bluuebunny/crossref_metadata_2025_split huggingface dataset:
1739-P: Genetic Deletion of Mitochondrial PEP Carboxykinase (PCK2) in Pancreatic α-Cells Increases Amino Acid-Stimulated Ca2+ Influx
Authors: JIN ERLI , FOSTER HANNAH R. , POTAPENKO EVGENIY , KNUTH EMILY R. , MERRINS MATTHEW J. 
Published: June 2024

Amino acids potently stimulate glucagon secretion, but their mechanisms of action remain largely unknown. To assess the effects of individual amino acids on α-cell Ca2+, we used GcgCreERT:GCaMP6s Ca2+ reporter. We focused on alanine, arginine, glutamine, and leucine, which have the potential to affect Ca2+ and glucagon release via their transport or metabolism. Under hypoglycemic conditions, when β-cells are inactive, alanine and arginine provoked a sustained increase in α-cell Ca2+, while the mitochondria fuels glutamine and leucine lowered Ca2+ after alanine and arginine are applied. However, when applying these four amino acids simultaneously, Ca2+ influx is increased above that stimulated by arginine and alanine alone, suggesting the effect of mitochondria fuels on Ca2+ is membrane-potential dependent. Phosphoenolpyruvate (PEP) cycle can be fueled by mitochondria fuels and potentially affects KATP channels via the ATP-generating enzyme pyruvate kinase (PK). To test this hypothesis, we used CRISPR to generate mice lacking the mitochondrial PEP-generating enzyme PCK2 in α-cells (GcgCreERT:Pck2f/f:GCaMP6s). PEP cycle ablation increased Ca2+ influx stimulated by alanine and arginine, much more strongly when leucine and glutamine were provided as mitochondria fuels. Pharmacological activation of PK reduces amino acid-stimulated Ca2+ influx. Taken together, the effect of mitochondria fuels on α-cell Ca2+ is most likely membrane potential dependent, and α-cell PEP cycle is an inhibitory pathway that lowers Ca2+ influx stimulated by amino acids.

Disclosure
E. Jin: None. H.R. Foster: None. E. Potapenko: None. E.R. Knuth: None. M.J. Merrins: None.

Funding
The Merrins laboratory gratefully acknowledges support from the NIH/NIDDK (R01DK113103 and R01DK127637 to MJM) and the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (I01BX005113 to MJM). ERK received a predoctoral fellowship from the NIH/NIDDK (F31DK134171).
1743-P: STING Mediates Glucose-Induced Insulin Secretion through Pax6
Authors: ZHANG ZIYUE , QIAO JINGTING , LIU YANG , LIU MING 
Published: June 2024

Introduction & Objective: Previous studies have shown that stimulator of interferon genes (STING) plays an important role in regulating glucose homeostasis, including insulin secretion. This study aimed to investigate the role of STING in glucose-induced insulin secretion.
Methods: Rat pancreatic β-cell line INS-1 cells and islets from adult wide-type (WT) mice were cultured with high-glucose (33.3 mmol/L) and low-glucose (2.8 mmol/L) and the expression of STING was detected by RT-PCR and western blotting. Glucose-stimulated insulin secretion (GSIS) tests were measured in islets from global STING knockout (KO) mice or high-glucose-induced islets of WT mice. The involvement of STING and Pax6 was evaluated by infecting islets with STING-overexpression adeno-associated virus (AAV-STING) or AAV-Pax6 in vitro.
Results: STING was highly expressed in pancreatic islets and INS-1 cells, but its levels were reduced in high-glucose-induced islets and INS-1 cells compared to controls. Overexpression of STING could restore GSIS in high-glucose-induced islets of WT mice. In addition, the expression levels of several genes involved in insulin secretion, including Pax6, Abcc8, Kir6.2, were significantly reduced in high-glucose induced islets of WT mice and were increased when STING expression was restored. Moreover, GSIS was significantly decreased in islets from STING KO mice, and the overexpression of either STING or Pax6 resulted in an increased expression of Pax6, Abcc8, Kir6.2 and improved GSIS.
Conclusion: This study provides the first in vitro experimental evidence supporting that STING may play an important role in glucose-induced insulin secretion through transcription factor Pax6.

Disclosure
Z. Zhang: None. J. Qiao: None. Y. Liu: None. M. Liu: None.

Funding
National Natural Science Foundation of China (82220108014, 81830025, 82200892), National Key R&D Program of China (2022YFE0131400, 2019YFA0802502), Key project of Tianjin Municipal Health Commission(TJWJ2021ZD001), Tianjin Key Medical Discipline (Specialty)Construction Project (TJYXZDXK-030A), Tianjin Medical University General Hospital Clinical Research Program (22ZYYLCZD02), Tianjin Municipal Education Commission (2021KJ209)
1744-P: Exenatide Activates PPARd to Promote Mitochondrial Function for Insulin Secretion in Islet ß-Cells
Authors: LIU ZHIGU , CHEN YALAN , LIN BEISI , SU YANNA , PENG YUEYUE , CHEN DANRUI , YANG YANLING , XU FEN , LIANG HUA , YAN JINHUA , XU WEN 
Published: June 2024

Aim: Glucagon-like peptide 1 receptor agonists can lower blood glucose by increasing glucose-stimulated insulin secretion (GSIS). However, related molecular mechanisms remain to be further explored.
Methods: C57BL/6J mice were treated with exenatide, GW501516 (GW, a PPARδ agonist) or saline for 8 weeks after a 12-week high-fat diet (HFD) challenge. Phenotypic evaluations were performed during and after the interventions. In vitro, mouse pancreatic β cells (NIT1) were treated with palmitic acid (PA), PA+exendin-4 (Exe), PA+GW, PA+GSK0660 (GSK, a PPARδ antagonist), and PA+GSK+Exe, respectively. PPARδ knockout (KO) NIT1 cells were constructed using CRISPR/Cas9 method. The KO cells were also treated by PA and PA+Exe. After a 24-hour incubation, GSIS tests were performed, and PPARδ expression and mitochondrial function were also detected.
Results: Compared with HFD mice treated with saline, exenatide and GW treatments lowered body weight and fasting blood glucose, improved glucose tolerance and insulin sensitivity. Moreover, normal mitochondrial morphology in pancreatic islets of exenatide and GW treated mice were found with Transmission electron microscopy, while significantly abnormal mitochondria were noted in saline group. In vitro, compared with PA treatment alone, NIT1 cells treated by PA+Exe and PA+GW showed enhanced GSIS, along with increased PPARδ expression, lower ADP/ATP ratio and lactic acid levels, more mitochondrial DNA and higher mitochondrial membrane potential. However, opposite results were found in cells treated with PA+GSK. In addition, in PA+GSK+Exe group, GSK weakened the effects of Exe on GSIS and mitochondrial function. KO cells treated with PA showed similar changes in GSIS and mitochondrial function as PA+GSK treated cells. Importantly, adding Exe couldn’t completely reverse the impairment.
Conclusion: Exenatide protects GSIS function in islet β cells by enhancing mitochondrial function through promoting PPARδ expression.

Disclosure
Z. Liu: None. Y. Chen: None. B. Lin: None. Y. Su: None. Y. Peng: None. D. Chen: None. Y. Yang: None. F. Xu: None. H. Liang: None. J. Yan: None. W. Xu: None.

Funding
Natural Science Foundation of Guangdong Province (2022A1515012364?
1757-P: Imeglimin Enhances Glucose-Induced Insulin Secretion with Activating Mitochondrial Function
Authors: TAKIGUCHI MAMI , IIDA HITOSHI , UZAWA HIROTSUGU , KANAI AKIKO , UEKI KYOSEI , IKEDA KOKI , KAKEHI SAORI , HARUNA HIDENORI , TAKUBO NORIYUKI , NISHIDA YUYA , SHIMIZU TOSHIAKI , WATADA HIROTAKA 
Published: June 2024

The underlying pathology of diabetes mellitus is inadequate insulin secretion and resistance. The resulting hyperglycemia leads to complications, decreased quality of life and shortened life span. New drugs to reduce blood glucose are still required. Imeglimin has a chemical structure derived from the antidiabetic compound metformin, and now is clinically used as an oral hypoglycemic agent with a tetrahydro-triazin structure in Japan. Several studies reported that imeglimin promotes glucose-stimulated insulin secretion (GSIS) in diabetic mouse models and protects pancreatic beta cells from inflammation and ROS-induced apoptosis, however, the underlying mechanism of enhanced GSIS has not been fully elucidated yet. The aim of this study is to investigate the effect of imeglimin on insulin secretion. First, we found that the in vivo administration of imeglimin to C57Bl/6 mice enhanced GSIS with increase of insulin secretion. Next, we investigated the effect of imeglimin on isolated islets from C57Bl/6 mice. Ten µM imeglimin, which is equivalent to the clinically used dose for 24 hours stimulated GSIS from isolated islets, however, 1000 µM imeglimin does not enhance GSIS. Intriguingly, 10 µM but not 1000 µM imeglimin enhanced mitochondrial oxygen consumption rate and membrane potential. While it has been reported that the imeglimin-induced increase in GSIS in streptozotocin-treated mice is attributed to an increase in NAD+ and enhanced calcium influx by activating NAMPT expression, no change in NAD+ levels by imeglimin was observed in C57Bl/6 mice. Our data showed that a clinical relevant dose of imeglimin enhanced GSIS with enhanced mitochondrial function in islets isolated from C57Bl/6 mice.

Disclosure
M. Takiguchi: Research Support; Sumitomo Dainippon Pharma Co., Ltd. H. Iida: Research Support; Sumitomo Dainippon Pharma Co., Ltd. H. Uzawa: Research Support; Sumitomo Dainippon Pharma Co., Ltd. A. Kanai: Research Support; Sumitomo Dainippon Pharma Co., Ltd. K. Ueki: None. K. Ikeda: None. S. Kakehi: Research Support; Sumitomo Dainippon Pharma Co., Ltd. H. Haruna: None. N. Takubo: Research Support; Sumitomo Dainippon Pharma Co., Ltd. Y. Nishida: Research Support; Sumitomo Dainippon Pharma Co., Ltd. T. Shimizu: None. H. Watada: Speaker's Bureau; Bayer Inc., Sanofi, Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Abbott Japan Co., Ltd., Eli Lilly and Company, Boehringer-Ingelheim, Daiichi Sankyo, Taiho Pharmaceutical Co. Ltd., Kowa Company, Ltd., Teijin Pharma Limited, Mitsubishi Tanabe Pharma Corporation. Research Support; Sumitomo Dainippon Pharma Co., Ltd., Boehringer-Ingelheim, Mitsubishi Tanabe Pharma Corporation, LifeScan Diabetes Institute, Abbott Japan Co., Ltd., Teijin Pharma Limited, Takeda Pharmaceutical Company Limited, Taiho Pharmaceutical Co. Ltd., Sanwa Kagaku, Souiken.
1778-LB: Comparing a Somatostatin Receptor 2 Antagonist (SSTR2a) to Exogenous Glucagon (EG) for the Treatment of Severe Insulin-Induced Hypoglycemia
Authors: HOFFMAN EMILY G. , DSOUZA NINOSCHKA , ALEALI NADIA , NOZARIASBMARZ NEWSHA , FATEHI SAMANEH , SHAKERI DORSA , CHAN OWEN , LIGGINS RICHARD , RIDDELL MICHAEL C. 
Published: June 2024

Introduction & Objective: Treatment of severe hypoglycemia (SH) with EG causes hyperglucagonemia, resulting in gastrointestinal distress that limits its real-world utility. Prophylactic dosing of SSTR2a augments glucagon counterregulation during insulin-induced hypoglycemia in diabetic rats. Here, we tested the use of SSTR2a as a rescue treatment for SH.
Methods: After 3 episodes of insulin-induced hypoglycemia to impair glucagon counterregulation, healthy male rats received an overdose of regular insulin before a SC injection of vehicle, EG (0.15 mg) or SSTR2a (10 mg/kg ZT-01) at the onset of level 2 hypoglycemia. Blood glucose (BG) and plasma glucagon were monitored for 2 h by saphenous venipuncture.
Results: BG continued to fall gradually with vehicle to a nadir of 1.7±0.6 mM at 110 min. Euglycemia was restored by EG in 6 of 8 rats from t=15-60 min (4.6±1.3 mM, n=8) and maintained in 1 of 8 rats from t=70-120 min (3.0±0.9 mM, n=8). SSTR2a raised BG to level 1 hypoglycemia in 5 of 8 rats (t=15-60 min: 3.4±1.0 mM, n=8) before restoring euglycemia in 4 of 8 rats (t=70-120 min: 5.0±2.3 mM, n=8). Compared to vehicle, BG was higher with SSTR2a from t=15-30 and 90-120 min and glucagon AUC (0-120 min) was 24- & 1.5-fold higher with EG and SSTR2a, respectively.
Conclusion: SSTR2a provided more gradual and sustained recovery from SH than EG without causing systemic hyperglucagonemia.

Disclosure
E.G. Hoffman: None. N. DSouza: None. N. Aleali: None. N. Nozariasbmarz: None. S. Fatehi: None. D. Shakeri: None. O. Chan: None. R. Liggins: Employee; Zucara Therapeutics. Stock/Shareholder; Zucara Therapeutics. M.C. Riddell: Consultant; Eli Lilly and Company. Speaker's Bureau; Novo Nordisk. Advisory Panel; Supersapiens. Consultant; Dexcom, Inc. Speaker's Bureau; Sanofi. Advisory Panel; Zealand Pharma A/S. Speaker's Bureau; Dexcom, Inc. Stock/Shareholder; Zucara Therapeutics.

Funding
Zucara Therapeutics Inc.
1788-LB: Machine Learning–Based Prediction of Diabetic Kidney Disease in Patients with Type 2 Diabetes
Authors: SUN PARK TAE , JI KIM YU , AE LEE KYUNG 
Published: June 2024

Background & Objective: Diabetic Kidney Disease (DKD) is leading cause of end-stage renal disease, cardiovascular disease, and mortality in patients with diabetes. This study is aim to develop and validate machine learning (ML)-based DKD prediction model for patients with type 2 diabetes (T2D).
Method: We conducted a retrospective study using common data model based on electronic health records of three tertiary referral hospitals in Korea: Jeonbuk National University Hospital (JNUH) cohort for developing ML model, Wonkwang University Hospital (WKUH) and Kyunghee University Hospital (KHUH) cohorts for external validation. Patients with T2DM who had been followed for more than 3 years were included. Three ML algorithms (Random Forest(RF), XGBoost(XGB), Ensemble(RF+XGB)) were applied, and the optimal model was selected according to the area under a receiver operating characteristic curve (AUROC) and accuracy.
Results: A total of 20,528 patients were included, with a DKD occurrence of 1,361 (26.6%), 269 (26.5%), 5,461 (37.9%) in the JBUH, WKUH, and KHUH cohort, respectively. The RF model yielded the highest AUROC of 0.79 and accuracy of 71% on the JNUH cohort, showing better performance than XGB, Ensemble models. The top five important features included baseline estimated glomerular filtration rate, age, hemoglobin, serum creatinine and hemoglobin A1c. Application of RF model in two external cohorts yielded 57-77% sensitivity, 73-79% specificity, and 0.76-0.85 AUROC.
Conclusion: This study suggested that the RF model could contribute to the prediction of the development of DKD in T2D. Further research is needed on larger samples of participants using different ML models to determine the most effective one.

Disclosure
T. Park: None. K. Lee: None.
179-OR: Assessing the Impact of Hypoglycemia among People with Diabetes in the U.S. and EU
Authors: BELTRAN ALAN , ZENG ALISON , CHANEN SYDNEY , BELL TREVOR , WOOD RICHARD 
Published: June 2024

Hypoglycemia, where blood glucose falls below 70 mg/dL, can be an unfortunately common and serious burden for people with diabetes (PWDs) on insulin. Despite this, its prevalence in the daily lives of PWDs is understudied among specific therapy types. This research aimed to comparatively assess patient experiences with hypoglycemia in the US and Europe (EU). From August-October 2023, insulin-using PWD in the US (n=3,355) and EU (n=2,480) took an online survey assessing the impact of hypoglycemia in their lives. Respondents reported how frequently they experience mild (55-70 mg/dL) and moderate (40-54 mg/dL) hypoglycemia. In the study’s analysis, highly impacted individuals were operationalized as PWD experiencing near-daily milds and occasional (weekly) moderates. Hypoglycemia impact was compared across region by type of diabetes and insulin therapy regimen (T1 adults on a pump, T1 adults on multiple daily injections (MDI), T1 kids (&lt;18 years), T2 adults on MDI, and T2 adults on basal insulin only). The prevalence of highly impacted PWD is significantly higher in EU than in the US for all patient segments except PWD on MDI. Compared to in EU, high hypoglycemia impact rates in the US are significantly lower among T1 adults on a pump (15% vs. 21%, p&lt;.001), T1 kids (21% vs. 33%, p&lt;.01), T2 adults on basal insulin only (2% vs. 6%, p&lt;.05). There are no significant differences in the prevalence of high hypoglycemia impact among T1 adults on MDI in the US (20%) and EU (22%), nor among T2 adults on MDI in the US (3%) and EU (4%). It is notable that all patient segments except those on MDI are more impacted by hypoglycemia in EU than in the US, especially given the differences in US and EU health systems. Further research should aim to uncover the origin of this disparity, why it specifically affects pump users and not MDI users, and assess whether it also translates into clinical outcomes and daily lived experiences of PWDs.

Disclosure
A. Beltran: Research Support; Abbott, Dexcom, Inc., Eli Lilly and Company, diaTribe, Insulet Corporation, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc., Ypsomed AG, Teladoc Health. A. Zeng: Employee; dQ&A. Research Support; Abbott, Dexcom, Inc., Eli Lilly and Company, diaTribe, Insulet Corporation, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc., Ypsomed AG, Teladoc Health. S. Chanen: Research Support; Abbott, Dexcom, Inc., Eli Lilly and Company, diaTribe, Insulet Corporation, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc., Ypsomed AG, Teladoc Health. T. Bell: Research Support; Abbott, Dexcom, Inc., Eli Lilly and Company, diaTribe, Insulet Corporation, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc., Ypsomed AG, Teladoc Health. R. Wood: Research Support; Abbott, Dexcom, Inc., Eli Lilly and Company, diaTribe, Insulet Corporation, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc., Ypsomed AG, Teladoc Health.
1794-LB: Comparison of Metabolic Visceral Fat Score with Other Abdominal Obesity Indicators in Predicting Left Ventricular Hypertrophy in Individuals with Type 2 Diabetes
Authors: WANG LU , WANG DI , WANG YAN , WEI LINGLING , YANG LONGYAN 
Published: June 2024

Introduction & Objective: Left ventricular hypertrophy (LVH) is a common complication associated with higher cardiovascular risk in Type 2 diabetes mellitus (T2DM) patients. Although many abdominal obesity indices (AOIs) have been established, studies investigating their associations with LVH in T2DM are limited. This study aimed to investigate the relationship between AOIs and LVH in T2DM.
Methods: A cross-sectional study involving 5,105 T2DM patients without prior cardiovascular disease was conducted in Beijing, China. LVH was assessed using echocardiography. Metabolic Score for Visceral Fat (Mets-VF), Waist Circumference (WC), Hip Circumference (HC), Visceral adipose tissue (VAT), BMI, Waist-to-Hip Ratio (WHR), Waist-to-Height Ratio (WHtR), Body Roundness Index (BRI), Abdominal Volume Index (AVI), Conicity Index (CI), Lipid Accumulation Product (LAP), Cardiometabolic Index (CMI), Visceral Adiposity Index (VAI), and Chinese Visceral Adiposity Index (CVAI) were investigated. Multivariate logistic regression and restricted cubic spline regression models were used to evaluate associations and potential nonlinear relationships between AOIs and LVH risk.
Results: Among 5,105 participants (aged 49.8 ± 12.2 years), 560 (10.9%) had LVH. After adjusting for confounding factors, METS-VF showed the strongest association with LVH (OR 9.78; 95% CI 6.15-15.75, p value &lt;0.001). WC, HC, VAT, BMI, WHR, WHtR, BRI, LAP, CMI, and CVAI also maintained significant associations with LVH (ORs 1.003 to 1.916, p value &lt;0.05). Linear associations were observed for METS-VF, WC, VAT, BMI, and WHtR, while nonlinear associations were found for HC, WHR, BRI, LAP, CMI and CVA. AVI, CI, and VAI showed no independent significant association with LVH.
Conclusions: METS-VF outperforms other well-established AOIs in predicting LVH, highlighting its potential as a valuable tool for assessing cardiovascular risk in T2DM patients.

Disclosure
L. Wang: None. D. Wang: None. Y. Wang: None. L. Wei: None. L. Yang: None.
1802-LB: Magnetic Peripheral Nerve Stimulation (mPNS) for Treatment of Painful Diabetic Neuropathy (PDN)—Sensory, QoL Results
Authors: BROWN LORA 
Published: June 2024

Objective: To determine if mPNS improved sensation, QoL in subjects with PDN over 90 days.
Methods: Seventy-one subjects with PDN were treated in 6 site RCT comparing safety, effectiveness of mPNS and Conventional Medical Management (CMM). Subjects were randomized 3:1 to mPNS+CMM or Sham+CMM and were followed through 30 days during double-blind phase. At 30 days, Sham+CMM subjects could crossover (CX) to treatment. mPNS+CMM & CX subjects were then followed to 90 days. Secondary endpoints included group summaries of mean change scores from baseline at Day 90 for Visual Analog Scale (VAS) numbness, QOL-DN, PDI, BPI, and DASS.
Results: Fifty subjects were enrolled mPNS+CMM, 21 were enrolled Sham+CMM. Of the 21 in CMM+Sham, 20 elected to crossover at Day 30. Of all subjects in the full analysis set (FAS), 85% completed through Day 90. One adverse event was reported in AT+CMM unrelated to the study device. After 90 days of treatment, mPNS+CMM subjects improved significantly (p&lt;0.05) on all measures (Table). CX subjects also showed significant improvement in numbness, QoL-DN, PDI, and BPI after 90 days, while DASS scores remained stable in all three areas.
Conclusions: mPNS improves sensation and QoL over a 90-day treatment. Because of the non-invasive nature of mPNS and lack of other effective non-invasive treatments for PDN, mPNS should be considered much earlier in treatment algorithm for PDN.

Disclosure
L. Brown: None.
1809-LB: Hyperglycemia Activated the STING Pathway to Induce Retinal Vascular Endothelial Inflammation and Breakdown of Retinal Tight Junctions
Authors: LIU MINTING , WEN SIYING , CHEN YANMING , SHI GUOJUN 
Published: June 2024

Introduction & Objective: Diabetic retinopathy is a common microvascular complications of diabetes mellitus characterized by hyperglycemia and chronic inflammation. Retinal endothelial cells are the primary target cells for diabetes-induced vascular damage causing acellular blood capillary and capillary leakage in clinical observation. This study investigated the role of the stimulator of interferon genes (STING) signaling pathway in human retinal vascular endothelial cells (HRVEC) damage and inflammation under the condition of hyperglycemia.
Methods: HRVEC were treated with Methylglyoxal (MGO), a mimic of hyperglycemia condition. Moreover, we investigated the role of STING in HRVEC by generating a STING-deficient HRVEC using the CRISPR/Cas9 system. The components of the STING signaling pathway and endothelial cell tight junctions at protein levels were determined by Western blotting. Last, RT-qPCR was used for detecting the genes expression of pro-inflammatory cytokines in HRVEC and STING-deficient HRVEC. All those treatment and methods were repeated in the STING siRNA-treated HRVEC.
Results: When treated with MGO, the protein levels of the STING signaling components were increased in a time- and dose-manner, suggesting the activation of the STING pathway, accompany by down-regulation of endothelial cell tight junction protein and increased transcription levels of inflammatory genes. At the same time, the increased transcription levels of inflammation genes and decreased expression levels of tight junction proteins caused by MGO were significantly repressed when the STING gene was deleted or knocked down in HRVEC.
Conclusion: STING deficiency can significantly inhibit the expression of proinflammatory factors in HRVEC, also improving the HRVEC damages induced by MGO.

Disclosure
M. Liu: None. S. Wen: None. Y. Chen: None. G. Shi: None.