bluuebunny/crossref_metadata_2025_split huggingface dataset:
1384-P: COVID-19 Vaccination Uptake among 3,779,733 Adults With and Without Diabetes
Authors: BUTALIA SONIA , SHAH BAIJU R. , SIGAL RONALD J. , BENHAM JAMIE L. , WICKLOW BRANDY , YU CATHERINE H. , DASGUPTA KABERI , AMED SHAZHAN , CONSTANTINESCU CORA , LUAN CHU MANH , KAUL PADMA 
Published: June 2024

Introduction & Objective: Public health measures, especially vaccination, are important for COVID-19 risk reduction. Population level vaccine uptake in people with diabetes is understudied. We assessed COVID-19 vaccine uptake among adults with and without diabetes and the factors associated with vaccination.
Methods: This retrospective, population-based cohort study included adults (18+ years) living in Alberta, Canada on December 14, 2020, the date of vaccine availability. Diabetes status was determined using a validated algorithm between April 1, 2002 and December 14, 2020. All individuals were followed until March 31, 2022. The primary outcome was full vaccination as defined by the manufacturer. Descriptive statistics were used to compare vaccination status among people with and without diabetes and multivariate logistic regression assessed the factors associated with full vaccination adjusting for age group, sex, diabetes status, material deprivation, urban/rural residence, and comorbidities (Charlson Comorbidity Index (CCI) score).
Results: We identified 3,779,733 adults (49.7% female, mean age 46.8 ± 17.8 years) with 9.8% having diabetes. Overall, 75.5% of the total cohort were fully vaccinated. A higher proportion of people with diabetes, compared to those without, were fully vaccinated (83.9% vs. 74.6%, p&lt;0.001). The presence of diabetes (aOR 1.48; 95% CI 1.46-1.49), female sex (aOR 1.20; 95% CI 1.91-1.21), and CCI score &gt;1 (aOR 1.67; 1.66-1.68) were associated with being fully vaccinated, whereas the age group of ≥ 75 years (aOR 0.84; 95% CI 0.83-0.86), rural residence (aOR 0.60; 95% CI 0.60-0.60) and higher material deprivation (aOR 0.88; 95% CI 0.87-0.89) were associated with lower vaccination.
Conclusions: People with diabetes had high COVID-19 vaccination uptake and were more likely than the general population to be fully vaccinated. We also identified several key factors associated with lower uptake highlighting the need for understanding facilitators of vaccination.

Disclosure
S. Butalia: None. B.R. Shah: None. R.J. Sigal: Research Support; Lexicon Pharmaceuticals, Inc., Bayer Inc., Novo Nordisk. J.L. Benham: None. B. Wicklow: None. C.H. Yu: None. K. Dasgupta: None. S. Amed: None. C. Constantinescu: Research Support; Pfizer Inc. Other Relationship; Sta HealthCare Communications, Canadian Research Network. M. Chu: None. P. Kaul: None.

Funding
Canadian Institutes of Health Research (CIHR) 483868
1423-P: A Longitudinal Analysis of Changes in Therapies and Outcomes among People with Type 2 Diabetes
Authors: BELTRAN ALAN , ZENG ALISON , BELL TREVOR , WOOD RICHARD 
Published: June 2024

About 1 in 10 Americans are estimated to have Type 2 diabetes (T2D). The ever-evolving landscape of T2D management demands continual adaptation to diverse therapeutic interventions. Through a 5-year retrospective cohort study, this research assesses therapy usage for people with T2D (PWT2) and the impact unique regimens have on clinical outcomes. From 2018 to 2023, 2,310 PWT2 on various therapy regimens were surveyed four times per year about their diabetes management. Therapy usage included insulin, GLP-1 agonists, SGLT-2 inhibitors, and continuous glucose monitoring (CGM). Key health outcomes assessed were clinically recommended HbA1c of ≤7 and obesity (BMI ≥30). Longitudinal analysis revealed notable shifts in therapy usage among PWT2. From 2018 to 2023, overall insulin usage decreased 3%, GLP-1 (16% to 33%) and SGLT-2 usage (10% to 20%) doubled, and CGM usage increased fourfold (4% to 15%). Notably, among patients on insulin, SGLT-2 usage exceeded GLP-1 usage, while among those not on insulin, GLP-1 usage increased at a higher rate than SGLT-2s. These shifts in therapy combinations had diverse impacts on health outcomes. PWT2 on insulin without any other therapy showed no significant reduction in HbA1c or BMI over the five years, but those on insulin and a GLP-1, SGLT-2, or both showed significant reduction in HbA1c (p&lt;.01). Among insulin users, those on an SGLT-2 only were the only group who did not experience reductions in BMI. PWT2 not on insulin or any other therapy experienced significant increases in HbA1c over the five-year period (p&lt;.01), though all PWT2 not on insulin were able to reduce BMI significantly (p&lt;.05). Results show that PWT2 who take insulin alone experience sub-optimal health outcomes, compared to those who take a combination therapeutic approach. While lifestyle changes will help PWT2 not on insulin, a lack of other therapies may lead to increased HbA1c. These findings underscore the need for tailored approaches to optimize T2D management and patient outcomes.

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. 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.
15-OR: Diabetic Retinopathy (DR) Is Associated with Markers of Alzheimer's Disease (AD) in Type 1 Diabetes (T1D)
Authors: PAULEY MEGHAN E. , SHAPIRO ALLISON , COUGHLAN CHRISTINA , DONG FRAN , SNELL-BERGEON JANET K. 
Published: June 2024

Introduction & Objective: DR is shown to predict AD in type 2 diabetes, but less is known in T1D where DR burden is significant. This study examined differences in levels of phosphorylated tau-181 (pTau181), a validated preclinical biomarker of AD neuropathology, between adults with and without T1D, and its relationships with DR.
Methods: Plasma samples from the Coronary Artery Calcification in Type 1 Diabetes study were analyzed for pTau181 (pg/mL). Participants were adults with T1D and age-similar controls. DR was classified as none/mild (Early Treatment Diabetic Retinopathy Study [ETDRS] score ≤31) or moderate/severe (ETDRS score ≥47). Log transformed pTau181 was examined by group via linear regression adjusted for age, BMI, sex, race, and smoking status.
Results: 121 participants (median age 53 years, 55% female) were included (T1D with moderate/severe DR, n=41; T1D with none/mild DR, n=41; controls, n=39). In the adjusted model, moderate/severe DR was associated with significantly higher pTau181 compared to controls (estimate=0.13, SE=0.05, p=0.01). Age was positively associated with pTau181 (p=0.001).
Conclusion: Adults with T1D and moderate/severe DR show evidence of preclinical AD neuropathology, but adults with T1D and no/mild DR do not differ from people without T1D. Further studies are needed to delineate relationships between DR and AD in T1D.

Disclosure
M.E. Pauley: None. A. Shapiro: None. C. Coughlan: None. F. Dong: None. J.K. Snell-Bergeon: None.

Funding
NIH R01 HL113029; NIH NIDDK (T325T32DK063687); DiabDocs Physician-Scientist Career Development Award: NIH NIDDK (K12DK133995) & The Leona M. and Harry B. Helmsley Charitable Trust to Stanford University (2305-06041)
1510-P: Adipocyte MicroRNA-802 Promotes Adipose Tissue Inflammation and Insulin Resistance by Modulating Macrophages in Obesity
Authors: YANG YUE , ZHANG FANGFANG , JIN LIANG 
Published: June 2024

Introduction & Objective: Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. Macrophages accumulate in the adipose tissue and surround the dying or dead adipocytes like corona, which is witnessed to be the contributors to inflammation and obesity-induced insulin resistance. In this study, we aimed to identify key microRNA that regulates inter-cellular communication between lipid-overloaded adipocytes and macrophages, ultimately leading to adipose tissue inflammation and insulin resistance.
Methods: RNA sequencing was performed to analyze the adipocyte tissue of high-fat diet (HFD)-fed mice and those of normal chow-fed mice (NCD). We found progressive increase of microRNA-802 (miR-802) expression in adipose tissue with the development of dietary obesity in obese mice and humans. Then, the mechanism of miR-802 regulating adipose function was investigated by flow cytometric analysis, mouse metabolic studies, magnetic resonance imaging, and animal energy metabolism monitoring system.
Results: Our findings validated miR-802 increasing prior to macrophage accumulation. Adipose tissue-specific knockout of miR-802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific miR-802 overexpression in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, miR-802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3, which translated into strong recruitment and M1-like polarization of macrophages.
Conclusion: We established that miR-802 expression is an inflammatory signal in adipocytes, and this effect occurs through sensitization of the NF-kB signaling pathway. Collectively, our data raise the possibility that manipulation of miR-802 action axis represents therapeutic potential for adipose inflammation treatment.

Disclosure
Y. Yang: None. F. Zhang: None. L. Jin: None.

Funding
National Natural Science Foundation of China (82373925,82070801); Natural Science Foundation of Jiangsu Province (BK20221520, BK20200569); The Fundamental Research Funds for the Central Universities (2020M671661,2632023GR07)
1515-P: Pyruvate Kinase Amplifies Insulin Secretion Downstream of the ß-Cell GLP1 Receptor
Authors: FOSTER HANNAH R. , LEWANDOWSKI SOPHIE L. , KIRCHNER RACHEL , CAPOZZI MEGAN , CAMPBELL JONATHAN , MERRINS MATTHEW J. 
Published: June 2024

The advent of GPCR agonists and co-agonists that target the β-cell incretin receptors - GLP1R and GIPR - have revolutionized therapeutics for diabetes, though the signaling pathways downstream of these receptors have yet to be fully understood. Previous work in our lab has demonstrated the critical role of the glycolytic enzyme pyruvate kinase (PK) in the closure of KATP channels. However, PK activators also potentiate insulin secretion independent of KATP channel closure, suggesting additional roles for PK. We therefore sought to determine if PK potentiates insulin secretion downstream of GPCRs by modulating cAMP signaling. To elucidate the role of PK downstream of GPCRs, we employed live-cell imaging with subcellularly-targeted biosensors to track cAMP signaling over time in intact human and mouse islets in response to glucagon, GLP1, GIP, and tirzepatide. To further characterize the role of GLP1R and GCGR, chemical antagonism and mice deficient in β-cell GLP1R/GCGR were utilized in combination with TEPP-46, a pharmacologic activator of PKm2 and PKL. Our data demonstrates that PK amplifies cAMP signaling at the plasma membrane downstream of β-cell GPCRs. Specifically, there is enhanced protein kinase A (PKA) activity and increased insulin secretion in the presence of a PK activator with glucagon as a ligand. PK did not potentiate insulin secretion or PKA activity in response to GIP, indicating a receptor specific effect. Chemical antagonists and knockout experiments show that PK potentiates PKA activity primarily downstream GLP1R more than GCGR. These studies, which link glycolysis to GPCR signaling, suggest that biased GLP1R agonists that work via PK will more efficiently increase insulin secretion.

Disclosure
H.R. Foster: None. S.L. Lewandowski: None. R. Kirchner: None. M. Capozzi: None. J. Campbell: Research Support; Eli Lilly and Company, Novo Nordisk, Merck & Co., Inc. Advisory Panel; Structure Therapeutics, Inc. M.J. Merrins: None.

Funding
American Diabetes Association (1-18-JDF-017); NIH/NIDDK (R01DK113103); United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (I01BX005113); NIH/NIDDK (T32DK007665 and F31DK126403); HRSA (T32HP10010); NIH/NIA (T32AG000213); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (T32 DK007012; F32 DK116542); NIDDK, NIH (DK123075 and DK125353); United States Department of Veterans Affairs (I01 BX003700); NIH/NIDDK (R01 DK102598)
1524-P: Estradiol's Net, Sweet or Not—Estradiol Actions on Amygdalar Perineuronal Nets Regulate Blood Glucose in Male and Female
Authors: ZHANG NAN , ZENG TIANSHU , WANG CHUNMEI , XU YONG 
Published: June 2024

Central regulation of blood glucose is getting more and more attention. However, amygdala is not traditionally considered as a regulation center for blood glucose. Here we show that perineuronal nets (PNNs) in posterodorsal medial amygdala (MePD) are required to maintain blood glucose levels and are regulated by estradiol. After gonadectomy (GDX), PNN intensity significantly decreased in both male and female mice in the MePD. Interestingly, 17β-estradiol, but not 5α-dihydrotestosterone, restored PNNs in the MePD and decreased glucose in both GDX male mice and female mice. To investigate the function of PNNs in the MePD, we manipulated PNN levels using the tetracycline-controlled Tet-On gene expression system. In TRE-PH20 mice, stereotaxic injection of AAV-hSynI-rtTAV16 to the MePD decreased PNN intensity in the MePD and caused increases in blood glucose and insulin resistance 3 weeks after the surgery, and increases in body weight gain and fat mass gain 9 weeks after the surgery. These mice showed a decrease in energy expenditure in HFD diet. In TRE-HAS2 mice, stereotaxic injection of AAV-hSynI-rtTAV16 to the MePD increased PNN intensity in the MePD and caused decreases in blood glucose, body weight gain and fat mass gain. PNNs enmesh GABAergic neurons in the MePD and destroying PNNs reduces both excitatory and inhibitor post-synaptic currents in GABAergic neurons. Our findings revealed an important role of estradiol in regulating glucose metabolism in not only female mice but also male mice, and identified PNNs in the MePD as novel participants in the central control of glucose homeostasis by estradiol.

Disclosure
N. Zhang: None. T. Zeng: None. C. Wang: None. Y. Xu: None.
1539-P: LRP1 Mediates Leptin Transport by Coupling with the Short-Form Leptin Receptor in the Choroid Plexus
Authors: KIM YOUNG-BUM , YANG WON-MO , RODRIGUES KELLEN , CHAN KIM SEUNG , FAN SHENGJIE , YOUNG JENNIE 
Published: June 2024

Leptin is an adipocyte-derived satiety factor that suppresses food intake and increases energy expenditure by reaching anorexigenic neurons in the brain. While leptin typically interacts with the leptin receptor (LepR), evidence reveals a high binding affinity of leptin to the choroid plexus (ChP), a distinct brain barrier that mediates peripheral-brain signal communication, in LepR-deficient db/db mice and obese Zucker rats. This suggests that the ChP may be a major site for leptin transport through specific receptors other than LepR. Here, we show that LRP1 (low-density-lipoprotein receptor-related protein-1) transports leptin across the blood-CSF barrier in Foxj1-expressing cells highly enriched at the ChP. LRP1 deletion in Foxj1-expressing cells of the ChP leads to impaired leptin transport, resulting in leptin resistance and obesity. Mechanistically, we found that LRP1 is associated with the short-form leptin receptor, LepRa, a crucial step for leptin entry into the brain. In vitro study with ChP-derived Z310 epithelial cells demonstrated that leptin rapidly stimulated a ~1.8-fold increase in LRP1 internalization over control conditions but failed to induce LRP1 internalization in the absence of LepRa, suggesting LepRa is required for leptin-induced LRP1 internalization. Notably, leptin-induced LRP1 binding to LepRa is attenuated in the ChP of diet-induced obese mice, highlighting the pathophysiological relevance of this interaction. Our findings unravel a new cellular mechanism by which LRP1 functions as a key mediator of leptin delivery for maintaining metabolic homeostasis in energy intake.

Disclosure
Y. Kim: None. W. Yang: None. K. Rodrigues: None. S. Kim: None. S. Fan: None. J. Young: None.

Funding
National Institutes of Health (R01 DK123002)
1562-P: A Rare Case of Metastatic Nonfunctional Pancreatic Neuroendocrine Tumor with Transformation into Insulinoma with Refractory Hypoglycemia Requiring Everolimus Use
Authors: WAX PAMELA , OCAMPO MASCARO JAVIER , EADS JENNIFER , AMARO ANASTASSIA 
Published: June 2024

Background: Most pancreatic neuroendocrine tumors (pNET) are non-functional and remain so over the course of a patient’s disease. Insulinoma is a form of functional pNET that manifests with hypoglycemia caused by inappropriate autonomous insulin secretion. These rare tumors usually present as a single benign tumor that is treated surgically. Surgery is not possible in patients with metastatic disease which leads to difficult to control often life-threatening hypoglycemia.
Clinical Case: We present a case of a 56 year old woman with a diagnosis of non-functional metastatic pNET that transformed into metastatic insulinoma with subsequent recurrent life-threatening hyperinsulinemic hypoglycemia. At the time of diagnosis, monthly lanreotide and temozolomide/capecitabine chemotherapy was started with initial successful control of disease. Upon disease progression, she was treated with peptide receptor radionuclide therapy (PRRT) during which she began having hyperinsulinemic hypoglycemic episodes refractory to treatment with both long and short acting somatostatin analogue therapy, glucocorticoids, and diazoxide. She received treatment with two cycles of 5-fluorouracil and oxaliplatin chemotherapy but was not well enough to continue. She was eventually started on everolimus in an attempt to control both hypoglycemia and pNET disease burden. This resulted in the resolution of hypoglycemia and later progression into hyperglycemia requiring insulin use. She was unable to tolerate higher doses of everolimus due to mucositis and cytopenias leading to a decreased dose. She passed away several months after initiation of therapy due to progression of malignancy.
Conclusion: This case not only demonstrates the rare ability of pNET to transform into a functional tumor, but also adds to other case reports that propose everolimus use as a potential option for management of hypoglycemia caused by insulinoma.

Disclosure
P. Wax: None. J. Ocampo Mascaro: None. J. Eads: Other Relationship; Janssen Pharmaceuticals, Inc. Advisory Panel; Merck & Co., Inc. Research Support; Seagen, Replimune, Arcus, Gilead Sciences, Inc., Oncolys, Merck & Co., Inc., Hutchmed, Amgen Inc. A. Amaro: Advisory Panel; Novo Nordisk Foundation. Research Support; Fractyl Health, Inc. Consultant; CVS Caremark. Research Support; Altimmune Inc., Novo Nordisk Foundation.
1580-P: FoxO1 Functions to Suppress Hepatic Stellate Cell Activation and Protect against Nonalcoholic Steatohepatitis
Authors: CHHETRI GOMA , GAO JINGYANG , USMAN TAOFEEK , QUAN ZHENG WEN , HENRY DONG H. 
Published: June 2024

Nonalcoholic steatohepatitis (NASH) is characterized by hepatic inflammation, steatosis and fibrosis. NASH concomitant with its cardiometabolic comorbidities is an underlying cause for the liver-associated mortalities. Critical for the etiology of NASH is the activation of hepatic stellate cells, liver-resident pericytes that account for 5-10% of the cell population in liver. HSCs remain quiescent in normal physiology, but become activated in response to hepatic inflammation and steatosis. Activated HSCs are primed for increased synthesis and secretion of collagen, contributing to the formation of extracellular matrix in the liver. This effect catalyzes the conversion of nonalcoholic fatty liver (NAFL) to NASH. To gain mechanistic insights into HSC activation, we investigated hepatic regulation of HSC homeostasis by FoxO1, a key transcription factor that mediates insulin and cytokine action on hepatic inflammation and steatosis (PMID:35700043). We found that FoxO1 expression, which remains at a baseline in quiescent HSCs in normal mice, is markedly upregulated in activated HSCs in mice with diet-induced NAFL. We generated HSC-conditional FoxO1-knockout mice, revealing that FoxO1-deficient HSCs, relative to wild-type HSCs, were more susceptible to undergoing HSC activation in response to hepatic inflammation and steatosis. This effect contributed to the development of severe liver fibrosis in HSC-FoxO1-knockout vs. wild-type mice, when fed a NASH-inducing diet. Mechanistically, FoxO1 acts to suppress HSC activation by counteracting TGF-beta, a multifunctional cytokine whose paracrine action on HSCs contributes to HSC activation in NASH. We conclude that FoxO1 is pivotal for safeguarding HSCs against abnormal activation to stem the evolution of NAFL to NASH.

Disclosure
G. Chhetri: None. J. Gao: None. T. Usman: None. W. Zheng: None. H. Dong: None.
1584-P: An Integrative Transcriptome Subtraction Strategy to Identify Human LncRNAs That Specifically Play a Role in Liver Fibrosis
Authors: MA YONGHE , HARRIS JAMIE B. , JIANG CHENGFEI , CAO HAIMING 
Published: June 2024

Liver fibrosis constitutes the most prominent predictor of overall mortality in non-alcoholic steatohepatitis. The fibrotic liver features excessive deposition of extracellular matrix, primarily produced from "activated" hepatic stellate cells (HSCs). Whereas targeting HSC in fibrosis therapeutics shows promise, the overall understanding of HSC activation remains limited, partly because defining the role of human long non-coding RNAs (lncRNAs) in HSC activation remains challenging. Although analyzing regulated human lncRNAs by HSC activation provides the most practical means to identify functional lncRNAs in the process, effective downstream approaches to further prioritize the regulated lncRNAs are often lacking. To address this challenge, we conceptualize that profibrogenic human lncRNAs in HSCs could be specifically identified by concurrent analysis of regulated lncRNAs during HSC activation with those in a process under which diverse gene networks are regulated, but the molecular elements of fibrogenesis are the only shared one with HSC activation. To implement this strategy, we compared those genes with TGFbeta-regulated ones in four additional cell types and found that only TGFbeta-induced transdifferentiation of vascular smooth muscle cells share the key elements of fibrogenesis with HSC activation. We utilized this approach to identify a highly filtered list of lncRNA candidates, and experimentally characterized and validated one fibrogenic human lncRNA named CARMN. Our work addresses a bottleneck in identifying human lncRNAs that specifically play a role in HSC activation and liver fibrosis through integrative transcriptome subtractions, and our study provides a framework to effectively select human lncRNAs that are essential for elucidating key pathological processes.

Disclosure
Y. Ma: None. J.B. Harris: None. C. Jiang: None. H. Cao: None.

Funding
NHLBI Division of Intramural Research funds to HC (1ZIAHL006103, 1ZIAHL006159)