fasting plasma glucose levels with survodutide 4.8 mg vs PBO, was -23.4 vs 0.4 pmol/L and -0.0 vs 0.6 mmol/L, respectively. Additionally, mean change from BL to Week 46 in adiponectin, glucagon, and c-peptide levels with survodutide 4.8 mg vs PBO was 1.9 vs
-0.15 mg/L, -15.2 vs -0.8 pmol/L, and -0.1 vs 0.0 nmol/L, respectively.
Conclusion: Survodutide treatment showed improvement in markers of insulin sensitivity, pancreatic islet cell function, and glucose biomarkers, in patients living with obesity/overweight and those with type 2 diabetes.

Disclosure
E.I. Ekinci: Advisory Panel; Lilly Diabetes. Research Support; Novo Nordisk, Boehringer-Ingelheim, Eli Lilly and Company. Board Member; Eli Lilly and Company. Advisory Panel; Abbott. Research Support; Endogenex, Versanis, AstraZeneca. J. Martinez: Employee; Boehringer-Ingelheim. A.M. Hennige: Employee; Boehringer-Ingelheim. C. Schölch: Employee; Boehringer-Ingelheim.

Funding
Boehringer Ingelheim
167-OR: Targeting Alpha Cells to Treat Hypoglycemia in Type 1 Diabetes
Authors: PANZER JULIA , LANG ANNA L. , PUGLIESE ALBERTO 
Published: June 2024

Increased glucagon release from alpha cells is the main defense against hypoglycemia, a mechanism lost in Type 1 Diabetes (T1D). We hypothesize that the absence of neighboring beta cells, and consequently the loss of their inhibitory signals, plays a crucial role in the impaired responsiveness of alpha cells to hypoglycemic conditions. We conducted experiments using isolated islets and pancreatic tissue slices from both nondiabetic organ donors and donors with T1D, revealing significant differences between slices and islets. Despite a decline, isolated islets exhibited residual insulin secretion similar to healthy islets, a phenomenon absent in slices. This discrepancy may imply a survival bias during isolation or the influence of the microenvironment, undetectable when using isolated islets. Unlike beta cells, alpha cells did not faithfully track glucose concentrations and their responses were transient, contrasting with the sustained responses of beta cells. Without inhibitory input reset, alpha cells couldn't mount subsequent responses. Remarkably, activating paracrine signals inhibiting alpha cells successfully restored glucagon secretion, with complete recovery observed after a 15-minute or longer reset using high glucose in healthy islets. In tissues from T1D donors, alpha cells failed to respond to declining glucose levels despite maintaining normal glucagon content. We systematically explored the inhibitory effects of three paracrine signaling molecules—serotonin, somatostatin, and GABA, and their potential to revive glucagon secretion. Surprisingly, all molecules demonstrated the ability to increase glucagon secretion in response to low glucose, contrary to anticipated inhibitory responses. This resulted in a significant sustained increase even after stimulus removal. Building on these insights, our latest findings show that these paracrine signaling molecules can rescue glucagon secretion in T1D.

Disclosure
J. Panzer: None. A.L. Lang: None. A. Pugliese: Advisory Panel; Provention Bio, Inc.

Funding
American Diabetes Association (4-22-PDFPM-12); The Leona M. & Harry B. Helmsley Charitable Trust (Grant#2018PG-T1D053, G-2108-04793)
1689-P: Clinical Outcomes among Nondiabetic Obese Population with Concomitant Protein-Calorie Malnutrition—A Nationwide Study
Authors: KISHORE SINDHU , KHOKHLOV LEONID , AJENAGHUGHRURE GODBLESS E. , MATEO FERNANDO R. , KISHORE GEHNA , IKPEZE TOCHUKWU , RAJBHANDARI PRANITA , RAI SHILPA , MISHRA AAVASH 
Published: June 2024

Introduction & Objective: Obesity, a disease increasing cardiometabolic risks and mortality, often accompanies protein-calorie malnutrition (PCM). PCM has been associated with delayed recovery from diseases. This study explores clinical outcomes in obese patients without DM co-diagnosed with PCM. Conducted as an observational study, it utilized data from the National Inpatient Sample from 2017 to 2020 focusing on obese adults over 18 years, with a BMI &gt;30 kg/m^2, and PCM diagnosis, excluding those under 18 or with DM. Multivariable logistic and Poisson regression analyses determined the clinical outcomes, considering a p-value &lt;0.05 significant. Among 11,979,333 obese adults without DM, 1.5% had PCM who were predominantly white males. The study compared PCM and non-PCM groups, revealing higher rates in % in the PCM group for conditions like anemia (26.8 vs 13.4), dyslipidemia (33 vs 31.6) pulm HTN (7 vs 4), HF (26.6 vs 16), Afib (22.8 vs 13.7), PVD (3.7 vs 2.1), ACS (5.4 vs 4.3), COPD (21.4 vs 14.6), CKD (21.9 vs 11), PE (7.8 vs 5) and incidence alcohol use (8.4 vs 4.5). The former group also had worse primary and secondary outcomes as detailed in Table 1. The findings underscore the importance of obesity management in such populations for better clinical outcomes and prognosis.

Disclosure
S. Kishore: None. L. Khokhlov: None. G.E. Ajenaghughrure: None. F.R. Mateo: None. G. Kishore: None. T. Ikpeze: None. P. Rajbhandari: None. S. Rai: None. A. Mishra: None.
169-OR: LC3+ Extracellular Vesicles (EVs) Are Associated with Altered ß-Cell Autophagy, Islet Inflammation, and Diabetes
Authors: XU JERRY , AUSTIN MATTHEW , LINNEMANN AMELIA K. , SIMS EMILY K. 
Published: June 2024

Introduction: EVs, nanoparticles housing molecular cargo, change based on parent cell health and contribute to cell-cell communication. Yet, mechanisms governing changes and physiological significance of β cell EV cargo remain unclear. Autophagy is a critical intracellular degradation and recycling process to clear damaged cellular components. EV-autophagy crosstalk is an emerging area of interest with implications for both physiological and pathological states. We have described altered β cell autophagy associated with islet inflammation and type 1 diabetes (T1D). Based on this and reports of autophagy machinery such as LC3 in EVs from other systems, we hypothesized that changes in the LC3+ EV population could yield insight into β cell autophagy.
Methods: Small EVs (&lt;200nm) were isolated from INS-1 and EndoC β cells, islets, or plasma using tetraspanin (CD9, CD81, CD63) or LC3 antibody-based bead pulldown and quantified with flow cytometry.
Results: We detected LC3 on the surface of EVs from β cells and normal islets. EV LC3 staining was also significantly increased by 24-hr treatment with 10 ng/mL IL-1β or 10μM caffeic acid phenethyl ester, a neutral sphingomyelinase-2 activator linked to regulation of EV subpopulations during inflammatory stress. Alternatively, LC3 staining was reduced in islet EVs from mice with β cell deletion of the critical autophagy enzyme ATG7, linking LC3+ EVs to autophagosome formation. LC3 pulldown specifically isolated β cell EVs and demonstrated the presence of proinsulin in LC3+ EVs. Finally, LC3 staining was significantly increased in plasma EVs of 20 children with new-onset T1D compared to age, sex, and BMI matched controls.
Conclusion: LC3 is present on the surface of β cell EV membranes, and both β cell and circulating EV LC3 are impacted by defects in autophagy, islet inflammation, and T1D. Future studies will determine whether and how the population of LC3+ EVs participate in specific stages of autophagy or β cell pathophysiology.

Disclosure
J. Xu: None. M. Austin: None. A.K. Linnemann: None. E.K. Sims: Consultant; Sanofi. Board Member; American Diabetes Association. Other Relationship; American Diabetes Association, Medscape. Consultant; DRI.
1692-P: Prevalence, Characteristics, and Clinical Burden among Patients with Overweight or Obesity and Established ASCVD in a U.S. Real-World Setting
Authors: MICHALAK WOJCIECH , BOAME NANA , ZHAO XIN , LAMARRE NEIL , RAVA ANDREW , DOAN QUAN V. , FAURBY MADS , O HARTAIGH BRIAIN , FABRICATORE ANTHONY , ZHAO ZHENXIANG 
Published: June 2024

This study aimed to estimate the prevalence of overweight or obesity (Ov/Ob; BMI ≥ 25.0 kg/m2) in individuals with established ASCVD (eASCVD; included MI, stroke, and PAD) and to compare patient characteristics and clinical burden of this population to those with eASCVD and normal weight (NW; BMI 18.5 - 24.9 kg/m2). The IQVIA’s US claims-linked EHR database (2017-2022) was used to include patients with eASCVD (index date). Prevalence was calculated based on the latest BMI in the 12 months before index (baseline). Characteristics and clinical burden in the baseline period were compared among patients with eASCVD, with vs. without Ov/Ob. Of 28,021 patients with eASCVD, the prevalence of Ov/Ob was 80.7% (95% CI: 80.2%; 81.2%). Those with Ov/Ob were more frequently male (59.1% vs. 44.6%, p&lt;0.001), had higher triglycerides (152 vs. 116 mg/dL, p&lt;0.001) and lower HDL levels (50.3 vs. 63.1 mg/dL, p&lt;0.001), and had a higher prevalence of several cardiometabolic comorbidities compared to those with NW (Figure 1). Among patients with eASCVD, Ov/Ob was highly prevalent, it was associated with an adverse lipid profile and increased prevalence of additional metabolic disease, including MAFLD, OSA, and type 2 diabetes. Treating excess adiposity in this population may confer benefits beyond managing ASCVD.

Disclosure
W. Michalak: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk, Eli Lilly and Company. N. Boame: None. X. Zhao: None. N. Lamarre: Consultant; Novo Nordisk. A. Rava: Other Relationship; Novo Nordisk. Employee; Genesis Research Group. Q.V. Doan: Consultant; Novo Nordisk, Daiichi Sankyo, Akebia Therapeutics, Inc., AbbVie Inc. M. Faurby: Employee; Novo Nordisk. B. O Hartaigh: Employee; Novo Nordisk A/S. A. Fabricatore: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. Z. Zhao: None.
1703-P: Integrated Transcriptome, Proteome, Metabolome, and Microbiome Analyses Identify Multiomics Signature of Glycolipid Metabolism Disorder—A Cross-Sectional Study
Authors: FANG XINYI , MIAO RUNYU , WU HAORAN , ZHANG YANJIAO , TIAN JIAXING 
Published: June 2024

Introduction: The prevalence of glycolipid metabolism disorder continues to increase globally and has become a serious threat to human health. Multi-omics provide unprecedented insights into the underlying pathophysiological mechanisms of glycolipid metabolism disorder and identifying potential biomarkers and therapeutic targets.
Methods: We collected blood/stool samples from 30 patients with type 2 diabetes and dyslipidemia (GL), 30 patients with hyperlipidemia (HL), and 30 healthy controls, conducted transcriptome/proteome/metabolome/microbiome analysis, and correlated it with clinical phenotypes. We further integrated multi-omics features and tested the discriminant efficacy of multi-omics datasets using receiver operating characteristic curves.
Results: Among patients with GL, insulin like growth factor binding protein 3 (IGFBP3) in the p53 signaling pathway was highly expressed at both the transcription and protein levels. Joint analysis of proteomics and metabolomics confirmed the link between fructose-bisphosphate aldolase B and altered N-acetylornithine metabolism in the amino acid biosynthetic pathway. The gut microbiota dysbiosis in patients with GL was characterized by a significantly reduced abundance of short-chain fatty acids-producing bacteria, and this reduction was related to a decrease in dodecanoic acid. The extracellular matrix-receptor interaction pathway was associated with HL, and collagen type I alpha 1 chain in this pathway was lowly expressed at both the transcription and protein levels. The abundance of Parabacteroides gordonii was significantly reduced in patients with HL. Matrix metallopeptidase 2 and IGFBP3, key differential molecules between GL and HL, were highly expressed at both the transcription and protein levels.
Conclusion: This study revealed the multi-omics signature and key drivers of glycolipid metabolism disorder.

Disclosure
X. Fang: None. R. Miao: None. H. Wu: None. Y. Zhang: None. J. Tian: None.

Funding
Capital Health Development Research Project (CD2020-4-4155); CACMS Outstanding Young Scientific and Technological Talents Program (ZZ13-YQ-026); Scientific and technological innovation project of China Academy of Chinese Medical Sciences (CI2021A01601); Open Project of National Facility for Translational Medicine (TMSK-2021-407); CACMS Guang'anmen Hospital Sustainability Project-Young Top-Notch Talent Project (NO.CZ40907).
1705-P: Obesity Phenotype Exhibit Differential Signatures of Circulating Biomarkers with Susceptible Obesity-Related Comorbidities
Authors: QI WEIER , TU XIAO , ROBERTSON DARREN , ACOSTA ANDRES , PARKER VICTORIA E. 
Published: June 2024

Background: Obesity is a heterogeneous disease with different phenotypes based on physiological and biological differences in energy intake and expenditure. A recent study determined that guided therapy based on the classification of obesity phenotypes achieved better outcomes with respect to body weight loss (Acosta et al 2021). We aimed to identify potential circulating biomarkers to predict phenotypes and susceptibility to comorbidities.
Methods: In a randomized placebo-controlled study which enrolled overweight and obese participants with T2DM, 18 subjects was subphenotype into 3 groups: hungry brain (HB) N=5, hungry gut (HG) N=5 and slow burn (SB) N=5 and unclassified N=3. Global plasma metabolomics and proteomics analysis were performed at baseline to identify the molecular signatures associated with each phenotype.
Results: In the metabolomics analysis with p&lt;0.05 cutoff, SB had lower homocysteine by 46% vs. HB. In contrast, SB had higher levels of proline, Lauroyl-L-carnitine and DL-2-Aminocaprylic acid (by 43%, 385% and 476% respectively) vs. HB. Consistently, SB had also increased levels of proline by 43% p&lt;0.43 vs. HG. In the proteomics analysis with p&lt;0.05 cutoff, Apolipoprotein M (APOM) decreased in SB by 39% with concomitant lipid oxidation protein (PCYNOX1) decreased by 40% vs. HB. Lower CV risks biomarkers of homocysteine and PCYNOX1 have been observed in SB. In contrast, SB had higher levels of liver collagen synthesis, and liver fat accumulation biomarkers (proline, Lauroyl-L-carnitine, and DL-2-Aminocaprylic acid.
Conclusions: These results suggest there may be some differential circulating biomarkers in different phenotypes that are susceptible to comorbidity differences such as CV and NASH-related risks. Further exploration of these differences may help better
understand metabolic mechanisms in these groups and permit more targeted therapy in the future. Larger studies are required to substantiate these findings.

Disclosure
W. Qi: Employee; AstraZeneca. X. Tu: Employee; AstraZeneca. D. Robertson: Employee; AstraZeneca. Stock/Shareholder; AstraZeneca. A. Acosta: Consultant; Amgen Inc., Regeneron Pharmaceuticals Inc., Nestlé Health Science, Structure Therapeutics, Inc., Boehringer-Ingelheim. Research Support; Vivus. Consultant; Currax. Other Relationship; Gila Therapeutics, Phenomix Sciences. Speaker's Bureau; Eli Lilly and Company. V.E. Parker: Employee; AstraZeneca. Stock/Shareholder; AstraZeneca.
1734-P: ADP Privation of Human Beta-Cell Mitochondria by Pyruvate Kinase
Authors: RUZ-MALDONADO INMA , CARDONE REBECCA L. , KIBBEY RICHARD 
Published: June 2024

Introduction & Objective: A revised mechanism for glucose stimulated insulin secretion (GSIS) in beta-cells endorses that pyruvate kinase (PK) outcompetes oxidative phosphorylation (OxPhos) for ADP and generate the ATP/ADP ratio to close KATP channels. Here we investigate how PK deprives mitochondria of ADP.
Methods: Competition between OxPhos vs. PK for ADP was assessed by monitoring OxPhos-dependent oxygen consumption rate (OCR) in intact and permeabilized human islets using allosteric, nutrient modulation of enzyme and mitochondrial function including substrate transport.
Results: Up and down titration of mitochondrial coupling ruled out significant substrate-driven OxPhos. Phosphoenolpyruvate (PEP) decreased OxPhos-dependent OCR in a dose-dependent manner when ADP was limiting (33±0.6, 40±1.3 and 59±0.7% reduction by PEP at 156, 313 and 625µM, respectively; p&lt;0.0001). At submaximal PEP, the PK activator PKa1 further reduced respiration 10µM (55±2.3% reduction respect to PEP; p&lt;0.01). At maximal PEP, 4mM of the PK inhibitor L-phenylalanine partially improved OxPhos by 65±1.8% (p&lt;0.0001). Likewise, 10mM creatine rescued OCR by 35% (p&lt;0.0001) OxPhos by regenerating intramitochondrial ADP. PEP inhibition of OxPhos required 1) PEP hydrolysis to pyruvate by PK, 2) ADP/ATP exchange, and 3) ADP privation but 4) did not inhibit leak pathways 5) regardless of whether electrons entered at Complex I, II, III, or IV.
Conclusion: PEP metabolism by PK starves OxPhos by ristricting mitochondrial ADP availability in human beta-cells. These data are consistent with the newly proposed role for PEP and PK regulating the ATP/ADP mediated closure of KATP channels during GSIS.

Disclosure
I. Ruz-Maldonado: None. R.L. Cardone: None. R. Kibbey: None.

Funding
5R01DK127673-02
1741-P: The Type 2 Diabetes–Associated K+ Channel TALK-2 Is Localized to the Endoplasmic Reticulum and Modulates Beta Cell Ca2+ Handling and Insulin Secretion
Authors: DOBSON JORDYN , DADI PRASANNA , NAKHE ARYA Y. , JACOBSON DAVID 
Published: June 2024

Introduction and Objective: KCNK17, which encodes TALK-2, is one of the most abundant β-cell K+ channel transcripts. Polymorphisms in KCNK17 are associated with an increased predisposition for developing T2D. Therefore, our objective was to determine the β-cell functions of TALK-2.
Methods: Localization of TALK-2 was investigated with immunofluorescent staining and TALK-2-GFP constructs. TALK-2 function was tested with Ca2+ imaging of inducible TALK-2 cells, adenoviral KCNK17 shRNA mediated knockdown (KD) of dispersed human islets, and β-cell TALK-2 KD pseudoislets. Insulin secretion was performed with pseudoislets.
Results: TALK-2 protein displayed ER localization in β-cells within human pancreatic sections. Additionally, TALK-2-GFP colocalized with an ER-RFP marker and a plasmalemma dye in HEK293 cells. Overexpression of TALK-2 in HEK293 cells accelerated ER Ca2+ release (by 62±13%), reduced ER Ca2+ storage (by 67±12%) and increased basal cytosolic Ca2+ (by 11±0.5%). In human β-cells TALK-2 KD increased ER Ca2+ storage (by 16±5%). Moreover, TALK-2 KD increased Ca2+ influx at 11mM glucose in human β-cells that were dispersed (by 20±6%) and in pseudoislet preps (by 208±64%). Finally, β-cell TALK-2 KD pseudoislets showed reduced insulin secretion at 1mM (by 36±10%).
Conclusion: These data support that ER and plasmalemma localized TALK-2 channels function to reduce β-cell ER Ca2+ stores and limit glucose-induced Ca2+ influx respectively. Furthermore, TALK-2-mediated augmentation of ER Ca2+ leak likely enhanced basal insulin secretion by increasing cytosolic Ca2+. Therefore, polymorphisms in KCNK17 that increase TALK-2 activity or expression would be predicted to diminish β-cell ER Ca2+ stores, impair glucose-stimulated Ca2+ influx, elevate basal insulin secretion, and thus enhance insulin resistance.

Disclosure
J. Dobson: None. P. Dadi: None. A.Y. Nakhe: None. D. Jacobson: None.

Funding
Initiative for Maximizing Student Development at Vanderbilt (T32GM139800)Multidisciplinary Training in Molecular Endocrinology(T32DK007563); National Institutes of Health (DK-097392)
176-OR: Association between Clustering of Hypoglycemic Symptoms, Psychological Traits, and Problem-Solving Abilities in Adults with Type 1 Diabetes
Authors: SAKANE NAOKI , SAKANE SEIKO 
Published: June 2024

Background: Precision medicine in diabetes care requires a dedicated focus on hypoglycemic symptoms. This study aimed to explore the interrelationship between the clustering of hypoglycemic symptoms, psychological characteristics, and problem-solving capabilities in adults with type 1 diabetes (T1D).
Methods: A total of 251 adults with T1D (mean age: 51.5±12.9 years, mean HbA1c: 7.7 ± 0.9%) participated in this survey. Hierarchical clustering was employed to analyze eleven hypoglycemic symptoms (Edinburgh). Data encompassed diabetic complications, fear of hypoglycemia (HFS-behaviour and HFS-worry), depressive symptoms (PHQ-9), the hypoglycemia problem-solving scale (HPSS), and treatment details.
Results: Three distinct clusters emerged: individuals not sensitive to autonomic and neuroglycopenic symptoms (cluster 1, n=138), those sensitive to both autonomic and neuroglycopenic symptoms (cluster 2, n=19), and those sensitive to autonomic but not to neuroglycopenic symptoms (cluster 3, n=94). Compared to cluster 1, clusters 2 and 3 exhibited younger ages, higher fear of hypoglycemia, increased depressive symptoms, and greater use of CSII. Cluster 2 also displayed enhanced HPSS scores, indicating better detection control and a more proactive approach to seeking preventive strategies compared to cluster 1. No significant differences were observed in terms of diabetes duration, BMI, HbA1c levels, or diabetic complications. However, certain lifestyle factors, such as breakfast skipping, snack and sweetened beverage intake, and sleep deficits, varied among the clusters.
Conclusion: This study identifies three distinct clusters among adults with T1D. The findings may serve as valuable insights for diabetes professionals seeking to educate these individuals on how to effectively manage hypoglycemia.

Disclosure
N. Sakane: None. S. Sakane: None.