bluuebunny/crossref_metadata_2025_split huggingface dataset:
412-P: Acute Hyperglycemia-Induced Endoplasmic Reticulum and Oxidative Stress Increases Monocyte Cholesterol Content and Cytokine Secretion
Authors: ZHANG RONG MEI , OH JISU , KUTZ GRETA A. , BAMBOUSKOVA MONIKA , DUSSO ADRIANA S. , BERNAL-MIZRACHI CARLOS 
Published: May 2022

Background: Cardiovascular disease (CVD) is an inflammatory disorder enhanced by diabetes. The mechanisms by which recurrent acute hyperglycemia promotes inflammation and CVD are unclear. We showed that acute hyperglycemia mediates increased monocyte cholesterol uptake and cytokine release, but the underlying signaling pathways are unknown. We hypothesized that acute hyperglycemia-induced oxidative and ER stress in circulating monocytes increases cholesterol uptake and a pro-inflammatory phenotype.
Methods: Circulating monocytes from 35 healthy subjects were isolated and exposed to euglycemic (5mM) or hyperglycemic (16.7 mM) conditions with or without inhibitors of ER stress (4 phenyl butyric acid) or oxidative stress (N-Acetyl cysteine) for 2 or 6 hrs to assess changes in LDL or oxLDL uptake and cytokine (TNF-α, IL1-β) release.
Results: We found that acute hyperglycemia-induced ER and oxidative stress increased total and free cholesterol content via enhanced LDL (18% and 26%, p&lt;0.05) and oxLDL (56% and 30%, p&lt;0.05) uptake as a result of enhanced CD36 and LDL receptor expression. Conversely, inhibiting monocyte oxidative stress or ER stress attenuated monocyte LDL and oxLDL uptake. Finally, blocking monocyte ER stress decreased acute hyperglycemia-induced monocyte TNF-α (87% and 40%, p&lt;0.05) and IL1-β (41% and 44%, p&lt;0.05) secretion after 2 and 6 hrs.
Conclusion: Recurrent acute hyperglycemia promotes inflammation by increasing monocyte ER and oxidative stress, which accelerates cholesterol uptake, cholesterol deposition, and cytokine secretion. Future studies are needed to test if acute hyperglycemia-induced monocyte cholesterol deposition is a mechanism to contribute to increased CVD in diabetes.

Disclosure
R.Zhang: Research Support; American Heart Association. J.Oh: None. G.A.Kutz: None. M.Bambouskova: None. A.S.Dusso: None. C.Bernal-mizrachi: None.
415-P: Leptin Treatment Has Vasculoprotective Effects in Lipodystrophic Mice
Authors: STÜRZEBECHER PAULINA E. , KRALISCH SUSAN , SCHUBERT MARIE R. , FILIPOVA VANINA , HOFFMANN ANNETT , BLÜHER MATTHIAS , MIEHLE KONSTANZE , EBERT THOMAS , LAUFS ULRICH , TÖNJES ANKE , BOECKEL JES-NIELS 
Published: May 2022

Introduction: Adipose tissue (AT) is involved in interorgan crosstalk by releasing adipokines such as leptin. Loss of AT, as seen in the human disease of lipodystrophy syndromes (LD) , results in low leptin levels, severe metabolic pathologies and increased risk for premature atherosclerosis. Therapeutical substitution of leptin improves the metabolic conditions and reduces the risk of death in LD patients. The effect of this treatment on atherosclerotic lesion development and endothelial integrity is unknown. We hypothesize that leptin exerts vasculo-protective effects and limits atherosclerosis.
Methods and Results: Endothelial cell (EC) inflammation (ICAM-1, -5.2-fold control, p&lt;0.05) and endothelial to mesenchymal transition (EndMT) (SM22, -2.3-fold control, p&lt;0.05) was reduced by leptin treatment in vitro at mRNA and protein level as determined by qPCR, immunoblot and immunofluorescence. The beneficial effect of leptin on EndMT was further confirmed by single cell sequencing. In a second step, we used a combined lipodystrophic and atherosclerosis-prone mouse model (LDLR-/-;aP2-nSREBP) and analyzed the effect of leptin treatment on the development of atherosclerosis in vivo. Histological sections of the aortic roots showed reduced plaque protrusion into the vessel lumen (-31%, p&lt;0.05, n=4-6) by leptin. Macrophage infiltration into the atherosclerotic lesion was reduced after 16 weeks of leptin substitution, which is in accordance with the reduced permeability of the endothelial layer after leptin treatment seen in vitro (-10.8-fold, p&lt;0.05, n=3) .
Conclusion: In vitro, leptin acts anti-inflammatory and reduces EC permeability and EndMT. In a lipodystrophic mouse model, leptin substitution reduced hallmarks of instable plaques like EndMT, plaque protrusion and macrophage invasion. In addition to an improvement of the metabolic complications of LD, leptin may also support endothelial identity and function and therefore be beneficial for the vasculature in LD patients.

Disclosure
P.E.Stürzebecher: None. A.Tönjes: None. J.Boeckel: None. S.Kralisch: None. M.R.Schubert: None. V.Filipova: None. A.Hoffmann: None. M.Blüher: Consultant; AstraZeneca, Lilly, Novo Nordisk A/S, Pfizer Inc., Sanofi, Speaker's Bureau; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG. K.Miehle: None. T.Ebert: Consultant; Sanofi, Santis, Research Support; AstraZeneca, Novo Nordisk. U.Laufs: None.

Funding
Collaborative Research Center SFB1052 “Obesity Mechanisms” (SFB-1052/C06)
43-LB: Diabetes Distress, Depression, Perceived Stress, and Medication Adherence in Type 2 Diabetes (T2D)
Authors: MUSTAFIZ FAYEL , HOOGENDOORN CLAIRE J. , GONZALEZ JEFFREY S. 
Published: May 2022

Objective: Diabetes distress and depression are associated with treatment nonadherence among adults with T2D. Evidence for the independence of these effects has been mixed. Whether perceived stress, or the degree to which situations in life in general are appraised as stressful, can account for these effects has not been examined. We tested whether perceived stress was associated with objective T2D medication adherence and whether effects of diabetes distress and depression showed independence from perceived stress.
Methods: Participants (N = 104, Age = 56.57 ± 9.32; A1C = 7.75 ± 1.55; 39% insulin use; 24% Latino, 24% White, 62.5% Black, 5.7% Other) completed validated self-reports of perceived stress, diabetes distress and depression and had oral medication adherence electronically monitored (EM) over 3 months. Multiple regression evaluated the association between perceived stress and EM medication adherence when modeled with covariates as well as with diabetes distress and depression.
Results: Perceived stress was correlated with lower EM adherence (r = -.24, p = .013) ; however, when accounting for age, insulin use, and days of EM monitoring, the association was attenuated (β = -.14, p = .109) . Diabetes distress (β = -.29, p = .001) and depression (β = -.34, p &lt; .001) were associated with lower adherence after covariate adjustment, when each were adjusted for perceived stress (diabetes distress: β = -.32, p = .005; depression: β = -.48, p &lt; .001) , and when both were modeled together with perceived stress (diabetes distress: β = -.22, p = .044; depression: β = -.41, p = .002) . In this final model, perceived stress showed an unexpected positive association with adherence (β = .27, p = .035) .
Conclusion: The associations of diabetes distress and depression with treatment nonadherence were not accounted for by perceived stress in this diverse sample of adults with T2D. Their independent associations with treatment nonadherence support both constructs as important targets for intervention.

Disclosure
F. Mustafiz: None. C. J. Hoogendoorn: None. J. S. Gonzalez: Consultant; Virta Health Corp.
441-P: Oleate Prevents Palmitate-Induced Abnormalities in Insulin Signaling in Human Cardiac Progenitor Cells by Inhibiting p38 MAPK and c-Jun Phosphorylation
Authors: DORIA ROSSELLA , CALDERONI ISABELLA , CACCIOPPOLI CRISTINA , GENCHI VALENTINA ANNAMARIA , SANTARPINO GIUSEPPE , LEONARDINI ANNA , NATALICCHIO ANNALISA , PERRINI SEBASTIO , CIGNARELLI ANGELO , GIORGINO FRANCESCO , LAVIOLA LUIGI 
Published: May 2022

Elevated saturated fatty acid deposition in the heart results in insulin resistance, stress kinase activation, and increased cardiovascular risk in humans. The viability of human cardiac progenitor cells (hCPC) is essential for myocardium homeostasis. This study investigates the ability of palmitate, a saturated fatty acid, to impair insulin signaling in hCPC isolated from right auricle biopsies, and the potential protective effects of oleate, a mono-unsaturated fatty acid. hCPC were found to express both insulin receptor (IR) isoforms, IR-A and IR-B, with higher IR-A:IR-B ratio. Exposure of hCPC to 100 nM insulin for 15 min induced Akt (S473) phosphorylation (p&lt;0.05) . However, treatment with 0.25 mM palmitate, but not with 0.1 mM oleate, for 24 h resulted in impaired insulin-induced Akt phosphorylation (p&lt;0.05) with no effect on total Akt protein levels. Palmitate, but not oleate, also induced p38 MAPK (T180/Y182) and c-Jun (S63) phosphorylation (p&lt;0.05) . Pretreatment for 1 h with 15 µM SB202190, a p38 MAPK inhibitor, or with 20 µM SP600125, a JNK inhibitor, significantly inhibited the ability of palmitate to impair insulin-induced Akt phosphorylation (p&lt;0.05) . Interestingly, co-incubation of palmitate with oleate abolished the palmitate-induced p38 MAPK and c-Jun phosphorylation (p&lt;0.05) and inhibition of insulin-induced Akt phosphorylation (p&lt;0.05) . In addition, palmitate, but not oleate, was associated with downregulation of IR protein levels (p&lt;0.05) , although with increased expression of total IR mRNA, IR-A, IR-B, and increased IR-A/IR-B ratio (p&lt;0.05) . Co-incubation with oleate also prevented the palmitate-induced changes in IR (p&lt;0.05) .
In conclusion, oleate prevents the palmitate-induced abnormalities in insulin signaling in hCPC, largely by counteracting p38 MAPK and JNK activation. Hence, oleate supplementation might limit lipotoxicity, thus contributing to cardiac protection.

Disclosure
R.Doria: None. F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. L.Laviola: Advisory Panel; Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Speaker's Bureau; A. Menarini Diagnostics, Abbott Diabetes, Medtronic, Terumo Corporation. I.Calderoni: None. C.Caccioppoli: None. V.Genchi: None. G.Santarpino: None. A.Leonardini: None. A.Natalicchio: Consultant; Novo Nordisk, Other Relationship; AstraZeneca, Lilly Diabetes, Sanofi. S.Perrini: None. A.Cignarelli: None.
46-OR: Differential Effects of RBP3 and Anti-VEGF on Retinal Dysfunctions in Diabetic Retinopathy
Authors: LI QIN , ONIZUKA SATORU , PARK KYOUNGMIN , PARK HYUNSEOK , LI QIAN , FICKWEILER WARD , FU JIALIN , WU I-HSIEN , KING GEORGE L. 
Published: May 2022

Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the treatment of severe diabetic retinopathy (DR) , but significant subset of patients showed inadequate response to anti-VEGF. We have previously reported that retinol binding protein 3 (RBP3) prevented hyperglycemia induced retinal pathologies and progression to severe DR. Hypothesis: RBP3 and Anti-VEGF have differential protective profiles in preventing retinal dysfunctions induced by diabetes.
Methods and Results: Recombinant human RBP3 (rhRBP3, 5ug/ml) and anti-VEGF (Avastin, 250mg/ml) inhibited VEGF-induced retinal vascular permeability (RVP) by 70% when intravitreal injections were given together in Lewis rats (P &lt; 0.01) . After 2 months of diabetes induced by streptozotocin (STZ) , intravitreal injection of rhRBP3 and anti-VEGF for 3 days suppressed RVP by 64% and 53% (P &lt; 0.01) in Lewis rats. This was accompanied by reductions of VEGF levels by both proteins. Electroretinogram (ERG) amplitudes of A wave, B wave, C wave were decreased in rats after 2 months of diabetes (P &lt; 0.01) . rhRBP3 increased amplitudes of C wave (P &lt; 0.01) , while anti-VEGF did not improve any waveforms. Furthermore, rhRBP3 decreased retinal mRNA expression of Cd11b and Tnfa (P =0.1) in diabetic rats. In cultured primary bovine Müller cells, rhRBP3 decreased mRNA expressions of Tnfa and Il-6 induced by high glucose (25mM) (P &lt; 0.01) , whereas, anti-VEGF showed no effect. Metabolic function studies using Seahorse assays showed that isolated retina from intravitreal rhRBP3 treated rats exhibited reduced glycolysis rate in ECAR while anti-VEGF treatments had no effects.
Conclusions: Both intravitreal anti-VEGF and RBP3 treatments normalized retinal vascular dysfunctions caused by diabetes. However, only RBP3 reversed abnormal neural-retinal dysfunctions and elevated inflammatory cytokines induced by hyperglycemia, possible by decreasing glucose uptake and glycolysis levels in retinal cells.

Disclosure
Q.Li: None. S.Onizuka: None. K.Park: None. H.Park: None. Q.Li: None. W.Fickweiler: None. J.Fu: None. I.Wu: None. G.L.King: Advisory Panel; Medtronic, Research Support; Janssen Pharmaceuticals, Inc.
548-P: Food Insecurity during COVID-Is Associated with Worse Outcomes among People with Type 2 Diabetes
Authors: STEVENSON JULIA , GOWEN REBECCA , YE EMILY , WOOD RICHARD 
Published: May 2022

Background: Low food security is associated with increased barriers to diabetes management, and COVID-has exacerbated food insecurity in the United States. This study assessed correlation between food insecurity and health outcomes among people with type 2 diabetes (T2D) during the first year of the COVID-pandemic from March 2020 to March 2021.
Methods: In March 2021, 3,235 adults with T2D completed an online questionnaire which included the validated 2-item Hunger Vital Sign screening tool to assess risk of household food insecurity in the last 12 months. Health and demographic information were collected.
Results: Twenty percent of the sample were at risk of food insecurity within the last 12 months. Those at risk of food insecurity were more likely to report adverse physical health outcomes and poor mental well-being. Disparities in outcomes between those at risk and those not at risk were present across household income brackets. Among those at risk of food insecurity, 35% reported spending less on food to be able to pay for diabetes medications or supplies in the last 12 months, whereas only 4% of those not at risk reported the same.

Conclusions: Food insecurity risk during the first year of COVID-is associated with a variety of adverse health outcomes for people with T2D. As the pandemic continues, further attention must be devoted to improving accessibility of nutritious food for people with diabetes.

Disclosure
J.Stevenson: Other Relationship; Abbott Diabetes, Ascensia Diabetes Care, Beta Bionics, Inc., Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, LifeScan, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc. R.Gowen: Other Relationship; Abbott Diabetes, Ascensia Diabetes Care, Beta Bionics, Inc., Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, LifeScan, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc., Virta Health Corp. E.Ye: Employee; dQ&A. R.Wood: Other Relationship; Multiple companies and patient organizations (&gt;10) .
55-LB: Effect of Dapagliflozin on Renal and Hepatic Glucose Kinetics in T2DM and NGT Subjects
Authors: CHEN XI , SOLIS-HERRERA CAROLINA , TRIPATHY DEVJIT , HANSIS-DIARTE ANDREA A. , CHILTON ROBERT , CERSOSIMO EUGENIO , DEFRONZO RALPH A. 
Published: May 2022

We previously have shown that both acute and chronic SGLT-2 inhibition increases endogenous glucose production (EGP) . However, the organ - liver versus kidney - responsible for the increase in EGP has not been identified. We assessed the effect of a single dose of Dapagliflozin or Placebo on renal glucose production in 13 T2DM (age=57.5±1.8 yrs, BMI = 30±1.4 kg/m2) and 9 NGT (age 42±2 3 yrs, BMI = 30±1.1 kg/m2) subjects. Renal glucose production was measured using arteriovenous balance technique across the kidney combined with [3-3H] glucose infusion and PAH infusion (for determination of renal blood flow) before and 4 hours after administration of Dapagliflozin (10 mg) and Placebo; thus, each subject served as their own control. EGP increased following DAPA in both T2DM (2.00±0.11 to 2.43±0.15, P&lt;0.05) and NGT (1.72±0.11 to 2.1±0.16, p&lt;0.05) , while it decreased after placebo in T2DM (2.02±0.12 vs. 1.15±0.06) and NGT (2.10±0.2 vs. 2.05±0.1) (both p&lt;0.01, DAPA vs. placebo) . The fractional renal extraction of glucose (0.02± 0.004 vs. 2.99 ± 1.0, p=0.001 in T2DM, and 0.02± 0.004 vs. 1.62± 1.4 in NGT, p=NS) and renal glucose uptake (0.067 ± 0.02 vs. 0.347 ± 0.06 in T2DM and 0.08 ± 0.02 vs. 0.27 ± 0.08 mg/kg.min in NGT) were higher following DAPA vs. placebo (p&lt;0.05) and were entirely explained by the increase in glucosuria. There was a small, non-significant increase (0.065 & 0.032 mg/kg.min, respectively) in renal glucose production (RGP) following dapagliflozin in T2DM and NGT compared to the 0.45 mg/kg.min increase in total body EGP.
Conclusion: A single dose of Dapagliflozin significantly increases EGP which primarily is explained by an increase in hepatic glucose production.

Disclosure
X. Chen: None. C. Solis-herrera: Speaker’s Bureau; Novo Nordisk. D. Tripathy: None. A. A. Hansis-diarte: None. R. Chilton: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Nova Biomedical. E. Cersosimo: Research Support; AstraZeneca. R. A. Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker’s Bureau; AstraZeneca.

Funding
Astra Zeneca
55-OR: Veterans with Type 2 Diabetes: An Explanatory Sequential Mixed-Methods Approach to Understanding Diabetes Distress
Authors: LEWINSKI ALLISON , CROWLEY MATTHEW J. , JEFFREYS AMY S. , COFFMAN CYNTHIA , WHITFIELD CHELSEA , HOWARD TERESA , SHAPIRO ABIGAIL , MCCONNELL ELEANOR S. , TANABE PAULA , BARCINAS SUSAN J. , BOSWORTH HAYDEN B. 
Published: May 2022

Diabetes Distress (DD, i.e., regimen, emotional, interpersonal, clinician) in adults with type 2 diabetes (T2DM) is associated with poor glycemic control, poorer diet and exercise, and more T2DM complications. We describe a multi-phased study to develop and test a tailored intervention to reduce DD to improve health outcomes. Phases 1-3 identified factors related to DD in Veterans with T2DM to inform intervention development. We used an explanatory sequential mixed methods design to identify how Veterans with T2DM experienced DD. Veterans (n=210) completed measures (DD, depression, empowerment, stigma) . A subset of Veterans (n=36) also completed in-depth qualitative interviews. We fit a multivariable linear regression to examine associations with DD score. We completed thematic analysis on interview transcripts. We integrated measurement and interview data using matrices and analyzed results by medication type, hemoglobin A1c (HbA1c) , and severity of DD (low, moderate, high) . Mean age was 63 years (SD 10.2) ; 15% female; 69% non-white; 56% on insulin; mean A1c 8.9% (SD 2.0) ; mean DD score was 2.0 (SD 0.9) , indicating moderate distress. In the regression model, female gender (β= -0.31; 95% CI: -0.57, -0.04) , diagnosis of multiple mental health comorbidities vs. one condition (β=-0.29; 95% CI: -0.55, -0.03) , higher depression symptom (β=0.15; severity (95% CI: 0.08, 0.23) and stigma (β=0.02; 95% CI: 0.01, 0.04) were associated with higher DD. Higher T2DM self-efficacy (β=-0.34; 95% CI: -0.51, -0.18) was associated with lower DD. Interviews elaborated on themes including the impact of pain and comorbidities on DD. Integrating the measurement and interview data indicated that experiences of DD varies by many characteristics based on medication type, HbA1c, and severity of DD. Elucidating contributors to DD in Veterans using mixed methods will improve our ability to develop a tailored intervention addressing DD in a manner relevant to Veteran populations.

Disclosure
A.Lewinski: Other Relationship; Otsuka America Pharmaceutical, Inc., PhRMA Foundation. S.J.Barcinas: None. H.B.Bosworth: Advisory Panel; Sanofi, Board Member; preventics diagnostics, Consultant; VIDYA, webmed, Research Support; Boehringer Ingelheim International GmbH, improved Patient Outcomes, Merck & Co., Inc., Novo Nordisk, Otsuka America Pharmaceutical, Inc. M.J.Crowley: None. A.S.Jeffreys: None. C.Coffman: None. C.Whitfield: None. T.Howard: None. A.Shapiro: None. E.S.Mcconnell: None. P.Tanabe: None.

Funding
Durham Center of Innovation to Accelerate Discovery and Practice Transformation (CIN 13-4) and VA HSR&D grants #18-234 (to AAL) and #08-027 (to HBB) .
56-OR: Relationship between Delay Discounting and Psychological Health in Adults with Type 2 Diabetes
Authors: CAMPBELL JENNIFER A. , EGEDE LEONARD E. 
Published: May 2022

Background: Delay discounting is the process of making choices that provide small immediate rewards versus choosing to wait for a greater more meaningful reward. Measured by two constructs, delay discounting measures the gain or loss of value on an outcome when delay is present, and delay aversion, measures the emotional response when a delay is present. Emerging evidence shows delay discounting is associated with poor self-care behavior, glycemic control, and quality of life. There is limited data on the impact of delay discounting on psychological health (depression, anxiety, perceived stress) and social support.
Methods: This study used data from 365 adults with T2DM to evaluate relationships between delay discounting and psychological health and social support. Delay discounting was measured with the validated QDQ scale with 2 subscales for delay discounting and delay aversion. Depression was measured by the PHQ-9, anxiety by the GAD-8, perceived stress by the PSS-4, and social support by the DUSOC. Adjusted linear regression was used to assess the relationship between delay discounting and delay aversion on psychological health (depression, anxiety, perceived stress) and social support controlling for relevant covariates.
Results: Mean age of the sample was 61.8 years, 54.5% were African American, 41.8% were White, and 3.7% were Hispanic/Other. After adjusting for sociodemographic factors, delay aversion was significantly associated with depression (B=.35; p&lt;0.001) , anxiety (B=.52; p&lt;0.001) , stress (B=.22; p&lt;0.001) , and lower family support (B=-.62; p&lt;0.05) . Delay discounting was significantly associated with depression (B=.32; p&lt;0.001) , anxiety (B=.46; p&lt;0.001) , and stress (B=.26; p&lt;0.001) .
Conclusion: Both constructs of delay discounting (delay discounting and aversion) are significantly associated with poor psychological health and poor social support. Future studies need to examine mechanisms and pathways for potential interventions.

Disclosure
J.A.Campbell: None. L.E.Egede: None.

Funding
National Institute of Diabetes and Digestive Kidney Disease (K24DK093699, R01DK118038, R01DK120861, PI: Egede) National Institute for Minority Health and Health Disparities (R01MD013826, PI: Egede/Walker) .