bluuebunny/crossref_metadata_2025_split huggingface dataset:
1722-P: Suppression of Glucagon Signaling Promotes α-to-ß Reprogramming
Authors: TAGUCHI TOMOMI , SUZUKI AGENA , SHIMIZU NAOYA , FUJISHIMA REI , KIMURA KAORI , ITO SHIORI , SHIMOTATARA HIDEAKI , INOUE MITSUKO , MIYATSUKA TAKESHI 
Published: June 2024

The generation of surrogate β cells has attracted a lot of attention for the cure of diabetes. Recently, we have revealed that glucagon antibody induces α-cell neogenesis in adult mice, suggesting that the suppression of glucagon signaling could play a role in cellular plasticity in α-cell lineage. Therefore, we hypothesized that inhibiting glucagon signaling may affect the efficiency of α-to-β reprogramming. We generated a transgenic mouse line (αPdx1) that exogenously and inducibly expresses Pdx1 specifically in α cells, and treated the mice with glucagon receptor antagonist. As FLAG-tagged sequence is attached to Pdx1, the exogenous expression of Pdx1 can be distinguished from the endogenous Pdx1 gene. The reprogramming efficiency was evaluated by counting FLAG-tag/insulin double-positive cells, that is, α-cell-derived insulin-producing cells. Immunohistological analysis demonstrated that the number of α-cell-derived insulin-producing cells was significantly increased in αPdx1 mice treated with glucagon receptor antagonist (GRA), compared with the mice treated with vehicle (26.0 ± 1.6 vs 13.5 ± 1.3%, p &lt; 0.0001). In addition, GRA significantly increased α-to-β reprogramming ratio in αPdx1 mice after β-cell ablation (73.7 ± 3.3 vs 52.0 ± 1.8%, p = 0.0004). Furthermore, when the mice were induced hyperglycemia by alloxan, the administration of GRA significantly improved hyperglycemia during intraperitoneal glucose tolerance test (IPGTT), compared αPdx1 mice administered by vehicle (p = 0.012). Notably, the insulin levels during IPGTT were significantly higher in the mice treated with GRA (p = 0.034). Thus, the suppression of glucagon signaling promotes α-to-β reprogramming in mice, which could lead to establishing efficient methods for generating surrogate β cells.

Disclosure
T. Taguchi: None. A. Suzuki: None. N. Shimizu: None. R. Fujishima: None. K. Kimura: None. S. Ito: None. H. Shimotatara: None. M. Inoue: None. T. Miyatsuka: None.
1727-P: Low-Protein Diet during Pregnancy and Lactation May Impair Islet Function of the Female Offspring Mice Potentially Due to Islet Epigenetic Changes
Authors: PENG YUEYUE , CHEN YALAN , LIU ZHIGU , LIN BEISI , LING PING , LI YANLI , XU FEN , LIANG HUA , YAN JINHUA , XU WEN 
Published: June 2024

Objective: This study aimed to investigate how the low-protein diet during pregnancy and lactation affects the islet function of the female offspring mice, and explore the potential mechanisms.
Methods: Female mice were treated with control diet (28% protein) or low protein diet (9% protein) throughout their pregnancy and lactation. Their female offspring were divided into the control diet group (CD) and the low-protein diet (LPD) group based on their maternal diet. After weaning, all offspring received a standard diet until week 18. Body weight and FBG of the female offspring were measured. At week 17, intraperitoneal glucose tolerance test, simultaneous serum insulin test and intraperitoneal insulin tolerance test were performed in all offspring. Thereafter, transcriptome sequencing of offspring's primary islets was conducted. The bioinformatics analysis applied between the targeted genes of differentially expressed LncRNAs and the differentially expressed mRNA. LncRNA Gm38850 knockdown Min6 cell model was used to study the relationship between Gm38850 and lactate dehydrogenase A (Ldha).
Results: The LPD group showed impaired glucose tolerance and reduced insulin release compared to the control group. However, no significant differences were seen in FBG and intraperitoneal insulin tolerance. Transcriptome sequencing found 55 differentially expressed mRNAs and four down-regulated LncRNAs in islet cells. Pathway enrichment analysis suggested that these differentially expressed RNAs were mainly involved in the biological functions of pyruvate metabolism, IL-17 signaling, glucagon pathway, AGE-RAGE signaling, and HIF-1 signaling. Up-regulated Ldha expression in islets and Min6 cells after Gm38850 knockdown were confirmed with immunofluorescence.
Conclusions: Low-protein diet during pregnancy and lactation may impair islet function of the offspring female mice, potentially due to islet epigenetic changes.

Disclosure
Y. Peng: None. Y. Chen: None. Z. Liu: None. B. Lin: None. P. Ling: None. Y. Li: None. F. Xu: None. H. Liang: None. J. Yan: None. W. Xu: None.

Funding
Guangdong Natural Science Foundation (2022A1515012364); Guangzhou Science and Technology Plan Project (202102010175); Guangzhou Science and Technology Plan Project (202201020550)
1746-P: Understanding the Pancreatic Islet Proteome in Response to Prolonged High-Glucose Exposure
Authors: KHOSRAVIFAR MINA , HAEMMERLE MATTHEW W. , SEN SABYASACHI , STOFFERS DORIS A. 
Published: June 2024

Introduction & Objective: Acute hyperglycemia challenges augment the functional status of β cells, whereas chronic high glucose exposure paradoxically impairs the ability of β cells to respond to and secrete appropriate amounts of insulin. We have found that 72 hr exposure of mouse islets to high glucose markedly increases glucose, and IBMX stimulated insulin secretion, while basal insulin secretion was also moderately elevated. Here, we examine the impact of 72 hr of 16.7 mM vs 2.8 mM glucose on the whole pancreatic islet proteome.
Methods: Isolated C57BL/6N mouse islets were treated with low (2.8 mM) or high (16.7 mM) glucose for 24 hr or 72 hr (n=6 islet preparations/group). The whole islet proteome was obtained using mass spectrometry. Pathway analysis was conducted using Gene Set Enrichment Analysis (GSEA) in R software.
Results: After 72 hr high vs low glucose exposure, a total of 5847 proteins were identified, with 136 proteins significantly upregulated, including Ins2 (Log2FC ≥1, Adj. PV&lt;0.05), and 55 proteins significantly downregulated, including Insr (Log2FC ≤ -1, Adj. PV&lt;0.05). The application of Principal Component Analysis to our proteomic data revealed a tightly clustered pattern that segregated according to glucose exposure. Our analysis revealed distinct regulatory patterns in cellular pathways in response to 72 h sustained high glucose. Among the prominent upregulated pathways were protein N-linked glycosylation, the ubiquitin-dependent ERAD pathway, and protein biosynthetic processes. Conversely, downregulated pathways predominantly centered around metabolic regulation and mitochondrial processes, including various components of the oxidative stress response and mitochondrial electron transport chain.
Conclusion: Considering the importance of glucose adaptation of islet function to the preservation of glucose homeostasis, this study provides a glucose response proteomic signature that raises known and novel targets for further exploration.

Disclosure
M. Khosravifar: None. M.W. Haemmerle: None. S. Sen: None. D.A. Stoffers: Other Relationship; Eiger BioPharmaceuticals.

Funding
National Institutes of Health (R01-DK-122039)
1765-P: Inhibition of NLRP3 Inflammasome Activation and Reduction in T-Cell Migration Are Key Mechanisms by Which PAHSAs Protect against Type 1 Diabetes
Authors: SYED ISMAIL , MAGUPALLI VENKAT G. , ARYAL PRATIK , SANTORO ANNA , SIEGEL DIONICIO , KAHN BARBARA B. 
Published: June 2024

Palmitic acid esters of hydroxy stearic acids (PAHSAs) are bioactive lipids with anti-inflammatory and anti-diabetic effects. PAHSAs markedly reduce the incidence and delay the onset of autoimmune T1D in NOD mice. PAHSAs attenuate autoimmune responses by lowering mature T helper cell activation and B cell number and increasing regulatory T cell activity in the islets of NOD mice. Toll-like receptors and NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome pathways play an essential role in T1D pathogenesis. NLRP3 is critical for inducing expression of chemokines and their receptors which stimulate pathogenic T cell migration into islets. Here, we aimed to determine the mechanisms by which PAHSAs attenuate immune responses to prevent T1D.
Results: Adoptive transfer of splenocytes from PAHSA-treated NOD mice delays and attenuates T1D incidence in immunodeficient NOD.SCID mice. These effects are associated with decreased expression of NLRP3 inflammasome components by 25-55% and chemokines by 60-70% without altering chemokine receptor expression in immune cells isolated from PAHSA-treated NOD mouse islets. In human islets from normal and type 2 diabetic donors, clonal pancreatic β-cells (MIN6 cells) and bone marrow-derived macrophages, PAHSAs attenuate pro-inflammatory cytokine and chemokine gene expression and secretion in response to LPS or Nigericin (NLRP3 inflammasome activator). In co-culture studies of MIN6 cells and CD4+ T cells, PAHSAs attenuate LPS and Nigericin-induced CD4+ T cell migration by 65%. Conclusions: PAHSAs’ protective effects against T1D can be conferred by transfer of immune cells from PAHSA-treated mice. Inhibition of NLRP3 inflammasome activation and T cell migration into islets are key mechanisms by which PAHSAs protect islets from immune-mediated attack. Thus, PAHSAs may serve as therapeutic agents to prevent and/or treat T1D.

Disclosure
I. Syed: None. V.G. Magupalli: None. P. Aryal: Employee; Cellarity. A. Santoro: None. D. Siegel: None. B.B. Kahn: Advisory Panel; Janssen Pharmaceuticals, Inc. Consultant; Vida Ventures Advisors, Arrowhead Pharmaceuticals, Inc.

Funding
NIH K01 DK118041 (IS).Joslin Pilot & Feasibility Grant P30 DK046200 (IS).NIH R01 DK106210 (BBK).JPB Foundation (BBK).
178-OR: Assessing Hypoglycemia Awareness—Validating HypoA-Q within the T1D Exchange Registry
Authors: KUEI LIN YU , YE WEN , HEPWORTH EMILY , MATUS AUSTIN M. , FLATT ANNELIESE , DE ZOYSA NICOLE , SHAW JAMES A. , RICKELS MICHAEL R. , AMIEL STEPHANIE A. , SPEIGHT JANE 
Published: June 2024

Introduction & Objective: Hypoglycemia awareness is commonly assessed using legacy patient-reported outcome measures (PROMs; e.g., Gold and Clarke). However, they may not meet current FDA PROM standards. The 5-item Impaired Awareness scale of the HypoA-Q short form (SF) was developed in accordance with FDA standards. Our aim was to validate it in a large cohort of US adults with type 1 diabetes.
Methods: We surveyed registrants of the national T1D Exchange registry, collecting demographics; 6-month severe hypoglycemia (SH) history; and responses to HypoA-Q SF, Gold and Clarke. The Clarke hypoglycemia awareness factor (“ClarkeHAF”) was calculated to exclude items about SH history. Analyses included Cronbach’s α (internal consistency reliability), Spearman correlations (convergent and divergent validity), multiple logistic regression analysis (predictive validity) and X2 test (SH odds with HypoA-Q SF score ≥12).
Results: The survey was completed by 1,580 participants (52% women, median[IQR] age 43[33—58]y, diabetes duration 24[12—37]y, 87% non-Hispanic Caucasian, 94% using continuous glucose monitors). The HypoA-Q SF had satisfactory reliability (α=0.79). Convergent validity was supported by moderate-to-strong correlations with the single-item Gold (rs=.63), 8-item Clarke (rs=.79), and ClarkeHAF scores (rs=.82; P&lt;.001 for all). Divergent validity was supported by weak correlation with diabetes duration (rs=.18, P&lt;.001), and no correlation with HbA1c. After adjusting for age, sex and diabetes duration, higher HypoA-Q SF scores were associated with greater SH risk (95%CI: .59—.65, P&lt;.001), performing comparably to Gold (.57—.63, P&lt;.001) and ClarkeHAF (.59—.65, P&lt;.001), while the 8-item Clarke score (retaining SH history items) performed better in predicting SH (.70—.75). HypoA-Q SF score ≥12 was associated with 5.2-fold higher odds of SH (P&lt;.001).
Conclusion: These findings support future use of the HypoA-Q SF for assessing hypoglycemia awareness and risk for SH.

Disclosure
Y. Lin: None. W. Ye: None. E. Hepworth: None. A.M. Matus: None. A. Flatt: None. N. de Zoysa: None. J.A. Shaw: Advisory Panel; Mogrify. M.R. Rickels: Consultant; Vertex Pharmaceuticals Incorporated, Sernova, Corp. Research Support; Dompé. S.A. Amiel: Advisory Panel; Vertex Pharmaceuticals Incorporated. Other Relationship; Sanofi. J. Speight: None.

Funding
National Institutes of Health (U01DK135111, K23DK129724)
1790-LB: The Value of Duke Treadmill Score in Predicting Severity of Coronary Artery Disease In Diabetic Patients by SYNTAX Score
Authors: TAIMUR SYED D.M. 
Published: June 2024

Aim & Object: One of the non invasive test is exercise tolerance test which carried out to identify prediction of severity of coronary artery disease and to assess the risk of major cardiac events. To establish prediction of coronary artery disease in patient having diabetic patient who performed exercise tolarence test by SYNTAX score.
Methodology: There were 520 patients included in this study, who were divided into groups based on their Duke tread mill scores. Diabetic patients with high Duke Treadmill score (DTS) (≤-11) were categorized in group I and diabetic patients with medium ( -10 to +4) and low Duke Treadmill score(≥+ 5) were included in group II.
Results: The mean age of the study population was 55.2 ± 9.0 years ranging from 18-75 years, According to the study, 52.58% of Group I patients were 51-65 years old, had more triple vessel disease, and had left main disease with or without other vessel involvement, which was significantly statistically significant (p=0.001).Patients with triple vessel disease had higher in SYNTAX score&gt; 22 than SYNTAX score &lt; 22 which was statistically significant (p=0.001). Diabetic patients with DTS &lt; -11 (high-risk group) carry more than 8.1(95% CI = 5.91 - 14.04)-fold higher risk of having severe CAD (SYNTAX score &gt; 22) than those with DTS ≥ -10 (low & medium risk) (p &lt; 0.001). It is evident from DTS as well as SYNTAX score that they exhibit a significant negative correlation (r = - 0.541, p 0.0001).
Conclusion: By calculating SYNTAX scores, it was found that high DTS is positively correlated with severity of coronary artery disease. Cardiovascular disease is predicted in patients who score high on the Duke Treadmill.

Disclosure
S.D.M. Taimur: None.
1792-LB: Long-Term Impact of Glucose Status on Risk of Restenosis after Percutaneous Transluminal Coronary Angioplasty—A Six-Year Follow-up Study
Authors: GU YAN , ZHANG LEI , ZHANG QI , LIU ZHENYU , LIU YUQING , DONG YANHU 
Published: June 2024

Patients with diabetes (DM) are at high risk for restenosis after coronary stenting. Information relating the long-term outcome of percutaneous transluminal coronary angioplasty (PTCA) to prediabetes is, however, limited. We retrospectively analyzed data of 951 patients (mean age 59.5±4.2 yrs, 60.5% of men, mean history of coronary heart disease 9.1±1.1 yrs) who undertook PTCA at Emergency Department between Jan 2008 and Dec 2011. Baseline measures included blood pressure (BP), fasting plasma glucose, lipid profile, A1c, C-reactive protein (C-RP), and 2-hour capillary glucose. All patients had follow-up coronary CTA 6 year after PTCA. Restenosis was defined as ≧ 50% stenosis in stent or within 5 mm adjacent to stent. The rate of restenosis was compared among patients with normal glucose tolerance (NGT, n=407), impaired glucose regulation (IGR, n=263), and DM (n=281) according to their baseline glucose levels or prior history of DM. Patients with DM had highest levels of body mass index (BMI), BP, triglycerides (TG), and C-RP, followed by those with IGR and NGT (P&lt;0.01).The number of lesion was 1.6, 1.8, and 2.6 in patients with NGT, IGR, and DM, respectively (p&lt;0.05). At year 6, the rate of restenosis, evaluated by coronary CTA, were 4.8%, 6.5%, and 14.2% in patients with NGT, IGT, and DM, respectively (P&lt;0.05). Among DM subgroup, compared with patients with A1c&lt;8%, those with A1c&gt;8% had increased rate of restenosis (15.8% vs. 12.4%, P&lt;0.05). In the logistic regression model, the odd ratio (OR) of having restenosis was 1.52 (95%CI: 1.03-2.90) for DM and 1.11 (95% CI: 1.01-1.54) for IGR, after adjusting for age, history of CHD, BMI, BP, LDL-C, TG, A1c and C-RP. Restenosis is more frequent in patients with compared those without DM. Prediabetes is associated with increased risk of restenosis after PTCA during a long-term follow-up period. The data indicates that intervention of hyperglycemia should be addressed in CHD patients even in those with prediabetes.

Disclosure
Y. Gu: None. L. Zhang: None. Q. Zhang: None. Z. Liu: None. Y. Liu: None. Y. Dong: None.
1808-LB: NIK-Mediated Microglia Polarization Induces Endothelial Dysfunction in Diabetic Retinopathy
Authors: LI HONGXUE , KUANG HONGYU 
Published: June 2024

Introduction & Objective: Chronic inflammation significantly contributes to endothelial dysfunction in diabetic retinopathy (DR). NIK, a central and specific signal component that regulates the activation of noncanonical NF-κB pathway, is overexpressed in inflammatory diseases, metabolic disorders, and cancer. Although some achievement have been made in the study of NIK, it is unknown whether NIK can participate in the progression of DR.
Methods: Mice fed a high-fat diet and injected with streptozotocin were induced to develop DR. At the same time, human microglial cells 3 (HMC3) and Human retina microvascular endothelial cells (hRMECs) were exposed to AGEs to mimic DR pathologies in vitro. B022 (a small-molecule inhibitor of NIK) was injected into DR mice and added into the cell culture medium to investigate the role of NIK in microglia polarization-induced endothelial dysfunction. To further explore the underlying mechanism, lentiviruses harboring a short hairpin RNA targeting NIK and an NIK overexpression were used to knock down and overexpress NIK, respectively.
Results: Compared with normal control, endothelial dysfunction, microglia M1/M2 polarization, and inflammatory factors they surged in both DR mice retinas and AGE-treated HMC3 cells or co-cultured model, according to HE staining, immunofluorescence, immunohistochemistry, TUNEL assay, vascular permeability assay, cell permeability assay, ELISA, RNA sequencing and western blotting. Moreover, NIK expression was higher in DR mice retinas and AGE-treated microglia. In the B022 treated mice or cells, endothelial dysfunction, M1/M2 polarization, and inflammatory microenvironment were improved. Manipulating NIK expression levels markedly regulated the non-classical NF-κB pathway and microglia polarization.
Conclusions: These results suggest that NIK maybe the potential target to treat diabetic retinopathy.

Disclosure
H. Li: None. H. Kuang: None.

Funding
National Natural Science Foundation of China (No. 82170832).
1816-LB: Examining the Human Diabetic Bone Marrow Niche
Authors: CIRKA HALEY , SAMANT AMRUTA , KOSTYRA DAVID M. , KHAIR LYNE , NGUYEN TAMMY T. 
Published: June 2024

Introduction & Objective: Patients with diabetes mellitus (DM) have a 30-fold increased risk of developing diabetes foot ulcers (DFUs), with 43% requiring lower extremity amputations (LEAs). While the underlying cause of non-healing DFUs is not known, abnormalities in bone marrow (BM)-derived immune cell dysfunction may play a key role. To study the effect of DM on human BM-derived innate immunity, we developed a human BM organoid system to directly study the human DM immune system from patients with DFUs.
Methods: BM was collected from a DM patient undergoing a LEA for treatment of a non-healing DFU. BM explants were cultured in a 3D protein matrix separately by two technicians. Resulting HSCs underwent in vitro differentiation into monocytes and macrophages. Human cord blood (HUCB)-derived HSCs cultured in a 3D protein matrix for expansion and characterized via FACS, a colony forming unit assay, and in vitro differentiation as a control.
Results: HUCB and BM derived HSCs were expanded in a 3D organoid culture. HSC pluripotency was tested by colony forming unit assay, FACS, and in vitro differentiation of HSCs to monocytes and macrophages. Monocytes and macrophages were produced in similar percentages and efficiencies before and after the 3D organoid culture. The in vitro differentiation of DM BM-derived HSCs yielded similar percentages of monocytes and macrophages and in similar efficiencies between technicians.
Conclusion: Our novel 3D organoid culture system successfully expands HSCs without altering HSC behavior. Expanded DM BM-derived HSCs are representative of inherent differences of the sample, as opposed to experimental handling. Therefore, this methodology can be used to directly understand the impact of DM on the human immune system and its role in DFUs.

Disclosure
H. Cirka: None. A. Samant: None. D.M. Kostyra: None. L. Khair: None.
1820-LB: Evaluating an HCP Diabetes Training Program in Kasese, Uganda
Authors: NARAYANAN SANDHYA , BASCH COREY , BAKER JASON ,   DIABETES CONSULTATION ASSOCIATION TEAM KASESE, UGANDA
Published: June 2024

Introduction & Objective: Health Care Provider (HCP) diabetes educational sessions are core to the mission of Diabetes Empowerment International (DEInt) in Kasese, Uganda. Understanding HCP profiles and their barriers to diabetes education access is essential to shape a successful training program. We evaluated the profile of the HCPs that are trained as well as the feedback received regarding how the training is implemented in patient care.
Methods: In person HCP diabetes seminars are held every 8 weeks DCA/DEINt Diabetes Education Center in Kasese, covering a curriculum of key topics related to care of diabetes. Each session hosts over 50 regional HCPs, and over 106 HCPs have attended 23 education seminars. Participant evaluations are performed for each seminar for impact on diabetes knowledge and patient care.
Results: The average distance traveled for the conferences was 29.4 km [range 0.5-63.2 km]. The majority of participants are enrolled nurses (n=51, 48.11 %), followed by assistant nursing officers (n=20, 18.87 %), and enrolled midwives (n=11, 10.38 %). The remainder of participants have varied healthcare provider titles. The majority of HCPs reported that there was a diabetes trained doctor in the facility where they worked (n=62, 58.49 %). The mean number of diabetes patients supported was 40 [range 0-418]. A total of 8,733 people with diabetes are being served by the HCPs with 289 type 1 diabetes patients and 770 type 2 diabetes patients. The topics that attendees expressed the most confidence in managing patients with diabetes was checking blood sugars and hypoglycemia. Topics that attendees indicated that they would change how they treat diabetes patients was insulin pumps (n=55, 62.5%) and carbohydrate counting (n=54, 61.36 %).
Conclusion: Our diabetes training programs supports a wide range of HCPs. HCP diabetes training can have a far-reaching impact on an underserved population of individuals with diabetes.

Disclosure
S. Narayanan: Employee; Dexcom, Inc. C. Basch: None. J. Baker: Speaker's Bureau; Insulet Corporation, Dexcom, Inc., Sanofi.