bluuebunny/crossref_metadata_2025 huggingface dataset:
355-OR: Targeting a Lipid Droplet Hydrolase-Mediated Lipid Signaling for Treatment of Type 2 Diabetes
Authors: LI XIN , SUN KAI
Published: June 2023

Lipid droplets (LDs) are cytosolic organelles that serve as the major energy reservoir in adipocytes. Excessive accumulation of neutral lipids in LDs has been linked to obesity-associated type 2 diabetes. The dynamics of LDs is regulated by multiple proteins bound to their surfaces. Recently, carboxylesterase 1d (Ces1d) was identified as a LD-targeting lipid hydrolase. It has been showed that blockage of Ces1d in adipose tissue led to not only decreased lipolysis, but also impaired β-adrenergic signaling-stimulated thermogenesis. The goal of the current study is to define the mechanism governing the function of Ces1d on lipid metabolism. The hypothesis is that the LD-targeting Ces1d generates free fatty acids (FFA) “third messenger” that trigger specific lipid signaling in adipose tissue which further affect the whole-body metabolic homeostasis. To test this hypothesis, an adipose tissue specific Ces1d knockout mouse model (Adipo-Ces1d KO) was generated. Mass Spectrometry analysis revealed that circulating docosahexaenoic acid (DHA, C22:6 n=3), an established PPARγ ligand, was dramatically decreased in Adipo-Ces1d KO mice. The production of DHA was confirmed by an in vitro lipid digestion assay on the recombinant Ces1d. Lack of DHA signaling further led to decreased transactivation of PPARγ in adipose tissue of the Adipo-Ces1d KO mice. As a result, the expression of thermogenic gene, UCP1 was significantly downregulated. The result agrees with previous observation that Adipo-Ces1d KO mice lost their ability to defense body temperature when exposed to coldness. More interestingly, the Adipo-Ces1d KO mice gained more body weight with increased fat mass during a HFD challenge, suggesting they experienced decreased energy expenditure in the whole process. The findings thus highlight the key role of a novel lipid signaling pathway mediated by Ces1d in energy expenditure and hence pinpoint it as a potential target for treatment of obesity-induced type 2 diabetes.

Disclosure

X.Li: None. K.Sun: None.

Funding

National Institutes of Health (R56DK124419, R01DK129815)
36-OR: The Effect of Glucagon-Like Peptide-1 Receptor Blockade on the ß-Cell Response to Glucagon Bolus in People With and Without Type 2 Diabetes
Authors: EGAN AOIFE M. , ZEINI MAYA , WELCH ANDREW A. , FARAHANI RAHELE A. , LAURENTI MARCELLO C. , COBELLI CLAUDIO , DALLA MAN CHIARA , VELLA ADRIAN
Published: June 2023

Glucagon acts as an insulin secretagogue in part via the glucagon-like peptide-1 receptor (GLP1R) expressed on β-cells. Type 2 diabetes (DM2) is characterized by increased (and inappropriate) glucagon secretion for the prevailing hyperglycemia. Increased islet glucagon staining has also been observed in DM2. This suggests that increased glucagon signaling via GLP1R is a mechanism to maintain β-cell secretion in DM2. To ascertain if this is the case, we quantified the relative contribution of GLP1R signaling to the insulin response to glucagon in the presence and absence of DM2. We studied 12 individuals without DM2 (54 ± 2 yrs, 33 ± 1 kg/m2) and 11 with DM2 (58 ± 2 yrs, 34 ± 2 kg/m2) on 2 occasions in random order. On one occasion Exendin-9,39 (300pmol/kg/min) was infused to block GLP1R, while on the other study day saline was infused. Following an overnight fast and a 3-hour hyperglycemic clamp (~9 mmol/L), 1 mg glucagon bolus was administered intravenously with subsequent measurement of insulin, and C-peptide over 30 minutes during hyperglycemia. Exendin-9,39 infusion decreased peak and integrated insulin and C-peptide concentrations in response to the glucagon bolus in both those with and without DM2. The symmetric % change in insulin (-49 ± 8 vs -32 ± 8, DM2 vs. subjects without diabetes respectively, p = 0.2) and C-peptide (-24 ± 5 vs -15 ± 4, p = 0.18) did not differ between groups. In addition, six of the subjects without DM2 completed two additional study days (± exendin-9,39) with infusion of Intralipid® and heparin to raise free fatty acids (FFA) and cause acute insulin resistance. Acute FFA elevation also did not alter the net contribution of GLP1R stimulation to the response to glucagon in individuals without DM2 (% change insulin: -34 ± 10, p = 0.42; C-peptide: -23 ± 7, p = 0.38). These data suggest that the % contribution of glucagon to the stimulation of β-cell secretion via GLP1R does not change significantly in the presence or absence of DM2 or of FFA elevation.

Disclosure

A.M.Egan: None. M.Zeini: None. A.A.Welch: None. R.A.Farahani: None. M.C.Laurenti: None. C.Cobelli: None. C.Dalla man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. A.Vella: Advisory Panel; Rezolute, Inc., Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S, Other Relationship; Novo Nordisk.

Funding

National Institutes of Health (DK126206)
361-OR: Hybrid Care Model Combining Telemedicine and Office Visits for Diabetes Management Is Effective in Older Adults with Type 1 Diabetes (T1D) Using Continuous Glucose Monitors (CGM)
Authors: TOSCHI ELENA , ADAM ATIF , HURLBERT REBECCA , FRIMPONG NANA , SLYNE CHRISTINE , LAFFEL LORI M. , MUNSHI MEDHA
Published: June 2023

Objective: CGM improves glycemic control and mitigates hypoglycemia using office visits for older adults with T1D. During COVID-19 pandemic, a hybrid (in-office and telemedicine) care model was implemented. Data on impact of hybrid care model on glycemic control in older adults with T1D are limited.

Methods: Demographic, clinical characteristics, and CGM metrics of older adults (age ≥65 yrs) with T1D were retrieved from electronic health records from 2 periods: pre-pandemic (April 1, 2019-March 1, 2020) and during pandemic (September 1, 2020 to August 31, 2021) (adjusted for length of follow-up).

Results: 299 (47% male; mean age 72±4 years; 51% pump users) older adult CGM users were seen in both periods. Comparison of CGM metrics (Table) between time periods showed no changes in overall control (mean glucose 170±31 vs 168±33 mg/dL; p=0.75), glucose management indicator (GMI) (7.4 vs 7.3% p=0.65) or coefficient of variation (CV) (36% vs 35%; p=0.82). During hybrid model of care, time in-range (64±15 vs 72±15%; p<0.001) improved, while time <70 mg/dL did not increase.

Conclusion: Glycemic control using a hybrid-care model was maintained compared with in-person visits in older adults with T1D using CGM without impacting risk of hypoglycemia. Further studies can clarify how to routinely use a hybrid-care model in older adults with T1D.

Disclosure

E.Toschi: Advisory Panel; Eli Lilly and Company. A.Adam: None. R.Hurlbert: None. N.Frimpong: None. C.Slyne: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. M.Munshi: Consultant; Sanofi.

Funding

Thomas J. Beatson, Jr. Foundation
382-P: Comparison of Intranasal and Injectable Glucagon Administration among Pediatric Population Responders
Authors: WANG YUE PEI , BERNATCHEZ FRANCESCA , CHOUINARD-CASTONGUAY SARAH , TREMBLAY MARIE-CLAUDE , VANASSE ANDRÉANE , MEGALLI MELISSA , MILLETTE MAUDE , BOULET GENEVIEVE , HENDERSON MÉLANIE , BRAZEAU ANNE-SOPHIE , RABASA-LHORET RÉMI , GAGNON CLAUDIA
Published: June 2023

Context: Intranasal glucagon (INg) might improve the management of severe hypoglycemia (SH) at school in children with type 1 diabetes (T1D), which is a major concern of our patient partners.

Objectives: We compared the performance of parents of children with T1D & school workers (SW) for INg and injectable glucagon (IJg) administration. We also assessed the enablers and barriers associated with each glucagon and preferred teaching methods.

Methods: After watching a video on glucagon administration, Patients and SW (30/group) administered both glucagon in random order in 2 simulated scenarios, followed by an individual interview. Performance was rated by a direct observer: completion time, successful execution of predefined key steps and critical steps.

Results: Both groups had a better performance with INg than IJg (Fig 1). The majority preferred INg for its ease of use, safety in the pediatric context and better acceptability by SW. Some participants thought that IJg is more effective and useful for off-label smaller doses to prevent SH. Preferred teaching methods were videos and workshops, but only videos could be sufficient for INg.

Conclusions: INg is faster and more likely to be successfully administered than IJg by. Implementing mandatory video-based trainings for SW could improve SH management and the involvement of SW.

Disclosure

Y.Wang: None. A.Brazeau: Other Relationship; Dexcom, Inc., Diabète québec, Ordre des diététistes nutritionnistes du Québec, Research Support; Canadian Institutes of Health Research, Fonds de recherche du Québec en Santé. R.Rabasa-lhoret: Consultant; Dexcom, Inc., Abbott, Janssen Pharmaceuticals, Inc., Novo Nordisk Canada Inc., Sanofi, Lilly, Tandem Diabetes Care, Inc., Insulet Corporation. C.Gagnon: Advisory Panel; Novo Nordisk, Other Relationship; Ascendis Pharma A/S, Research Support; Novo Nordisk. F.Bernatchez: None. S.Chouinard-castonguay: None. M.Tremblay: None. A.Vanasse: None. M.Megalli: None. M.Millette: Advisory Panel; Novo Nordisk Canada Inc., Pfizer Inc. G.Boulet: Other Relationship; Dexcom, Inc. M.Henderson: None.

Funding

Canadian Institutes of Health Research (157204); JDRF (2018651)
400-P: Spatial Metabolomics Analysis by MSI-DeepPath Identifies Key Pathways in ZDF Diabetic Kidney Disease Model
Authors: HEJAZI LEILA , SHARMA SHOBA , RUIZ AARON , ZHANG GUANSHI , TUCCI FABIO C. , SHARMA KUMAR
Published: June 2023

Background: The Zucker Diabetic Fatty (ZDF) rat is a popular model of type 2 diabetes as it develops pathologic changes in the kidney similar to human diabetic nephropathy. To identify metabolic pathways linked to pathologic features MALDI mass spectrometry imaging (MSI) can be a powerful platform. However, quantification of metabolites from MALDI-MSI is very challenging. Our MSI-DeepPath computational platform enables spatial quantitation of metabolites from any tissue section size.

Methods: Control and obese ZDF male rats (age 6mo, n=5/group) were studied. Spatial metabolomics analysis of kidney tissue sections was performed using MALDI-MSI at 20 µm resolution. Metabolites were detected at mass accuracy <2 ppm using Q-Exactive orbitrap MS followed by annotations using METASPACE. SygnaMap’s MSI-DeepPath computational platform was used to quantify the annotated metabolites.

Results: Of 400 metabolites annotated at m/z range 70-500 Da the top features were selected using t-test, p value and fold change analysis. The top 20 biomarkers that separated ZDF from controls included glucose, serine, histidine, and glutamate. The most significantly upregulated metabolite was tyrosinamide (8.2-fold, p=8.02 x 10-9 ). The most significant downregulated metabolite was L-threonine (0.3-fold, p=2.03 x 10-9). Pathway analysis revealed that aminoacyl-tRNA biosynthesis, galactose, glyoxylate and dicarboxylate metabolic pathways can discriminate healthy from diabetic kidney samples.

Conclusion: MSIDeepPath enables quantification of spatial metabolomics of tissue sections using MALDI-MSI data. This new tool can be applied across normal and diseased samples allowing for robust statistical analysis of spatial omics data. Using MSI-DeepPath on kidney sections from the ZDF rat we identified regulation of metabolites linked to key pathways of diabetic kidney disease.

Disclosure

L.Hejazi: None. S.Sharma: None. A.Ruiz: None. G.Zhang: None. F.C.Tucci: None. K.Sharma: Advisory Panel; Reata Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc.

Funding

National Institutes of Health (1R43DK130732-01A1)
409-P: Post Hoc Analyses of Longitudinal Changes of Plasma Proteins Associated with Progression to End-Stage Kidney Disease in Type 2 Diabetes Patients with Chronic Kidney Disease Treated with GLP-1 Receptor Agonist Dulaglutide (AWARD-7)
Authors: MCFARLIN BRANDON E. , SATAKE EIICHIRO , MD DOM ZAIPUL , RICCA JOSEPH , KECHTER AFTON V. , WILSON JONATHAN M. , DUFFIN KEVIN L. , KROLEWSKI ANDRZEJ
Published: June 2023

The AWARD-7 clinical trial of patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) reported a slower decline in estimated glomerular filtration rate (eGFR) and decreased urinary albumin-to-creatinine ratio (UACR) in patients treated with dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, compared to insulin glargine over one year. Previous studies identified 21 circulating plasma risk proteins highly associated with progression to end stage kidney disease (ESKD) in patients with diabetes (Joslin Kidney Panel). The aim of this study was to determine the longitudinal changes of these proteins in AWARD-7 to evaluate their predictive performance as biomarkers of kidney disease progression. Plasma samples were obtained from patients with T2D and CKD stages 3-4 who received dulaglutide 1.5 mg (n=124) or insulin glargine as basal therapy (n=125) for 52 weeks. Using the Olink custom platform we measured the concentration of 21 proteins at baseline, 26-weeks, and 52-weeks of treatment. At baseline all 21 proteins were correlated with eGFR (r=-0.2 to -0.8; all p<0.0003) and UACR (r=0.2 to 0.6; all p<0.0001). After 26 weeks of treatment, 13 risk proteins significantly increased in glargine group (3 to 13%; all p<0.05) whereas no significant change was observed in dulaglutide group at 26 weeks. By 52 weeks, 5 proteins remained significantly elevated in the glargine group compared to dulaglutide. Several proteins were correlated with declining kidney function (change of eGFR) and increasing UACR in patients with glargine, but not in patients treated with dulaglutide. In this study, the increase of plasma risk proteins associated with ESKD was slowed in dulaglutide-treated patients and is consistent with the hypothesis that several proteins within the Joslin Kidney Panel can serve as predictive biomarkers of treatment efficacy.

Disclosure

B.E.Mcfarlin: Employee; Eli Lilly and Company. E.Satake: None. Z.Md dom: None. J.Ricca: None. A.V.Kechter: Employee; Eli Lilly and Company. J.M.Wilson: Employee; Eli Lilly and Company. K.L.Duffin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company, Pfizer Inc. A.Krolewski: None.
41-LB: Regular Physical Activity Plays a Crucial Role in Improving the Anti-inflammatory Status of Healthy Individuals by Modulating TLR2 Expression
Authors: BAHMAN FATEMAH , ALSAEED HALEMAH , ALBELOUSHI SHAIMA , ALMULLA FAHD , AHMAD RASHEED , ALRASHED FATEMA
Published: June 2023

Toll-like receptors (TLRs) are dominant components of the innate immune system and have been targeted for therapeutic drug development for several inflammatory disorders including cancer, cardiovascular diseases, and diabetes mellitus. Daily levels of physical activity (PA) and dietary intake have been purported to influence the systemic circulation of cytokines, affecting the overall activation of TLRs and influencing the inflammatory milieu. The aim of this study is to investigate the association between daily physical activity and monocytic TLR2 expression in lean individuals. Normal-weight participants (n = 69) were recruited for this study. Daily physical activity was tracked for seven days using an ActiGraph accelerometer. The intensity of PA was determined by Freedson’s cut-offs, and participants were divided according to the 25th lowest (Q1), median (Q2), and top (Q3) percentiles of their activity level. Blood pressure measurements and heart rates were taken for each individual. Moreover, blood glucose, fasting insulin, cholesterol, high-density lipoprotein (HDL), and triglycerides were determined. Surface expression of TLR2 was quantified on peripheral monocytes by flow cytometry. Our data show that individuals with higher levels of moderate-to-vigorous PA and daily step count were found to have higher levels of circulatory CD14+TLR2+ subset. The top 25th percentile groups also showed significantly lower diastolic blood pressure (DBP), triglyceride (TG), and matrix metallopeptidase 9 (MMP9) levels in their circulation. Pearson correlation analysis revealed a negative relationship between CD14+TLR2+ subset and cardiovascular risk markers. The presented results highlight a positive influence of higher daily PA on cardiovascular health, driven by the upregulation of monocytic TLR2+ subsets in circulation, suggesting that TLR2 may play a modulatory role in the regulation of inflammation and lipid metabolism.

Disclosure

F. Bahman: None. H. Alsaeed: None. S. Albeloushi: None. F. Almulla: None. R. Ahmad: None. F. Alrashed: None.
417-P: Functional Characterization of a Rare, Pathogenic Missense Variant Implicates FRAS1 as a Novel Gene for Risk of Progression to End-Stage Kidney Disease in Diabetes
Authors: CHEN TIEHUA , NEELEY MATTHEW B. , LAZARO-GUEVARA JOSE M. , PEZZOLESI MELISSA , SIMEONE CHRISTOPHER A. , RODAN AYLIN , HOLLAND WILLIAM L. , PEZZOLESI MARCUS G.
Published: June 2023

Progressive renal decline is the central manifestation of diabetic nephropathy (DN) that ultimately leads to end-stage kidney disease (ESKD). Leveraging an innovative family-based approach that integrates electronic medical record data, a unique population-based genealogy resource, and next-generation sequencing, we recently identified a rare missense variant (p.R2516C, allele frequency=0.00002) in FRAS1, which encodes an extracellular matrix protein that regulates epidermal basement membrane adhesion and mediates glomerular integrity, in a family with diabetes and ESKD. While this rare missense variant is predicted to be deleterious (CADD score=32), whether this impacts FRAS1 function is unknown; here, we set out to assess the functional impact of this variant. To do so, we used CRISPR-Cas9 gene editing technology to generate 3 novel HEK293 cell lines (2 FRAS1 knock-in cell lines (a synonymous p.H2520H control cell line and a missense p.R2516C variant cell line) and a FRAS1 knock-out cell line) and performed in vitro cell migration and cell adhesion assays. Relative to the control cell line, both the FRAS1 knock-out cell line and the missense variant cell line displayed significantly inhibited cell migration (p = 1.54X10-13 and p = 5.05X10-5, respectively). Similarly, cell adhesion was significantly inhibited in cells in which FRAS1 was knocked out and in those carrying the p.R2516C variant compared to the control cell line (p = 6.72X10-9 and p = 6.63X10-6, respectively). Together, these data suggest that the FRAS1 p.R2516C variant negatively impacts FRAS1 function and further implicates this gene as having a potential role in the progression of ESKD in individuals with diabetes.

Disclosure

T.Chen: None. M.B.Neeley: None. J.M.Lazaro-guevara: None. M.Pezzolesi: None. C.A.Simeone: None. A.Rodan: None. W.L.Holland: Research Support; SymbioCellTech, LLC. M.G.Pezzolesi: Research Support; Renalytix.

Funding

National Institutes of Health (R01DK128641)
430-P: Glycemic Control Assessed by Continuous Glucose Monitoring among Dialysis Patients With and Without Diabetes Mellitus
Authors: MAYEDA LAURA , ZELNICK LEILA , TRIKUDANATHAN SUBBULAXMI , HIRSCH IRL B. , WATNICK SUZANNE , DE BOER IAN
Published: June 2023

Introduction: Glycemic control for dialysis patients with diabetes mellitus (DM) is challenging due to limitations of HbA1c, risk of hypoglycemia, and fewer options for glucose-lowering agents. We sought to comprehensively describe glycemic patterns among dialysis patients using continuous glucose monitoring (CGM).

Methods: The Blood Sugar Sensing On Maintenance Dialysis (BLOSSOM) study is a prospective community-based cohort of people treated with dialysis, with or without DM, designed to assess the prevalence, causes, and consequences of dysglycemia. Each participant wore a Dexcom G6 CGM for 10 days. This interim analysis examined the first 153 BLOSSOM dialysis participants.

Results: Dialysis participants had a mean (SD) age of 61 (14) years, 132 (86%) underwent hemodialysis, and 21 (14%) were treated with peritoneal dialysis (PD). Among 90 dialysis participants with DM, mean (SD) glucose management indicator (GMI) was 7.9% (1.2%), time in range (TIR) (70-180 mg/dL) was 50% (29%) and 27 (30%) participants achieved TIR ≥70%. Mean (SD) time high (>180 mg/dL), very high (>250 mg/dL), low (<70 mg/dL) and very low (<54 mg/dL) was 49% (29%), 21% (23%), 2% (11%) and 1% (11%), respectively. Of 63 dialysis participants without DM, mean (SD) GMI was 6.2% (0.4%), and time in normal range (70-140 mg/dL) 75% (18%). Mean (SD) time low and very low were 2% (8%) and 0% (3%), with low and very low sensor glucose values seen in 38 (60%) and 23 (37%) participants, respectively. PD patients without known DM (n=9) had a mean (SD) GMI of 6.6% (0.3%) and spent mean (SD) 54% (21%) of time in normal range.

Conclusions: In this community-based sample of maintenance dialysis patients, uncontrolled hyperglycemia was highly prevalent among patients with DM. PD patients without DM were in normal range less than half of the time. Hypoglycemia was seen in patients with and without DM. Our findings warrant additional investigation into causes and consequences of glycemic patterns in patients on dialysis.

Disclosure

L.Mayeda: None. L.Zelnick: None. S.Trikudanathan: Research Support; Insulet Corporation, Bionic pancreas. I.B.Hirsch: Consultant; Abbott Diabetes, Lifecare, Inc., Hagar, Research Support; Beta Bionics, Inc., Insulet Corporation, Dexcom, Inc. S.Watnick: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126373)
439-P: Microalbuminuria and Hypertension among Indian Patients with Type 2 Diabetes—A Community-Based Cross-Sectional Study
Authors: SABOO BHARAT , DEV MEHTA KAPIL , NAIK AAFREEN
Published: June 2023

Background and Aims: The India Microalbuminuria Survey (IMS) was a cross-sectional, national survey to understand the prevalence of microalbuminuria (MAU) in Indian hypertensive patients. In the IMS study, 992 patients out of 1369 were diabetic. The objectives of this subset analysis were to estimate the prevalence of microalbuminuria in Indian hypertensives patients with concomitant T2DM.

Methods: This cross-sectional subset analysis included 992 diabetic patients visiting a physician’s clinic, from 121 centres across India. Inclusion criteria were male and female outpatients aged ≥ 18years with hypertension and concomitant type II DM and no reason for false positive microalbuminuria reflected in dipstick tests. Exclusion criteria were presence of secondary hypertension and existing CKD. Microalbuminuria was diagnosed if the urinary albumin excretion was more than 30 mg/L using the ACR Kit manufactured by Biosense Technologies Pvt. Ltd. Patient data was analyzed with the help of the SPSS software.

Results: The mean age of the patients was 54.04 years. There were 186 (18.75 %) patients below 45 years of age and 806 (81.25%) patients more than 45 years of age. The prevalence of microalbuminuria in hypertensive patients with concomitant type II DM was 31.04 %. The prevalence was 34.4% in patients below 45 years of and 30.27% in patients above 45 years age.

Conclusions: This study reports a high prevalence of microalbuminuria in Indian patients with hypertension and concomitant type II DM. Hence, early recognition of renal dysfunction through detection of microalbuminuria and to start treatment without any delay will confer future protection from end stage renal disease as well as hypertension and its complications in type 2 diabetic patients.

Disclosure

B.Saboo: None. K.Mehta: Employee; JB Chemicals and Pharmaceuticals Ltd. A.Naik: Employee; JB Chemicals and Pharmaceuticals Ltd.
449-P: Truncations of Apolipoproteins C-I and C-II Are Associated with Coronary Artery Calcium Progression in Multiethnic Study of Atherosclerosis (MESA)
Authors: KOSKA JURAJ , FURTADO JEREMY , HU YUEMING , BILLHEIMER DEAN , ALLISON MATTHEW , BUDOFF MATTHEW , NEDELKOV DOBRIN , MCCLELLAND ROBYN , REAVEN PETER
Published: June 2023

Higher truncated-to-native proteoform ratios of apolipoproteins (apo) C-I (C-I’/C-I) and C-II (C-II’/C-II) are associated with less atherogenic lipid profiles, including lower triglycerides (TG) and higher HDL levels. Here we examined the relationships of C-I’/C-II and C-II’/C-II, and total apoC-I and apoC-II concentrations with coronary artery calcium (CAC) progression. Apo C-I and C-II proteoforms were measured by mass spectrometry immunoassay in 5,791 baseline MESA plasma samples. Total apo C-I and C-II concentrations were assayed in 3,851 samples. CAC was measured 1 to 4 times (mean 2.5) over 10 years. Repeated measures regression models were adjusted for age, gender, race/ethnicity, and follow-up time (Model 1), then for BMI, diabetes, systolic BP, use of tobacco, statins and antihypertensive medications (Model 2), and then for plasma HDL and TG (Model 3). Among 5,069 participants with at least one follow-up CAC CT scan, 2,513 had CAC progression defined as events of CAC changing from 0 to > 0, or ≥ 10 units/yr from CAC > 0 but ≤ 100, or ≥ 10%/yr from CAC > 100. Progression was inversely associated with C-I’/C-I (Risk Ratio per 1 SD: 0.93 [95% CI 0.87, 0.97], Model 3). In those with baseline CAC = 0 (n = 2,581), risk of CAC > 0 (897 events) was inversely associated with C-I’/C-I in Model 1 only (0.85 [0.79, 0.93]). In those with baseline CAC > 0, C-II’/C-II was positively associated with follow-up change in density score (β-estimate per 1 SD 0.02 [95% CI: 0.001, 0.03] units) in Model 3, indicating a potentially more stable plaque. Baseline-adjusted follow-up density score was also positively related to total apoC-I in Model 2 (0.02 [0.004, 0.04]). None of the CAC measures were related to total apoC-II. In conclusion, increased truncation of apo C-I and C-II is associated with reduced CAC progression and/or improved stability of coronary atherosclerotic plaque that is not explained by total concentrations of both apolipoproteins.

Disclosure

J.Koska: None. J.Furtado: Employee; Biogen. Y.Hu: None. D.Billheimer: Advisory Panel; AstraZeneca. M.Allison: None. M.Budoff: Research Support; Novo Nordisk, Novartis, Boehringer Ingelheim Inc., Speaker's Bureau; Boehringer Ingelheim and Eli Lilly Alliance. D.Nedelkov: None. R.Mcclelland: None. P.Reaven: Research Support; Dexcom, Inc.

Funding

National Heart, Lung, and Blood Institute (R01HL138969, 75N92020D00001, HHSN268201500003I, N01HC95159, 75N92020D00005, N01HC95160, 75N92020D00002, N01HC95161, 75N92020D00003, N01HC95162, 75N92020D00006, N01HC95163, 75N92020D00004, N01HC95164, 75N92020D000
467-P: Reinterventions after Abdominal Aortic Aneurysm Repair in People with Diabetes Mellitus—A Systematic Review and Meta-analysis
Authors: DHATARIYA KETAN , OTIFY EMAN A.A. , MEKKI MOHAMED A.E. , STATHER PHILIP W.
Published: June 2023

Background: There is a known negative association between diabetes (DM) and abdominal aortic aneurysm (AAA). Patients with DM have a higher long-term mortality following AAA repair. However, whether that is related to their AAA is unclear.

Aims: To determine the rates of reinterventions in patients with DM post-AAA repair. Outcomes included; AAA sac enlargement, reinterventions, endoleaks, AAA rupture, and conversion.

Methods: Pubmed, Embase and Cochrane databases were searched for primary research studies between 2005 and 2022 according to PRISMA guidelines. Patients undergoing AAA repair either via endovascular aneurysm repair or open surgical repair were included. Meta-analysis was conducted using Review Manager.

Results: Eight studies were identified totalling 75678 patients in the control group, and 22284 in the DM group. Patients with DM had a lower rate of reintervention compared to the control group, (6.63% v 9.15%; OR 0.80, 95%CI[0.67, 0.94], P=0.007). There was no significant difference in rate of all endoleaks (8.54% v 12.38%; OR 0.91, 95%CI[0.53-1.58], P=0.74), which remained non-significantly in favour of DM when comparing type 1 and 2 separately, with similar results with sac expansion. There was a significant reduction in rates of conversion to open surgery in those with DM (3.07% v 4.21%; OR 0.75, 95%CI[0.55-0.99], P=0.04), and a reduction in post op AAA rupture (3.35% v 5.69%; OR 0.53, 95%CI[0.49-0.58], P<0.001).

Conclusion: Postoperative AAA ruptures, reinterventions, and conversion to open surgery were lower in patients with DM. However, the rates of endoleaks were not significantly different, so the reason for higher complication rates remains unknown.

Disclosure

K.Dhatariya: Other Relationship; Novo Nordisk, AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company. E.A.A.Otify: None. M.A.E.Mekki: None. P.W.Stather: None.
47-OR: Association of Early Pregnancy Triglycerides and HbA1c in a UK Multiethnic Cohort
Authors: GHEBREMICHAEL-WELDESELASSIE YONAS , SUKUMAR NITHYA , SARAVANAN PONNUSAMY
Published: June 2023

Introduction: Role and ethnic variations of early pregnancy triglycerides and HbA1c on birthweight in women without gestational diabetes (GDM) is not clear.

Aim: To explore the association of early pregnancy HbA1c and triglycerides in multi-ethnic women at risk of developing GDM

Methods: PRiDE study, designed to address the role of B vitamins on incident GDM, recruited 4746 women (12.5 weeks of gestation) from 10 centres across UK, who fulfilled NICE criteria for GDM screening (OGTT at 26.5 weeks). Intergrowth centiles were used to assess LGA. Multiple regression analyses were used to explore the effects of early pregnancy triglycerides and HbA1c, adjusted for key covariates. Additional model included 0- and 120-min glucose values at OGTT.

Results: 3782 did not have GDM (74% Whites; 10.1% South Asians). 81.3% were nulliparous. Mean age: 30.3 ± 5.2; BMI: 30.6 ± 7.1. Mean birthweight: 3417.1 ± 590.0 (at 39.1 ± 1.7 weeks). Early pregnancy plasma triglyceride but not HbA1c was independently associated with birthweight, macrosomia and LGA. Addition of OGTT glucose values reduced the effect size for macrosomia and LGA. No ethnic specific interactions were observed.

Conclusion: In women who are at high risk but did not develop GDM, early pregnancy triglyceride but not HbA1c levels was independently associated with birthweight. These effects were independent of ethnicity and partially mediated through plasma glucose levels at OGTT.

Disclosure

Y.Ghebremichael-weldeselassie: None. N.Sukumar: None. P.Saravanan: Other Relationship; Novo Nordisk, Research Support; Novo Nordisk, Amgen Inc., Abbott.

Funding

Medical Research Council, UK (MR/J000094/1)
484-P: Newer Glucose-Lowering Drugs and Risk of Parkinson’s Disease—A Meta-analysis of Randomized Outcome Trials
Authors: TANG HUILIN , LU YING , DONAHOO WILLIAM T. , OKUN MICHAEL S. , WANG FEI , BIAN JIANG , GUO JINGCHUAN
Published: June 2023

Background: Cumulative results from preclinical studies have shown that newer glucose-lowering drugs (GLDs), i.e., dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose co-transporter-2 (SGLT2) inhibitors, have been associated with a decreased risk of Parkinson’s disease (PD). The findings from clinical and epidemiological studies are however mixed. We aimed to evaluate the potential effect of newer GLDs on the risk of PD through a meta-analysis of randomized outcome trial data.

Methods: We systematically searched Pubmed, Embase, and CENTRAL up to December 2022 for published randomized placebo-controlled outcome trials evaluating DPP-4 inhibitors, GLP-1RAs, and SGLT2 inhibitors. We extracted PD outcomes from clinicaltrials.gov. We estimated pooled odds ratios (OR) and 95% confidence interval (CI) using the Peto method and we performed a subgroup analysis by type of newer GLDs.

Results: Of 24 trials that qualified for inclusion, there were 33 incident PD cases among 185,305 participants with or without type 2 diabetes over a median follow-up of 2.2 years. Newer GLDs were significantly associated with a lower risk of PD than placebo (OR, 0.50; 95%CI, 0.25-0.98). Our subgroup analysis showed that DPP-4 inhibitors (OR, 0.71; 95%CI, 0.23-2.22), GLP-1RAs (OR, 0.51; 95%CI, 0.10 - 2.55), or SGLT2 inhibitors (OR, 0.37; 95%CI, 0.13-1.01) were all associated with a decreased risk of PD, but the differences were marginally or not statistically significant.

Conclusion: Newer GLDs may be associated with a decreased risk of developing PD. Given the low number of events and short duration of follow-up of existing clinical trials, comparative effectiveness studies using real-world data (RWD) are warranted. These RWD-based studies can pave the way for evaluating the potential drug repurposing value of these newer GLDs for PD, before moving to large-scale randomized controlled trials.

Disclosure

H.Tang: None. Y.Lu: None. W.T.Donahoo: None. M.S.Okun: None. F.Wang: None. J.Bian: None. J.Guo: Consultant; Pfizer Inc., Research Support; PhRMA Foundation, NIH - National Institutes of Health.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK133465)
486-P: Reduced Serum Netrin-1 Levels Correlate with Corneal Nerve Fiber Loss in Diabetic Neuropathy
Authors: MONDAL ASIF , BOSE CHIRANJIT , PRAMANIK SUBHASISH , MUKHERJEE AYAN , MUKHERJEE BIDISHA , MUKHOPADHYAY SATINATH
Published: June 2023

Objective: Deficiency of endogenous neurotropic factors are implicated in diabetic neuropathy (DN). While Netrin-1, a neurotropic factor, is downregulated in type 2 diabetes, its involvement in Diabetic Neuropathy (DN) is yet to be reported. While corneal confocal microscopy (CCM) is a sensitive, in-vivo, non-invasive technique for detection of DN at its earliest stages, the association between CCM parameters and serum Netrin-1 levels has not been reported before. The present study looked at serum netrin levels in populations with type 2 diabetes with or without neuropathy, using CCM as the gold standard.

Methods: Sixty subjects with type 2 diabetes (DN- 30, DN+ 30)] were stratified using DN4Q and Vibration perception Threshold Test (VPT). Cornea was assessed using CCM. Serum Netrin-1 level was measured by ELISA. Data compared 27 healthy controls were also studied.

Results: There was a significant reduction in corneal nerve fibre density (CNFD), branch density (CNBD), and fibre length (CNFL) in T2D. DN was associated with a greater reduction in all CCM parameters compared to those with type 2 diabetes but no DN (p<0.05). There was a progressive decline in the mean serum netrin-1 level from healthy controls to T2D DN- to T2D DN+ (Control vs T2D, p<0.05; T2D DN- vs DN+, p<0.01)]. Netrin-1 correlated only with CNBD in T2D DN- group, (p=0.02). While ROC analysis showed CNFD, CNBD and CNFL to predict DN in 55.6%, 57.1% and 62.1% respectively, Netrin-1 alone predicted DN in 63.3%. CNBD and CNFL correlated with Netrin-1 (p=0.04 and p=0.01) in T2D DN+ group.

Conclusion: Serum netrin-1 levels declined progressively from controls to T2D to T2D with DN; netrin-1 levels correlated significantly with the CCM parameters. Serum Netrin-1 levels showed a significant positive correlation with CNBD in type 2 diabetes (DN- or DN+). A strong correlation was seen between CNFL and netrin-1 levels in more advanced diabetic neuropathy (abnormal VPT). The results of our pilot study need validation in larger populations.

Disclosure

A.Mondal: None. C.Bose: None. S.Pramanik: None. A.Mukherjee: None. B.Mukherjee: None. S.Mukhopadhyay: None.

Funding

Research Society for the Study of Diabetes in India
492-P: Utility of Measures of Nerve Fiber Function and Structure for the Diagnosis of Diabetic Peripheral Neuropathy
Authors: CASELLINI CAROLINA M. , PARSON HENRI , CUSHMAN COURTNY , INGRAM AMBER M. , PETTAWAY JORDAN L. , SEARS TANEISHA , SIRAJ ELIAS S.
Published: June 2023

Introduction: Identifying diabetic neuropathy (DPN) in the clinic is challenging. The purpose of this study is to investigate the utility of various diagnostic tools for the detection of DPN

Methods: The following measures were assessed in controls and patients with type 2 diabetes with and without DPN: clinical neuropathy scores, quantitative sensory testing, corneal confocal microscopy, and sudomotor function. Receiver operating characteristics and areas under the curve with sensitivity and specificity were calculated

Results: See Table and Figure

Conclusions: Functional measures were more sensitive but less specific than structural ones. Similar to other studies, our study shows that no individual test is reliable per-se. Future studies are needed to investigate the best combination of tests for assessing DPN.

Disclosure

C.M.Casellini: None. H.Parson: None. C.Cushman: None. A.M.Ingram: None. J.L.Pettaway: None. T.Sears: None. E.S.Siraj: Research Support; Novo Nordisk, Speaker's Bureau; Novo Nordisk, Boehringer Ingelheim and Eli Lilly Alliance.
495-P: Comparing Detection of Diabetic Retinopathy by Three Artificial Intelligence Platforms in Subjects Not Known to Have Diabetes
Authors: BUTLER ALEXANDRA E. , KILPATRICK ERIC S. , HUNT STEVEN C. , ATKIN STEPHEN
Published: June 2023

Background: The glycemic threshold for the diagnosis of type 2 diabetes (T2D) was determined based upon the prevalence of moderate retinopathy; however, diabetes related complications may occur below that threshold. This study utilized three companies to analyse retinal images using their commercial software and returned data on absence or presence of features of any diabetic retinopathy (DR) on a per-eye basis.

Methods: Ophthalmic retinal images from 11,449 subjects (right and left eyes for each, totalling 22,898 images) not known to have diabetes from the Qatar Biobank were subjected to assessment for detection of features of DR using three Conformitè Europëenne (CE)-marked independent commercial Artificial Intelligence (AI) software systems.

Results: From 11,449 patients: •DR was recorded as absent in both eyes in 7,094 (62.0%) patients by all 3 methods (Test Negative at patient level).•DR was detected by 2 or 3 of the AI systems in at least one eye in a total of 2,408 (21.0%) patients (Test Positive at patient level). Of these, in 1,532 (13.4%) cases DR was detected in just one eye of any given patient and in 876 (7.6%) cases DR was detected in both eyes of a patient. •Overall, 1,947 (17.0%) patients had at least one eye reported as unassessable by 2 or 3 of the AI systems; hence, No Overall Result for DR features could be obtained for these patients. Results from the three AI companies differed markedly: 17.7%, 32.9% and 46.6% ranked Test-Positive results at patient level. Only 304 right eyes and 280 left eyes were positive for all 3 companies.

Conclusion: This is the first direct comparison of three independent AI companies when simultaneously assessing retinal images from more than 10,000 individuals. It showed markedly differing prevalences of diabetic retinopathy between existing AI systems, indicating inconsistencies if wishing to apply these tools to detect retinopathy in subjects not already known to have diabetes, and may differ in patients with known diabetes.

Disclosure

A.E.Butler: None. E.S.Kilpatrick: None. S.C.Hunt: None. S.Atkin: None.
497-P: Hypertension Aggravated the Risk of Diabetic Retinopathy over 10 Years
Authors: NAM NGUYEN NHAT , THY KHUE NGUYEN
Published: June 2023

Background: Diabetic retinopathy (DR) is a sight-threatening complication of diabetes. Hypertension may worsen DR risk due to additional vascular damage. We aimed to investigate whether hypertension could increase the 10-year incidence of DR in type 2 diabetes (T2DM) patients.

Method: We included T2DM individuals who were free of DR at baseline, completed at least one further clinic visit from 1997 to 2008, and followed up for ten years. Patients were categorized into normotension or hypertension based on the clinician’s diagnosis. The retinal photograph was taken annually. The Kaplan-Meier curve was used to estimate the cumulative incidence of DR, stratified by normotensive/hypertensive status. Log-rank test was used to compare the distribution of time until the occurrence of DR in two groups. A p-value <0.05 was considered statistically significant.

Results: After a median follow-up duration of 61 months, cumulative incidences of DR among normotensive and hypertensive participants were 49% (95% CI 36%-60%) and 73% (95% CI 67%-78%), respectively. There was a significant difference in the risk of new-onset DR among groups (p <0.001). The gap between the two Kaplan-Meier curves occurred early in the first year after recruiting (Figure).

Conclusion: Hypertension could further increase the risk of DR among type 2 diabetes patients. An effective strategy of DR screening is recommended for patients coexisting with hypertension.

Disclosure

N.Nguyen: None. N.Khue: None.
504-P: Association between Handgrip Strength and Triglyceride-Glucose Index Based on the Korean National Health and Nutrition Examination Survey
Authors: BAE LEE SANG , MI CHOI YUN , KYUNG KIM MIN
Published: June 2023

Handgrip strength (HGS) is a simple, reliable method to measure muscle strength and assessing sarcopenia. Insulin resistance (IR) is important contributing factor to cardiovascular disease and also related with sarcopenia. In this study, we investigated the association between IR and muscle strength via the Triglyceride glucose index (TyG) index and HGS. We used data from the sixth Korean National Health and Nutrition Examination Survey to evaluate a total of 10048 subjects aged over 40. The TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2] to represent IR. We defined absolute HGS as sum of the maximum values of the right and left sides of each of the three measurements. The relative HGS was calculated by dividing the absolute HGS by body mass index. The subjects were stratified into quartiles according to the TyG index. Relative HGS was decreased as the TyG index increased in total subjects. In linear regression analysis, relative HGS showed negative correlation with metabolic parameter and the TyG index in all groups of age and gender. According to logistic regression analysis after adjusting for multiple risk factors, odds ratio (95% CI) for low muscle strength (defined as the lower 10% on relative HGS) for the highest and lowest quartiles of the TyG index was 2.513 in male and 2.161 in female on total subjects. In group of subjects with mid-age (age between 40 to 64 years old), the prevalence of low muscle strength was positively correlated with increased the TyG index both in male and female. However, in the elderly groups (age over 65 years old), relationships between the increased the TyG index quartiles and prevalence of low muscle strength were not significant in all subjects. In conclusion, the TyG index was independently associated with relative HGS and low muscle strength in mid-aged subject and could have predictive value for sarcopenia and further metabolic disease.

Disclosure

S.Lee: None. Y.Choi: None. M.Kim: None.
535-P: Identifying and Addressing Educational Needs Regarding the Increased Risk of Complications Due to Influenza Infection in People with Diabetes
Authors: ROBINSON KATIE , CARSON BENJAMIN , SCAVONE JILLIAN L. , FREDERICK JENNIFER , ESGRO ROBERT A.
Published: June 2023

Rationale: Compared with the general population, patients with diabetes are more likely to develop severe influenza and associated complications. Timely recognition and treatment of high-risk patients can improve patient outcomes, yet morbidity and mortality remain high in this population in part due to low awareness among patients and providers.

Methods: To address this, Vindico provided a comprehensive continuing education (CE) expert panel and e-monograph targeted to primary care providers (PCPs) who treat diabetes. Baseline knowledge and practice patterns as well as educational impact were assessed via pre- and post-test.

Results: A total of 1,989 PCPs participated, with complete datasets available for 978. At baseline, knowledge was low on all topics - burden of influenza in patients with diabetes (27% correct), risk factors for severe outcomes (34%), and management approaches (38%). Of note, 70% underestimated the risk of admission to the ICU in patients with diabetes and influenza. These knowledge gaps translated into practice gaps, with only 18% always reporting early identification and management of patients with diabetes and suspected influenza. Importantly, there was an average increase in knowledge of 46. At 60-day follow-up, 89% had implemented practice improvements and 23% had improved interprofessional care practices, which contributed to improved patient outcomes, including earlier patient identification and intervention.

Conclusion: In our dataset, PCPs who manage patients with diabetes had inadequate knowledge regarding increased risk for adverse outcomes due to influenza infection. These data demonstrate the benefit of targeted education to improve HCP knowledge and the translation of knowledge to practice improvements for enhanced patient outcomes.

Disclosure

K.Robinson: None. B.Carson: None. J.L.Scavone: None. J.Frederick: None. R.A.Esgro: None.

Funding

Genentech (G-90568)
540-P: Clinical Practice Gap Analysis of T1D Risk, Diagnosis, and Screening, and Emerging Therapies
Authors: LARKIN AMY
Published: June 2023

Introduction: Understanding clinical practice gaps in the clinical understanding, diagnosis and staging, and emerging treatments for T1D can inform development of tools to improve physician practices. Methods: A survey instrument of 25 multiple choice, knowledge- and case-based questions allowed participants to assess their clinical knowledge with regard to T1D. The survey was available online to physicians without monetary compensation or charge. Respondent confidentiality was maintained and responses were de-identified and aggregated prior to analyses. Initial data collection occurred from January 8, 2022 to April 6, 2022. Results: In total, 84 diabetologists/endocrinologists (D/Es) and 76 pediatricians completed the full assessment within the data collection period. Physicians demonstrated gaps in the following areas.

Conclusion: This educational research on assessment of physicians’ clinical practices yielded important insights into clinical gaps related to T1D risk, diagnosing and staging, and emerging treatments. Further studies are planned to assess the effect of medical education on decreasing these clinical practice gaps.

Disclosure

A.Larkin: None.

Funding

Dompe