bluuebunny/crossref_metadata_2025_split huggingface dataset:
175-OR: Level 3 Hypoglycemia in Diabetes—An Age-Old but Not (Just) Old-Age Problem (iNPHORM, USA)
Authors: RATZKI-LEEWING ALEXANDRIA , BLACK JASON E. , ZOU GUANGYONG , RYAN BRIDGET L. , HARRIS STEWART B. 
Published: June 2024

Introduction & Objective: Whether advanced age increases Level 3 severe hypoglycemia (SH) rates remains surprisingly unresolved by research, despite its often-presumed association. Leveraging iNPHORM data, we aimed to address this gap.
Methods: Adults (≥18 y.o.) with T1DM or T2DM on insulin and/or secretagogues were recruited from a US-wide, probability-based internet panel. Prospective data were captured via an online screener, baseline, and 12 monthly follow-up questionnaires. For complete cases with ≥1 follow-up, we estimated the total (unadjusted) population-average effect of age on annualized Level 3 SH rates by diabetes type using negative binomial regression with generalized estimating equations. An interaction term tested subgroup effects by age &lt;65 vs ≥65 y.o. (α=0.05).
Results: N=978 were analyzed (T1DM: 16.7%; male: 49.6%; retention rate: 80.1%). The mean age was 51.0 (SD:14.3) (T1DM: 44.6 [SD:13.8]; T2DM: 52.2 [SD:14.1]) years; 20.4% (T1DM: 9.8%; T2DM: 22.5%) were ≥65 y.o. Level 3 SH incidence proportions were 44.2% (≥65 y.o.: 43.8%) in T1DM, and 31.8% (≥65 y.o.: 16.4%) in T2DM. Rates were 3.6 events per person-year (EPPY) (≥65 y.o.: 2.0 EPPY) in T1DM, and 5.3 EPPY (≥65 y.o.: 0.8 EPPY) in T2DM. The interaction term (&lt;65 vs ≥65 y.o.) was statistically significant for T1DM (p=0.03) and T2DM (p&lt;0.001). In T1DM, a 5-year increase in age reduced Level 3 SH rates by 23% (95%CI: 16%-30%, p&lt;0.001) for those &lt;65 y.o., and increased rates by 51% (95%CI: -15%-170%, p=0.16) for those ≥65 y.o. In T2DM, event rates decreased by 41% (95%CI: 38%-43%, p&lt;0.001) for those &lt;65 y.o., and increased by 21% (95%CI: -7%-57%, p=0.15) for those ≥65 y.o.
Conclusion: Level 3 SH rates declined with age until 65 y.o., when rates began to increase. Our results emphasize the need for age-specific hypoglycemia prevention. Clinical efforts should address the impact of advancing age among older adults, particularly those with T1DM; yet interventions targeting young adults, especially with T2DM, should not be overlooked.

Disclosure
A. Ratzki-Leewing: Research Support; Sanofi. Advisory Panel; Dexcom, Inc. Consultant; Abbott. Advisory Panel; Sanofi-Aventis U.S. Other Relationship; American Diabetes Association. Consultant; Novo Nordisk, Eli Lilly and Company. J.E. Black: None. G. Zou: None. B.L. Ryan: None. S.B. Harris: Consultant; Abbott. Research Support; Boehringer-Ingelheim. Consultant; Dexcom, Inc. Advisory Panel; Eli Lilly and Company. Consultant; Eli Lilly and Company, Novo Nordisk, Sanofi. Research Support; Novartis AG. Consultant; Bayer Inc.

Funding
The iNPHORM study was funded through an investigator-initiated grant from Sanofi Global.
1756-P: Dynorphin Expression in Beta-Cells—Insights into Regulation
Authors: MOVAHED MIRANDA , BLANDINO-ROSANO MANUEL 
Published: June 2024

The expression of dynorphin within beta-cells, an endogenous opioid peptide predominantly expressed in the CNS and involved in stress response, pain, and addiction, has intrigued researchers for over two decades. Yet, its functional implications in islet physiology remain incompletely elucidated. Genetically, the Pdyn gene is prominently upregulated in beta-cells under high-fat diet conditions and in human beta-cells affected by Type 2 Diabetes, emphasizing its potential relevance in metabolic disorders. This comprehensive investigation elucidates the regulatory mechanisms and developmental dynamics of dynorphin within this specific subset of beta-cells. Our investigation revealed a developmental progression in dynorphin expression, with undetectable levels at birth gradually escalating with advancing age. Notably, dynorphin expression was heterogeneous within beta-cells, manifesting in approximately 15% of beta-cells at two months. In vitro studies show that an increase in glucose levels notably correlates with increased dynorphin expression specifically in beta-cells already expressing dynorphin, unveiling a critical interplay where cAMP, Ca2+ and Creb signaling cascades emerge as pivotal regulators governing dynorphin expression within this subset of beta-cells. Furthermore, our findings show the synergistic effect of palmitate in conjunction with high glucose, amplifying dynorphin levels in these specific beta-cells expressing dynorphin. This selective interaction underscores the complex interrelationship between nutrient exposure and dynorphin expression, offering intriguing insights into the responses of a subset of beta-cells to diverse dietary components.

Disclosure
M. Movahed: None. M. Blandino-Rosano: None.

Funding
1R01DK132095
1760-P: The Role of Branched-Chain Amino Acids in Augmenting Insulin Secretion in Human Islets at Different Glucose Concentrations
Authors: HOR CHENG KOH , CHAN JAMES C.Y. 
Published: June 2024

Nutrient sensing is an important feature of pancreatic islets to manage glucose homeostasis. Islets are highly responsive to glucose yet are significantly less sensitive to individual amino acids. Conversely, combinations of ingested amino acids may augment insulin secretion when given with glucose. We explored the insulinotropic effect of different amino acid combinations when co-administered with low (3 mM) and high (11 m) glucose levels.
Batch incubations were performed with islets from healthy and lean (BMI &lt; 25 kg/m2) Caucasians. Islets were starved at 3 mM glucose before being sequentially treated with amino acids in conjunction with low and high glucose, followed by KCl. Insulin secretion was analysed using ELISA and normalized by islet equivalent (IEQ) counts.
When BCAA is given with low glucose, insulin secretion significantly increases, comparable to high glucose alone. When given with high glucose, BCAA had no insulinotropic effects. Other combinations did not result in a significant increase in insulin secretion at both low and high glucose. In summary, our data examines the insulinotropic effect of different amino acid combinations at high and low glucose respectively, representing fasted and fed states.

Disclosure
K. Hor Cheng: None. J.C.Y. Chan: None.
1762-P: The Dynamic Role of PPAR-γ and Related Pathways in Beta Cells during Type 2 Diabetes Mellitus Progression
Authors: XIAO YU , SHI JIANXIANG , ADAMA MAHARANA PRATHAP R. , KIM GRACE J. , WELCH MEGHAN , JIANG YINAN 
Published: June 2024

Type 2 Diabetes (T2D) is characterized by peripheral insulin resistance, deteriorating beta-cell function and eventual beta-cell failure. The role of Peroxisome proliferator-activated receptor γ (PPAR-γ) in beta-cells, as opposed to its role in peripheral cells in glucose metabolism, is not well understood during T2D progression. Here, we utilized S961, a specific insulin receptor inhibitor, to induce glucose intolerance and hyperglycemia in mice, thereby simulating the stages of T2D progression. Using beta-cell-specific knockouts of PPAR-γ, WNT5A and SMAD7, we explored the molecular mechanisms through which PPAR-γ and related signaling pathways affect beta-cell proliferation, insulin secretion, and dysfunction in T2D. Our results indicated an initial increase in PPAR-γ expression in beta-cells of pre-diabetic patients, followed by a reduction in diabetic patients. In mice, PPAR-γ expression in beta-cells rose after 7 days of S961 treatment (paralleling pre-diabetic conditions) but fell after 14 days (reflecting diabetic conditions). Conversely, SMAD7 levels in beta-cells were stably minimal initially but increased in later stages in both mice and diabetic patients. Assisted with single-cell RNA sequencing, we found that S961-treated mice experienced an upregulation in the TGF-β signaling cascade in beta-cells, leading to the activation of pSMAD3, which subsequently upregulated PPAR-γ, enhancing beta-cell proliferation and secretion. However, prolonged S961 exposure and the direct effects of hyperglycemia augmented SMAD7 levels, which inhibited SMAD signaling, resulting in reduced PPAR-γ, compromised beta-cell functionality and the onset of diabetes. This late upregulation of SMAD7 was likely mediated through WNT5A/Smarf2/ubiquitin signaling, which was progressively altered during T2D progression. Our findings underscore the intricate interplay of PPAR-γ and related pathways in beta-cells during T2D pathogenesis.

Disclosure
Y. Xiao: None. J. Shi: None. M.R. Adama: None. G.J. Kim: None. M. Welch: None. Y. Jiang: None.

Funding
Internal grants
1769-P: Empowering Islet Biology—Advancing Scientific Rigor and Reproducibility, Resource Discoveries, and Effective AI/ML Collaboration via dkNET
Authors: CHEN SHUIBING 
Published: June 2024

The NIDDK Information Network (dkNET; dknet.org) is an open community resource for researchers supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), including islet biology investigators. The primary objective is to provide tools, access to diverse resources, and training modules to foster scientific rigor and reproducibility, and collaboration among researchers. dkNET offers various services such as Resource Reports for finding resources and tracking the use and performance of resources (antibodies, model organisms, cell lines, plasmids, biosamples, software tools, and protocols) through the use of Research Resource Identifiers (RRIDs); FAIR Data Resources that provide guidance to meet NIH’s most recent data management and sharing mandates; and the Hypothesis Center that provides tutorials enabling researchers to utilize online datasets and analytics and visualization tools. Building on its success, dkNET is extending its services to provide Artificial Intelligence (AI)/Machine Learning (ML) techniques and cloud computing resources to the NIDDK research community to fully leverage data assets cataloged by dkNET to explore and develop hypotheses. A successful pilot use case, powered by Texera, has been developed to apply machine learning tools to identify the key factors controlling aging of human endocrine cells.

Disclosure
S. Chen: None.

Funding
NIH NIDDK (U24DK09777)
1770-P: Gymnemic Acid Functions as NFE2L2 Activator to Enhance Antioxidant Defense against Cellular Stress Caused by Inflammation and Hypoxia in Human Pancreatic Islets
Authors: KUNCHA JAYACHANDRA , DARDEN CARLY , KIRKLAND JEFFREY , MATTKE JORDAN D. , LAWRENCE MICHAEL C. , NAZIRUDDIN BASHOO 
Published: June 2024

Introduction & Objective: Increasing the mass of pancreatic beta cells through neogenesis and proliferation while protecting islets from oxidative stress and inflammation is a possible therapeutic strategy for treating all types of diabetes. We examined the effect of the natural phytocompound Gymnemic Acid I (GA) on human pancreatic islets to reduce oxidative stress and inflammation.
Methods: Human pancreatic islets were exposed to various stress-induced, well-established models like hypoxia and cytokine cocktails (CC) with or without GA. Flow cytometry, Luminex assay, and RT-qPCR techniques were used to assess the oxidative stress and inflammatory markers. All the results were statistically compared with appropriate experimental controls.
Results: Treatment with GA maintained islet viability for &gt;24 h and significantly increased (P&lt;0.024) insulin secretion assessed by GSIS and substantially (P&lt;0.05) upregulated beta-cell functional genes (PCSK1, SLC2A, GCK). Reactive oxygen species (ROS), hypoxia, and CC-induced cell death were all substantially reduced by GA treatment. Additionally, inflammatory, pro-apoptotic genes (HIF1A, CCL5, IL-6, INFb1, IP10, CASP3) and secretory cytokine production were considerably (P&lt;0.05) downregulated. It protected the islets by making it easier for the transcription factor NFE2L2 to bind ARE which in turn led to a significant (P&lt;0.05) upregulation of promotor regions encoding cytoprotective and antioxidant genes (HOMOX1, SOD1, CAT, NQO1, BCL2).
Conclusion: GA functions as an NFE2L2 activator or stabilizer, protecting and extending the viability of islets. It has improved islet function by boosting endogenous antioxidant defense enzymes, preventing oxidative damage and apoptosis in response to cellular stress driven by inflammation, hypoxia, or both. GA can serve as a treatment for improving human islet survival and function.

Disclosure
J. Kuncha: None. C. Darden: None. J. Kirkland: None. J.D. Mattke: None. M.C. Lawrence: None. B. Naziruddin: None.
1779-LB: Hospitalization for Hypoglycemia and Its Risk Factors among Patients with Diabetes and Cognitive Impairment
Authors: TANG HUILIN , LU YING , DONAHOO WILLIAM T. , DEKOSKY STEVEN T. , BIAN JIANG , GUO JINGCHUAN 
Published: June 2024

Introduction: Hypoglycemia is the most common serious adverse effect of diabetes treatments and a major cause of hospitalization, with an increased risk in the presence of cognitive impairment. This study aimed to identify risk factors associated with hospitalization for hypoglycemia in patients with diabetes and cognitive impairment.
Methods: Using 2012-2020 electronic health records data from University of Florida Health, we included patients with diabetes and cognitive impairment aged ≥50 years. The outcome was the first occurrence of hospitalization for hypoglycemia. Baseline variables include demographics, comorbidities, and comedications. Multivariate logistic regression was employed to calculate the adjusted odds ratio (AOR) and 95% confidence interval (CI) of hospitalization for hypoglycemia associated with baseline risk factors.
Results: This study included 3,263 patients diagnosed with both diabetes and cognitive impairment, with a mean age of 71.8 years. Female and non-Hispanic Black population accounted for 55.8% and 36.1%, respectively. In a median follow-up period of 1.95 years (Interquartile range, 0.97-3.55), 12.6% (410 patients) experienced hospitalization for hypoglycemia. Compared with those with HbA1c of 7-7.9%, the AOR of hospitalization for hypoglycemia was 0.64 (95% CI 0.34-1.19), 0.89 (0.52-1.52), 2.19 (1.20-3.98), and 2.26 (1.24-4.10) among those with HbA1c &lt;6, 6-6.9, 8-8.9, and ≥9%, respectively, in the multivariable logistic regression model. Additionally, prior hypoglycemia (AOR, 5.58, 95%CI, 2.67-11.67), chronic kidney disease (1.65; 1.08-2.53), and insulin use (2.25; 1.37-3.70) were independent risk factors for hospitalization for hypoglycemia.
Conclusion: We identified several risk factors associated with hospitalization for hypoglycemia among patients with diabetes and cognitive impairment, offering insights into the identification of high-risk patients and potential preventive strategies.

Disclosure
H. Tang: None. Y. Lu: None. W.T. Donahoo: None. S.T. DeKosky: Advisory Panel; Acumen Pharmaceuticals, Cognition Therapeutics. Consultant; Eisai Inc., Novo Nordisk. Other Relationship; Prevail Pharmaceuticals, Vaccinex. Consultant; Biogen. Advisory Panel; Otsuka America Pharmaceutical, Inc. J. Bian: None. J. Guo: None.
1782-LB: Treatment Efficacy of Diabetic Kidney Disease with a Novel Specific Cathepsin L Inhibitor
Authors: ZHAO MIAOMIAO , LI MING-JIA , LI XIAO-YA , YANG JIN-KUI 
Published: June 2024

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD), yet there are no specific drugs for DKD. In previous research, we found that the lysosomal enzyme Cathepsin L (CTSL) is upregulated in diabetic patients, and high glucose levels can activate CTSL protein function (eLife, accepted). We also discovered the important role and mechanism of CTSL in COVID-19 infection (PMID: 33774649, 35668062). Previous studies have shown that CTSL activation can lead to podocyte fusion and detachment, resulting in proteinuria. Broad-spectrum cathepsin inhibitors protect renal function in animals and prevent proteinuria. However, current cathepsin inhibitors have non-specific targets and result in significant side effects, making them unsuitable for human use. Here, we developed a novel CTSL inhibitor (US Patent No: US11858905B1) that specifically targets CTSL without significant side effects. We confirmed in db/db mice (with early-stage DKD phenotype) and BKS-db-eNos-/- mice (with late-stage DKD phenotype) that: 1. Acute administration for 3 days at a dose of 1000mg/kg showed no significant toxicity; chronic administration for 16 weeks at a dose of 20mg/kg showed no significant toxicity and reduced the mice’s water and food intake. 2. Chronic administration for 16 weeks improved markers of kidney damage in db/db mice and BKS-db-eNos-/- mice, such as urine albumin creatine ratio, urine NGAL creatine ratio, and urine Kim-1 creatine ratio. 3. Pathological results showed a significant reduction in glomerular volume, renal interstitial inflammation, and PASM staining indicated a significant improvement in glomerular sclerosis with the use of the novel CTSL inhibitor. Masson staining suggested a significant improvement in renal interstitial fibrosis with the CTSL inhibitor. Our study demonstrates the significant improvement in diabetic kidney disease treatment with the novel CTSL inhibitor.

Disclosure
M. Zhao: None. M. Li: None. X. Li: None. J. Yang: None.
1785-LB: Potential Noninvasive Markers Predicting Diabetic Kidney Disease Development
Authors: WU JIANBO 
Published: June 2024

Introduction: Diabetic kidney disease (DKD) is one common microvascular complication of diabetes. When the kidney is damaged, it may communicate abnormally with cells in the blood system. Renipuncture is invasive and traumatic for patients, and a noninvasive panel that predicting DKD occurrence or progression needs to be identified.
Method: The single-cell RNA sequencing (scRNA-seq) dataset (GSE183279) comprise kidney samples from normal individuals (n=18) and patients with DKD (n=12). The bulk RNA sequencing (RNA-seq) dataset (GSE96804) consist of renal glomerular tissue samples from normal individuals (n=20) and DKD patients (n=41). The proteomics data (PXD047872) include serum samples from normal, diabetic mellitus, early-stage and late-stage diabetic nephropathy. In brief, we utilize "Seurat" package in R (version 4.3.1) to analyze the scRNA-seq data, Tensor-cell2cell to identify intercellular communication, and ClusterGVis package to extract protein expression matrices.
Results: By integrating bulk-seq and scRNA-seq, we have identified 5 critical receptor-ligand pairs and 17 hub genes, emphasizing the vital role of integrin-mediated cell interactions in DKD's pathogenesis. By Integrating the serum protein data and scRNA-seq, we have identified 7 significantly upregulated proteins and 3 significantly downregulated proteins in DKD group.
Conclusion: These findings set a foundation for future clinical applications. We will verify these markers in clinical samples and confirm their functions for the kidney in the future.

Disclosure
J. Wu: None.

Funding
This research was funded by National Natural Science Foundation project (82370823, 82370356); Beijing Tongzhou District Science and Technology Plan Project (JCQN2023001, KJ2023SS011).
1787-LB: Pathological Characteristics of Ferroptosis in Diabetic Kidney Disease
Authors: LI MIN , ZHOU YARU , GAO QIAN 
Published: June 2024

Introduction & Objective: Diabetes kidney disease (DKD) is common complication of diabetes and it is currently considered as the primary cause of end-stage renal disease. Ferroptosis is a newly defined regulatory cell death caused by iron-dependent lipid peroxidation, and it plays a key role in the development of DKD. This study was aimed to examine in vivo the involvement of ferroptosis in diabetes-related pathological changes in the kidney.
Methods: 30 DKD patients diagnosed with renal tissue pathology from the Third Hospital of Hebei Medical University and 10 healthy controls were selected for H&E, PASM staining, and immunohistochemical staining to evaluate pathological changes such as renal inflammation and fibrosis, as well as changes in the expression of iron death related proteins; At the same time, general statistical data and clinical test data of each group of patients were collected, and further logistic regression analysis and receiver operating characteristic curve (ROC) analysis were performed to explore independent risk factors and diagnostic efficacy of DKD.
Results: The expressions of iron death-related proteins GPX4, ACSL4, FTH and FTL were increased in renal tissues of DKD patients, while the expressions of Nrf2 and TfR1 were decreased.And the expression levels of Nrf2 and ACSL4 proteins in kidney tissue are influential factors for the occurrence of DKD, and have high diagnostic efficacy for DKD.
Conclusion: The current study showed that ferroptosis contributes to diabetes-related pathological changes in the kidney, and we demonstrated that ferroptosis was involved in the development of DKD.

Disclosure
M. Li: None. Y. Zhou: None. Q. Gao: None.

Funding
Project of Hebei Provincial Health Commission (20230093)
1798-LB: STK25 Promotes Diabetic Atherosclerotic Plaque Formation via Septin2 Regulating Mitophagy
Authors: WANG DI , WANG LU , WANG YAN , YANG LONGYAN 
Published: June 2024

Introduction & Objective: Serine/Threonine protein kinase 25 (STK25) was reported to regulate lipid accumulation and activation of inflammatory and fibrotic pathways as well as oxidative and endoplasmic reticulum stress in human aortic endothelial cell. However, the direct substrate of STK25 in endothelial cells is not clear, and the mechanism of STK25 and its substrate in the diabetic atherosclerosis remained unknown. This study aimed to explore the substrate and potential mechanism of STK25 in the formation of diabetic atherosclerotic plaque.
Method: Male C57BL/6J mice were intraperitoneal injection of streptozotocin and tail-vein injection of the rAAV8-PCSK9 virus (5 ×1010 genome copies) or negative control to establish an diabetic atherosclerosis model. Thereafter, mice were fed a western-type diet. Morphological observation, blood triglyceride and cholesterol analysis, oil red O staining, immunofluorescent staining, electron microscope, real-time PCR, co-immunoprecipitation, and Western Blot were performed. Human aortic endothelial cells subjected to different concentrations of low density lipoprotein (LDL) was applied for assessing the related mechanism.
Result: STK25 increased, the endothelial barrier function was impaired, and mitophagy of aortic endothelial cells decreased in vivo and in vitro. While the silencing of STK25 reduces lipid accumulation and improve the mitophagy in aortic endothelial cells. And LC/MS and Co-IP showed that Septin2 had interaction with STK25. Moreover, STK25 regulates mitophagy of endothelial cell through phosphorylation of Septin2.
Conclusion: Together, we provide several lines of evidence that STK25 promoted diabetic atherosclerotic plaque formation, which is accounted for at least partly via septin2 regulating mitophagy.

Disclosure
D. Wang: None. L. Wang: None. Y. Wang: None. L. Yang: None.

Funding
Beijing Luhe Hospital Capital Medical University, Youth Research Incubation Project (LHYY2023-JC207)