bluuebunny/crossref_metadata_2025_split huggingface dataset:
260-OR: The ApoB/LDL-C Ratio Predicts Major Cardiovascular Events in Cardiovascular Disease Patients Independent of Type 2 Diabetes Status
Authors: LARCHER BARBARA , MAECHLER MAXIMILIAN , SPRENGER LUKAS , MADER ARTHUR , VONBANK ALEXANDER , PLATTNER THOMAS , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2023

A high ApoB/LDL-C ratio reflects small LDL particle size which like type 2 diabetes (T2DM) is associated with insulin resistance. Whether the ApoB/LDL ratio and the presence of T2DM are mutually independent predictors of major cardiovascular events (MACE) is unclear and is addressed in the present study. We enrolled a large high risk cohort of 1689 patients with established cardiovascular disease (1391 patients with angiographically proven stable CAD and 298 patients with sonographically proven peripheral artery disease). T2DM was diagnosed according to current ADA guidelines. Prospectively, MACE including death from cardiovascular cause, non-fatal stroke and non-fatal myocardial infarction were recorded over a mean follow-up period of 9.6±5.1 years. At baseline, the ApoB/LDL-C ratio was significantly higher in patients with T2DM (n=561) than in subjects who did not have T2DM (0.82±0.19 vs. 0.74±0.15 p&lt;0.001). During follow-up, 668 patients suffered MACE. The Apo B/LDL-C ratio predicted MACE in univariate analysis (HR=1.12 [1.04-1.20] p= 0.002), and the event rate was higher in patients with than in those without T2DM (49.1% vs. 34.9%; p&lt;0.001). In a multivariate adjusted Cox regression model both the ApoB/LDL-C ratio and T2DM significantly predicted MACE in a mutually independent manner, with standardized adjusted HRs of 1.17 [1.05-1.30]; p=0.005 and 1.49 [1.26-1.75]; p&lt;0.001, respectively. We conclude that in subjects with established cardiovascular disease the ApoB/LDL-C and T2DM are mutually independent predictors of MACE.

Disclosure
B.Larcher: None. C.H.Saely: None. M.Maechler: None. L.Sprenger: None. A.Mader: None. A.Vonbank: None. T.Plattner: None. A.Leiherer: None. A.Muendlein: None. H.Drexel: None.
262-OR: Use of CGM Adhesive Kits Increase Active CGM Use among NHB and Latinx Youth with T1D
Authors: GRUNDMAN JODY , PERKINS AMANDA G. , REILLY JENNIFER K. , HOLLY SARAH L. , BOWERS STEPHANIE , CLARY LAUREN , MAJIDI SHIDEH 
Published: June 2023

Introduction CGM use is lowest among minority youth in the US. This QI project aims to increase active CGM use from 39% to 70% and reduce CGM attrition from 74% to 30% among NHB and Latinx youth with T1D.
Methods We distributed CGM adhesive kits with overlay patches and adhesive wipes to youth with diabetes, with instructions on use and how to purchase. PDSA cycles were completed in an iterative process. Demographic and CGM use data (“active”, “attrition”, or “never”) were obtained over 9 months. Chi square tests compared data between NHB/Latinx youth who received versus did not receive kits at 3, 6, and 9 months from project initiation.
Results 103 kit-receiving youth (Mage 12.8±4.5, Male 51.0%, NHB 71.8%, Latinx 28.2%,T1D 81.6%) were compared with 917 youth seen in clinic over the same period who did not receive kits (Mage 14.4±4.1, Male 47.0%, NHB 70.1%, Latinx 29.9%, T1D 65.1%). CGM use rates are described in Figure 1. From baseline to follow-up, current CGM use increased and never CGM use decreased among those that received kits, while current and never CGM use rates remained relatively unchanged among non-kit receivers. At final visit, 48% of never users and 29.3% with CGM attrition prior to receiving kits became active users.
Conclusions There was a greater increase in active CGM use and decrease in never CGM use among NHB and Latinx youth who received CGM adhesive kits. QI projects can help to promote equity in use of diabetes technologies.

Disclosure
J.Grundman: Research Support; American Diabetes Association, Dexcom, Inc. A.G.Perkins: Research Support; Tandem Diabetes Care, Inc., Dexcom, Inc. J.K.Reilly: None. S.L.Holly: None. S.Bowers: None. L.Clary: None. S.Majidi: None.
268-OR: The Combined Use of SGLT2 Inhibitors and GLP-1 Receptor Agonists on the Risk of Cardiovascular Events among Patients with Type 2 Diabetes
Authors: AZOULAY LAURENT , SIMMS-WILLIAMS NIKITA , YIN HUI , LU SALLY , TREVES NIR , HOI YUN YU ORIANA 
Published: June 2023

Background: While sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to have cardiovascular benefits when used individually, it remains unknown whether their combined use is associated with further reductions in cardiovascular events in the real-world setting.
Objective: To determine whether the SGLT2 inhibitor-GLP-1 RA combination is associated with a decreased risk of major adverse cardiovascular events (MACE) compared with SGLT-2 inhibitors alone.
Methods: Using the United Kingdom Clinical Practice Research Datalink linked with the Hospital Episode Statistics and Office for National Statistics databases, we identified all patients, &gt;18 years of age, who initiated an SGLT2 inhibitor from 2013 to 2020. Using a prevalent new-user design, we matched 8980 patients initiating an SGLT2 inhibitor-GLP-1 RA combination, in a 1:1 ratio, with patients using SGLT2 inhibitors alone on time-conditional propensity scores. The primary outcome was MACE (myocardial infarction, ischemic stroke, and cardiovascular mortality). Secondary outcomes were the individual components of MACE and heart failure. Patients were followed using an on-treatment approach and Cox proportional hazards regression models were fit to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome.
Results: Compared with SGLT2 inhibitors alone, the SGLT2 inhibitor-GLP-1 RA combination was associated with a 34% decreased risk of MACE (HR: 0.66, 95% CI: 0.48-0.91). In secondary analyses, the combination was associated with a decreased risk of myocardial infarction (HR: 0.64, 95 CI: 0.42-0.98), while the other outcomes generated more modest effects with CIs including the null.
Conclusions: The results of this real-world study suggest that the SGLT2 inhibitor-GLP-1 RA combination is associated with further reductions in the risk of MACE, compared with the SGLT2 inhibitors alone.

Disclosure
L.Azoulay: Advisory Panel; Pfizer Inc., Consultant; Pfizer Inc., Speaker's Bureau; Roche Diagnostics. N.Simms-williams: None. H.Yin: None. S.Lu: None. N.Treves: None. O.Yu: Consultant; Novo Nordisk.

Funding
Canadian Institutes of Health Research (FDN143328)
269-LB: Modeling Alpha-Cell Dysfunction Using Stem Cell–Derived Alpha Cells
Authors: SHRESTHA SWIKRITI , PETERSON QUINN P. 
Published: June 2023

Type 1 Diabetes (T1D) therapies have focused on restoring beta cell function via exogenous insulin or islet transplant. While promising, these approaches fail to account for the role of alpha cells and intra-islet communication in disease etiology. Alpha cells secrete glucagon and maintain effective paracrine signaling with beta cells to maintain glucose homeostasis and metabolic control. Mounting evidences suggest that impaired alpha cell function is a significant contributor to disease progression. Understanding triggers of alpha cell dysfunction and the resulting effects will be crucial for restoring both beta and alpha cell function in T1D. Lack of human alpha cell models have limited progress towards this goal. We recently reported a protocol to generate human alpha cells from stem cell sources (SC-alpha). Using these SC-alpha cells, we have established a T1D disease model to identify the triggers that induce alpha cell dysfunction. Importantly, we have identified defects in proglucagon processing that mimic those observed in diabetes and have identified conditions that modulate proglucagon processing and secretion. Here we demonstrate that exposure of SC-alpha cells to diabetogenic stressors such as hyperglycemia, hyperlipidemia, and ER stress impacts the processing of proglucagon and ultimately results in alpha cell dysfunction. We show that upon exposure to these stressors, SC-alpha cells secrete elevated glucagon compared to the control conditions and show a loss of glucose responsiveness. We also observed changes in the secretion of alternate proglucagon processing products, GLP-1, GLP-2, and glicentin. Interestingly, glicentin levels were affected by ER stress induction, but were unaffected by other stressors, suggesting that ER stress plays a direct role in the disruption of proglucagon processing, leading to alpha cell dysfunction. Identifying triggers of alpha cell dysfunction and assessing impacts in proglucagon processing will be a step towards restoring islet paracrine signaling.

Disclosure
S. Shrestha: None. Q. P. Peterson: None.
269-OR: Empagliflozin on the Risk of Retinopathy in Patients with Type 2 Diabetes—Results from the EMPRISE Study
Authors: TESFAYE HELEN , HTOO PHYO T. , PAIK JULIE M. , ZAKOUL HEIDI , SCHMEDT NIKLAS , DERUAZ-LUYET ANOUK , KOENEMAN LISETTE , WEXLER DEBORAH J. , PATORNO ELISABETTA 
Published: June 2023

EMPRISE aims to assess the effectiveness and safety of empagliflozin in patients with type 2 diabetes (T2D) in routine care. Within EMPRISE, we investigated two diabetic retinopathy (DR) outcomes among adults with T2D initiating empagliflozin or DPP4 inhibitors (DPP4i) in 2 separate cohorts. Using data from Medicare-fee-for-service and 2 U.S. commercial claims databases (2014-2019), we compared the risk of non-proliferative DR (NPDR) onset (cohort 1) and the risk of DR progression (cohort 2). To evaluate the onset of NPDR, we identified 34,262 1:1 propensity-score matched (PSM) patient pairs without history of any DR (Table). To evaluate DR progression (see Table for definition), we identified 7,839 1:1 PSM patient pairs with history of NPDR and without diagnosis or treatment for advanced DR prior to cohort entry. We estimated pooled HR and RD/1,000 PY with 95% CI adjusting for 143 baseline covariates. Compared to DPP4i, a similar risk of NPDR onset was observed with empagliflozin initiation [HR: 1.05 (0.95, 1.16); RD: 1.52 (-1.61, 4.65)] and a decreased risk of DR progression [HR: 0.77 (0.62, 0.95); RD: -9.49 (-16.90, -2.08)], over a mean follow-up of ~8 months on treatment. In routine care in a broad population of patients with T2D empagliflozin was associated with a lower risk of DR progression in line with direction and magnitude of a similarly defined DR outcome in the EMPA-REG OUTCOME trial.

Disclosure
H.Tesfaye: None. P.T.Htoo: Employee; Johnson & Johnson. J.M.Paik: None. H.Zakoul: None. N.Schmedt: Employee; Boehringer Ingelheim International GmbH. A.Deruaz-luyet: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. D.J.Wexler: Other Relationship; Novo Nordisk A/S. E.Patorno: Research Support; Boehringer Ingelheim Inc., National Institutes of Health, Patient-Centered Outcomes Research Institute, US Food and Drug Administration.
270-LB: Pancreatic Glial Cells Distribution Patterns Are Distinct between Human and Mouse
Authors: NIU JINGJING , HACKNEY DARYL J. , AHMADI PABLO , HARA MANAMI , HULL-MEICHLE REBECCA L. , TONG JENNY 
Published: June 2023

Glial cells are components of the central and peripheral nervous systems, which provide physical support for neuron and modulate synaptic transmission. We and others previously showed that in mice, pancreatic glial cells are located in close association with the extensive neuro-endocrine-vascular network that surrounds the islet perimeter. It is well known that differences exist in mouse and human islet architecture, in particular in vascular density and innervation. We therefore sought to determine whether density and/or organization of pancreatic glial cells also differs between mouse and human. Glial fibrillary acidic protein (GFAP) was used to identify pancreatic glial cells and was examined by confocal microscopy. In mouse pancreas, GFAP+ cells were frequently identified around the islet periphery and were less frequently seen in the core of the islet. In human pancreas, however, most of the GFAP+ cells were found in the exocrine tissue, resulting in fewer peri-islet glial cells relative to mice (table). High-fat diet feeding significantly increased %peri-islet GFAP+ area in mice while no difference was seen between obese and lean human donors (table). These findings indicate that pancreatic glial cell distribution patterns differ between mouse and human, raising the possibility that these cells may affect islet-cell function differently between the two species.

Disclosure
J. Niu: None. D. J. Hackney: None. P. Ahmadi: None. M. Hara: None. R. L. Hull-meichle: Employee; Veterans Administration, Research Support; Casma Therapeutics, Cystic Fibrosis Foundation, NIH - National Institutes of Health, Veterans Administration. J. Tong: None.

Funding
University of Washington
273-LB: The Effect of Bispecific GLP-1R/GLP-2R Agonist Compared with Dual GLP-1R/GLP-2R Agonist and Dual GLP-1R/GIPR Agonist in Diet-Induced Obesity Mouse Model
Authors: OH TIMOTHY , YANG SANG-IN , ROH JAEIL , YOON SUNG JEE 
Published: June 2023

Obesity is a global health challenge with few pharmacological options associated with type 2 diabetes and cardiovascular (CV) complications. MG12, a bispecific GLP-1R/GLP-2R Fc-fused agonist, was manufactured to show its potential advantage over current comparable dual incretin agonists. In this study, we observed that MG12 was superior in body weight (BW) reduction when compared to dual GLP-1R/GLP-2R agonist as well as combination therapy of GLP-1R and GLP-2R Fc-fused agonist. We predicted this as the result of the optimized state of increasing GLP-1 activity and the bispecific structural nature. Also, MG12 showed BW reduction in a dose-dependent manner. Interestingly, MG12 at a high dose showed similar BW reduction to dual GLP-1R/GIPR agonist despite a lesser decrease in food intake after the first injection. Additionally, we noted a higher reduction in fat/muscle mass ratio after the last injection in the comparable BW reduced group. Furthermore, MG12 showed a decrease in low grade inflammation biomarkers, which may indicate a potential CV outcome benefit. Therefore, MG12 may be a promising new therapeutic approach for obesity-related metabolic disorders.

Disclosure
T. Oh: Employee; Progen. Co., Ltd, SL Metagen. Co., Ltd. S. Yang: None. J. Roh: None. J. Sung: None.
274-LB: Complement Factor D Contributes to Metabolic Dysregulation by Hepatic CD9 Deficiency
Authors: ZHENG YI 
Published: June 2023

Diabetes-induced metabolic diseases involve functional integration among inter-organ communication, and the liver is central to this process. Here we show that deficiency of cell-surface protein tetraspanin CD9 in the liver of diabetic mice stimulates hepatocytes to synthesize and secrete complement factor D (CFD), which undermines whole-body metabolic homeostasis. Specifically, silencing liver CD9 exacerbated diet-induced obesity and fatty acid synthesis in white adipose tissue of mice with a markedly elevated CFD expression in both liver and plasma. Consistently, liver CFD-overexpressed mice exhibited severe hepatic steatosis, increased fat adipose deposition and decreased energy expenditure under HFD feeding. Mechanistically, CFD exerted its deleterious metabolic effects by activating its receptor C5aR-AKT dependent axis in the adipose tissues, and blockade of C5aR in adipocytes obviously abolished the CFD-induced lipogenesis and -suppressed thermogenesis in vitro and in vivo. Furthermore, we determined an increased CFD with the decreased CD9 expression in the fatty livers of human subjects, and also a negative correlation between CD9 and CFD was established in NAFLD patient samples. Together, these findings identify CFD inhibition as a potential pharmacological target for the management of diabetes and related metabolic disorders.

Disclosure
Y. Zheng: None.

Funding
National Natural Science Foundation of China (82122013, 82100910)
279-LB: The Role of Body Composition Phenotypes on Insulin Resistance in Nondiabetic Asians—The Korea National Health and Nutrition Examination Survey (KNHANES) 2008–2011
Authors: REUM KHANG AH 
Published: June 2023

It is increasingly recognized that obesity as defined by body fat distribution as well as body mass index (BMI) contributes to metabolic disturbances. The relationship between body fat percent (%BF) and insulin resistance in the Asian population remains uncertain. We investigated the association between insulin dynamics and the four body composition phenotypes using BMI and %BF; normal with normal-fat percent (NN), normal with high-fat percent (NH), obese (overweight/obesity) with normal-fat percent (ON), and obese with high-fat percent (OH). We performed a cross-sectional study with 16,578 adult participants aged between 19 and 80 in the fourth and fifth KNHANES with Dual Energy X-ray Absorptiometry (DEXA) data. The subjects with diabetes are excluded. The mean age was 42.72 (standard error (SE) 0.30) years old. The prevalence of impaired fasting glucose, hypertension, and dyslipidemia was higher depending on the body composition phenotypes (p for trend &lt;0.001). Homeostatic model assessment of insulin resistance (HOMA-IR) increased and the quantitative insulin check index (QUICKI) decreased significantly according to the body composition phenotypes (p for trend &lt;0.001). The OH group exhibited significantly the highest HOMA-IR (mean 2.69, SE 0.03) and the lowest QUICKI (mean 0.335, SE 0.001) values. The odds ratio (OR) for high HOMA-IR (men &gt;2.5, women &gt;2.0) and low QUICKI (men &lt;0.347, women &lt;0.343) was increased according to the body composition phenotypes. NH group showed significantly higher OR than ON group, compared to NN group (OR 1.25, 95%CI 1.02-1.53 vs OR 0.91, 95% CI 0.70-1.19, respectively).
In conclusion, using body fat percent with BMI to categorize obesity is useful for estimating HOMA-IR and QUICKI. Although subjects have normal BMI, the amount of their fat mass plays an important role in insulin dynamics. The subjects with high-fat percent need to detect and intervene earlier for future prognosis.

Disclosure
A. Khang: None.
281-OR: Neonatal Outcomes in Early and Incident Gestational Diabetes Mellitus—Are They Normalized with Treatment from 24–28 Weeks’ Gestation?
Authors: SIMMONS DAVID , IMMANUEL JINCY , WAH CHEUNG N. , HAGUE WILLIAM , TEEDE HELENA , NOLAN CHRISTOPHER J. , BACKMAN HELENA E. , HIBBERT EMILY , PEEK MICHAEL J. , MCLEAN MARK , SWEETING ARIANNE , MOHAN VISWANATHAN , HARREITER JÜRGEN ,   TOBOGM CORE INVESTIGATOR GROUP
Published: June 2023

Aim: To compare neonatal outcomes between women with early GDM (eGDM: diagnosed&lt;20 weeks’ gestation), incident GDM (iGDM: diagnosed ≥ 24 weeks’ gestation) and normoglycemia
Methods: Pregnant women with GDM risk factors were enrolled &lt;20 weeks’ gestation into an eGDM treatment trial across 17 sites in Australia, India, Europe. Women undertook a 2-h 75g oral glucose tolerance test on entry & at 24-28 weeks’ gestation. GDM was defined by WHO 2013 criteria. Logistic regression compared outcomes between women with eGDM, iGDM and normoglycemia adjusted for age, body mass index (BMI), site, smoking status, parity and tertiary qualifications. Women randomized to receive eGDM treatment were excluded from this analysis.
Results: Baseline characteristics differed by age, BMI, parity and glycemia across the 3211 women (Table 1). Similar proportions of eGDM and iGDM women received pharmacotherapy. eGDM group gestational weight gain was lower; eGDM and iGDM neonatal outcomes were similar; neonatal intensive care unit admission and respiratory distress were higher in offspring of eGDM than normoglycemic women.
Conclusions: Adverse neonatal outcomes are increased in pregnancies complicated by eGDM with delayed treatment.

Disclosure
D.Simmons: Consultant; Sanofi, Speaker's Bureau; Abbott Diabetes. M.Mclean: None. A.Sweeting: None. V.Mohan: None. J.Harreiter: None. Tobogm core investigator group: n/a. J.Immanuel: None. N.Cheung: None. W.Hague: None. H.Teede: None. C.J.Nolan: None. H.E.Backman: None. E.Hibbert: None. M.J.Peek: None.

Funding
National Health and Medical Research Council (1104231, 2009326); Region Örebro Research Committee (OLL-970566, OLL-942177); Medical Scientific Fund of the Mayor of Vienna (15205); South Western Sydney Local Health District Academic Unit (2016); Western Sydney University Ainsworth Trust (2019)
290-OR: FoxK1-Associated Gene Regulatory Network—A New Transcriptional Regulator of Hepatic Insulin Action
Authors: ALLU PRASANNA , PAN HUI , DREYFUSS JONATHAN , RONALD KAHN C. 
Published: June 2023

Insulin acts on the liver to maintain glucose homeostasis, and disruption of insulin action in liver is central in the pathogenesis of diabetes and metabolic syndrome. While most previous studies of insulin action on gene expression in liver have focused on FoxO1, we have found that Forkhead box protein K1 (FoxK1) is another important regulator of hepatic gene expression which acts in a complementary manner. Thus, upon insulin stimulation, FoxK1 translocates from the cytoplasm to nucleus while FoxO1 translocates from nucleus to cytoplasm. Chromatin immunoprecipitation (ChIP) sequencing shows that FoxK1 binds to &gt;1000 gene regulatory elements in the proximal promoters and enhancers in hepatic chromatin, with TGTTTAC being the major FoxK1 DNA binding motif. De novo motif analysis suggested that HNF4A is also one of the major co-regulators for FoxK1 in mediating gene expression. Insulin stimulated binding of FoxK1 to promoters was observed in up-regulation of genes involved in steroid biosynthesis and cell cycle, and down-regulation of genes involved in autophagy. FoxK1 is also a potential transcription factor for insulin receptor (IRβ) mediated gene regulation as evidenced by its binding to LARS1 and TIMM22 promoters. Both FoxK1 and IRβ share regulation of genes involved in rRNA processing, mitotic cell cycle and nonsense-mediated decay. Interestingly, gene promoters of genes in glucose metabolism (PCK1, G6PC and PKM) are bound by FoxK1, but not by IRβ in response to insulin. FoxK1 can also work with FoxO1 in regulation of genes involved in mitochondrial translation, and with both IRβ and FoxO1 in insulin regulation of AHCY, PPRC1, and CDKN1A, i.e., genes involved in cell senescence, amino acid metabolism and mitochondrial biogenesis. Thus, FoxK1 is a potential factor priming the response to insulin and helps with the recruitment of IRβ or FoxO1 in regulation of gene expression in liver in metabolism and other important biological pathways.

Disclosure
P.Allu: None. H.Pan: None. J.Dreyfuss: None. C.Kahn: None.