bluuebunny/crossref_metadata_2025_split huggingface dataset:
10-LB: The Apelinergic System Improves Angiogenesis and Blood Flow Reperfusion in Diabetic Mouse Model of Lower Limb Ischemia
Authors: ROBILLARD STEPHANIE , GERALDES PEDRO 
Published: June 2021

Introduction: Peripheral vascular disease is a major risk factor for lower-extremity amputation in patients with diabetes due to an abnormal angiogenic response. The apelinergic system is known to improve cardiac function after ischemia by promoting angiogenesis.
The objective: is to study the effects of Apelin-13 (Ape-13) and Elabela (Ela) on blood flow (BF) reperfusion following limb ischemia in diabetic mice as well as on endothelial cell (EC) function.
Method: Primary EC were exposed to normal (5.6 mM; NG) or high (25 mM; HG) glucose concentrations for 24h and hypoxia (1% O2) for the last 16h. EC were stimulated or not with Ape-13 or Ela. Proliferation and migration assays were performed and apelin signaling pathway was evaluated by immunoblot and qPCR. In vivo, nondiabetic (NDM) and diabetic (DM) underwent femoral artery ligation to induce lower limb ischemia. DM mice received Ape-13 or Ela by subcutaneous osmotic pump. BF reperfusion was measured for 4 weeks post-surgery and exercise willingness was assessed in individual cages with voluntary wheel. The ischemic abductor muscles were collected for protein, genes and vascular density analyses.
Results: Inhibitory effects of HG exposure on EC migration and proliferation were prevented with Ape-13 and Ela treatment under hypoxia condition through activation of Akt, AMPK and Rock2. In vivo, our results indicated that BF reperfusion was recovered at 75% in NDM as compared to 37% in DM whereas Ape-13 and Ela treatment in DM mice improved BF reperfusion by 65% and 69%, respectively. Similar results were observed using voluntary wheel as Ape-13 and Ela enhanced distance run as compared to untreated DM mice. Finally, the expression of proangiogenic factors (VEGF-A, PDGF-B) was increased in the ischemic muscle of DM+Ape-13 or Ela as compared to DM mice.
Conclusion: We believe that stimulation of apelinergic system improved BF recovery in DM by increasing proangiogenic pathways and EC migration and proliferation.

Disclosure
S. Robillard: None. P. Geraldes: None.

Funding
Canadian Institutes of Health Research (PJT159627)
1007-P: Risk Factor for COVID-19 Infection-Related Hospitalization in Patients with Type 2 Diabetes
Authors: HORII TAKESHI , ANDO WATARU , OTORI KATSUYA , ATSUDA KOICHIRO 
Published: June 2021

Objective: Coronavirus disease (COVID-19) in 2019 is highly prevalent among patients with type 2 diabetes (T2D). Several factors, such as the older and obesity have been reported to be risks of COVID-19 infection, but little is known about the clinical factors limited to patients with T2D. Here, we aimed to identify clinical factors linked to hospitalization with COVID-19 infection in T2D.
Research Design and Methods: We used data from Electronic Medical Record (EHR) registered in the Healthjump database provided by the COVID-19 Research Database consortium. Primary outcomes were to determine clinical factors linked to COVID-19 infection-associated hospitalization.
Results: Of 4,445 T2D patients with COVID-19, hospitalization occurred in 228 (5.1%). The risk of Covid-19 infection-related hospitalization was higher with ≥65years old (hazard ratio [HR] 1.45; 95% confidence interval [CI], 1.30-1.63), high in patients with a body-mass index (BMI) ≥30 kg/m2 (HR 1.59; 95% CI, 1.10-2.31), and Blacks than in Caucasians (HR 1.39; 95% CI, 1.04-1.85). The risk was lower in Metformin users (HR 0.56; 95% CI, 0.34-1394) and SGLT2inhibitors users (HR 0.45; 95% CI, 0.22-0.91). Asians tended to be at increased risk, but there was no significant difference due to the small number of cases (HR 1.88; 95% CI, 0.59-5.96).
Conclusions: We revealed that the risk of hospitalization may be higher with older, obesity and blacks. Furthermore, we discovered a low risk of hospitalization in patients with treated SGLT2 inhibitors and/or metformin. These findings can help inform patient-centered care decision making for people with T2D at risk for COVID-19.

Disclosure
T. Horii: None. W. Ando: None. K. Otori: None. K. Atsuda: None.
1025-P: Rate, Reasons, and Predictors of 30-Day Readmissions among Patients with Type 2 Diabetes Admitted for Hyperglycemic Hyperosmolar State: A Nationwide Analysis
Authors: SHAKA HAFEEZ , AGUILERA MARIA C. , YAP SARA ELIZABETH T. , RAMIREZ MARCELO , CORPUZ CARLOS GABRIEL D. , EDIGIN EHIZOGIE , OJEMOLON PIUS E. , ASEMOTA IRIAGBONSE R. , AKUNA EMMANUEL 
Published: June 2021

Introduction: Hyperglycemic hyperosmolar state is an endocrinological emergency associated with type 2 diabetes (T2DM) patients. HHS is associated with significant morbidity and mortality. The burden of HHS, however, does not end with the index admission. This study sought to determine the rate, reasons and predictors of 30-day readmissions (30DR) in T2DM patients with index admission for HHS with the goal of identifying potentially modifiable factors to decrease the burden of readmissions.
Methods: The US Readmission database for 2018 was searched for index hospitalizations involving adult patients with T2DM who had HHS in 2018. Outcomes assessed included 30DR rates, top principal diagnosis for readmitted patients, comparison of mortality, length of stay (LOS), and hospitalization costs (THC), and predictors of 30DR.
Results: A total of 21,721 hospitalizations involved adults with T2DM with HHS during the index admissions. The 30DR rate was 13.77%. The most common reasons for readmission was DM type 2 with hyperglycemia (8.6%), DKA (8.1%), HHS (8.0%), sepsis unspecified (7.9%), and acute renal failure (4.2%). Readmission was associated with higher odds of mortality (2.55% vs. 0.65%, OR: 4.00, 95% CI: 2.63 - 6.07), longer LOS (5.8 vs. 3.9 days, p&lt;0.001), higher THC (12,700 vs. 8,300 USD, p&lt;0.001). In T2DM patients with HHS, readmissions accounted for a cumulative 17,189 days of hospitalization, costing over $38 million within the study period. Discharges against medical advice, protein energy malnutrition, COPD and overall higher Charlson Comorbidity index was associated with higher odds for readmission.
Conclusion: HHS is associated with significant complications following the index admission. 30DR is associated with increased mortality and healthcare utilization in this population. Proper discharge planning and addressing factors associated with readmissions would likely improve outcome in this population.

Disclosure
H. Shaka: None. M. C. Aguilera: None. S. T. Yap: None. M. Ramirez: None. C. D. Corpuz: None. E. Edigin: None. P. E. Ojemolon: None. I. R. Asemota: None. E. Akuna: None.
1047-P: Genetic Risk of Insulin Resistance Is Associated with Kidney Disease in Type 2 Diabetics and Nondiabetics
Authors: GARDUNO ALEXIS C. , RICHARD ERIN L. , CAO STEVEN , THAKER VIDHU , SALEM RANY 
Published: June 2021

Background: Diabetic kidney disease (DKD) is a microvascular complication of type 2 diabetes (T2D) with significant variability in disease onset and progression. The objective of this study is to evaluate the role of genetic propensity to insulin resistance with kidney disease (KD) in individuals with and without T2D.
Methods: A total of 373,487 unrelated European subjects (5.7% T2D) were selected from the UK Biobank. An insulin resistance polygenic risk score (IR-PRS) was constructed using 18 genome-wide significant SNPs from the latest GWAS for insulin resistance. A T2D-PRS was derived using 277 SNPs. Each PRS was categorized into high (&gt;90thpercentile), mid (10th-90th), and low (&lt; 10th) genetic risk groups. Ten KD phenotypes were constructed using eGFR and/or urine albumin cutoffs. T2D-stratified logistic regression models were run for IR-PRS and KD outcomes, adjusting for principal components, age, sex, education, Townsend Deprivation Index, BMI, hypertension, and statin use; similar models were run for T2D-PRS.
Results: Among T2D, higher IR-PRS was associated with higher odds of DKD (Mid PRS: OR=5.20, 95% CI: 1.28-21.09; High PRS: OR = 4.17, 95% CI: 0.94-18.52; overall p=0.007) and macroalbuminuria (Mid PRS: OR = 2.05, 95% CI:1.12-3.77; High PRS: OR = 1.62, 95% CI: 0.80-3.27; overall p=0.02). Among nondiabetics, higher IR-PRS was associated with higher odds of microalbuminuria (Mid PRS: OR = 1.08, 95% CI: 1.02-1.15; High Risk: OR = 1.15, 95% CI: 1.06-1.25; overall p=0.006) and albuminuria groups (Mid Risk, OR=1.08, 95% CI: 1.01-1.14; High Risk, OR = 1.15, 95% CI: 1.06-1.24; overall p=0.004). No associations were observed with T2D-PRS.
Conclusion: Genetic propensity for insulin resistance is associated with KD or its predisposition among subjects with and without T2D. In contrast, genetic risk of T2D is not associated with KD. Future work will focus on the replication of these results in independent cohorts.

Disclosure
A. C. Garduno: None. E. L. Richard: None. S. Cao: None. V. Thaker: None. R. Salem: None.

Funding
National Heart, Lung, and Blood Institute (1R00HL122515)
1066-P: Association of Food Security with Cardiometabolic Health during Young Adulthood: Comparison by Race and Ethnicity
Authors: NIKOLAUS CASSANDRA J. , HEBERT LUCIANA E. , ZAMORA-KAPOOR ANNA , SINCLAIR KAIMI 
Published: June 2021

Food insecurity, defined as insufficient access to nutritious foods, poses a significant public health problem in the U.S. In the general population, food insecurity is related to poor cardiometabolic health. American Indians (AIs) have some of the greatest burdens of food insecurity and cardiometabolic disease in comparison to other racial/ethnic groups. However, few studies have established how food insecurity is related to cardiometabolic health with data disaggregated for AIs. The objective of this study was to assess the cross-sectional association of food insecurity and cardiometabolic risk factors among AI adults during young adulthood in comparison with non-Hispanic white, non-Hispanic Black, and Hispanic respondents. Data from the fourth wave of the National Longitudinal Study of Adolescent to Adult Health (Add Health) was used. Measures included one survey item on risk of food insecurity, objective measures of cardiometabolic health (body mass index, hemoglobin A1c, fasting blood glucose), and sociodemographic items. Multivariable regression models were used to assess the association of food insecurity with cardiometabolic health, while controlling for sociodemographic variables. All analyses were weighted and accounted for complex sampling survey design. In models inclusive of all adults, AI and non-Hispanic Black adults had significantly higher odds of reporting risk of food insecurity than non-Hispanic white adults. In models stratified by race, measures of cardiometabolic health were not significantly associated with risk of food insecurity among AI adults. Results suggest that AIs’ elevated risk of food insecurity is present in young adulthood, but its relationship with cardiometabolic health is unclear. Study implications are limited by the cross-sectional design, age of respondents, and reliance on a single-item measure of food insecurity. Future work should capitalize on longitudinal data and the USDA food security surveys.

Disclosure
C. J. Nikolaus: None. L. E. Hebert: None. A. Zamora-kapoor: None. K. Sinclair: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK092923)
107-LB: Relative Contribution of Fasting Plasma and Postprandial Glucose to HbA1c and TIR in People with T1D on Basal-Bolus Insulin Therapy
Authors: PIRAS DE OLIVEIRA CAROLINA , DELLVA MARY A. , BUE-VALLESKEY JULIANA M. , CHANG ANNETTE M. , CHIGUTSA FARAI B. , LIAO BIRONG 
Published: June 2021

Background: A recent report was published on the contribution of fasting plasma glucose (FPG) and postprandial glucose (PPG) to HbA1c and time in range (%TIR) in people with type 2 diabetes on multiple daily injection regimens using prandial Humalog® (Lispro). We extended this analysis to type 1 diabetes (T1D) using data from people randomized to 26 weeks of mealtime ultra rapid lispro (URLi; N=451), postmeal URLi (N=329) or mealtime Humalog (N=442) in the phase 3 trial, PRONTO-T1D, and its continuous glucose monitoring (CGM) substudy.
Methods: A multivariate regression model was used to quantify the contribution of FPG and PPG change to the change in HbA1c and %TIR. The contribution of PPG relative to FPG was determined. %TIR was derived from 10-point self-monitored blood glucose (SMBG) and CGM data from the CGM substudy. Only results for the mealtime groups are presented here.
Results: With URLi treatment, a 1 mmol/L reduction in FPG and PPG was associated with a 0.11% ± standard error 0.02% and 0.09% ± 0.01% reduction in HbA1c, respectively, both p&lt;0.0001, with a contribution of PPG relative to FPG of 82%. Similar results were obtained with Humalog: A 1 mmol/L reduction in FPG and PPG was associated with reduction in HbA1c of 0.12% ± 0.02% and 0.07% ± 0.02%, respectively, both p&lt;0.0001, but the contribution of PPG relative to FPG was 58%. For SMBG-derived %TIR, with URLi treatment, a 1 mmol/L reduction in FPG and PPG was associated with an increase in %TIR of 10.0% ± 0.53% and 8.6% ± 0.47%, respectively, all p&lt;0.0001. Similarly, with Humalog, a 1 mmol/L reduction in FPG and PPG was associated with an increase in %TIR of 9.8% ± 0.56% and 8.6% ± 0.52%, respectively, all p&lt;0.0001 A similar trend was observed with CGM data, although the absolute values of contributions of FPG and PPG differed.
Conclusions: Changes in FPG and PPG significantly impacted HbA1c and %TIR in people with T1D, reinforcing the need to manage both FPG and PPG to achieve optimal glycemic control.

Disclosure
C. Piras de oliveira: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. M. A. Dellva: Employee; Self; Eli Lilly and Company. J. M. Bue-valleskey: Employee; Self; Eli Lilly and Company. A. M. Chang: Employee; Self; Eli Lilly and Company. F. B. Chigutsa: None. B. Liao: Employee; Self; Eli Lilly and Company.

Funding
Eli Lilly and Company
1079-P: Maternal Gestational Diabetes and Childhood Hyperlipidemia
Authors: HU GANG 
Published: June 2021

Very few studies have assessed the impact of maternal gestational diabetes mellitus (GDM) on lipid profiles in the offspring in China. We aim to compare the lipid profile between children exposed to maternal GDM and those not exposed, and assess association between maternal GDM and offspring’s dyslipidemia risk. We recruited 1144 mother-child pairs (572 GDM and 572 non-GDM women matched by their offspring’s age and sex). We used general linear models to compare mean values of different lipid profiles among children born to mothers with and without GDM. Logistic regression models were used to assess associations of GDM with abnormal lipid profiles in offspring. After adjustment for maternal and children’s characteristics, children born to mothers with GDM had lower mean values of high-density-lipoprotein (HDL) cholesterol (1.40±0.01 vs. 1.50±0.01; P &lt;0.05) and higher mean levels of triglycerides/HDL cholesterol ratio (0.37±0.01 vs. 0.35±0.01; P &lt;0.05) in comparison with their counterparts born to mothers without GDM. Multivariate-adjusted odds ratios among children exposed to mothers with GDM compared with the counterparts were 2.07 (95% confidence interval [CI 1.13-3.79]) for low HDL cholesterol and 1.36 (95% CI 1.01-1.82) for high triglycerides/HDL cholesterol ratio, respectively. Exposure to GDM mothers was an independent risk factor for the abnormal lipid profile among children, which can emerge as early as in the preschool period.

Disclosure
G. Hu: None.

Funding
Tianjin Women’s and Children’s Health Center; Tianjin Public Health Bureau; European Foundation for the Study of Diabetes/Chinese Diabetes Society/Lilly Programme for Collaborative Research; National Institute of Diabetes and Digestive and Kidney Diseases
1080-P: Trends in Clinical Inertia in Diabetes Treatment Intensification in the U.S. Veterans Affairs Health Care System (VA)
Authors: RAGHAVAN SRIDHARAN , PHILLIPS LAWRENCE S. , CAPLAN LIRON , REUSCH JANE E. 
Published: June 2021

Despite mounting clinical trial evidence to guide second-line diabetes treatment, clinical inertia could be a persistent barrier to improved care. We analyzed secular trends in second-line diabetes prescribing and timing of intensification in the largest integrated healthcare system in the US. We studied 93,317 Veterans in VA primary care with type 2 diabetes incidence and initial metformin monotherapy from 2004-2015 who were subsequently newly started on add-on therapy from 2010-2015 with a sulfonylurea (SU, n=78,924), insulin (INS, n=10,251), thiazolidinedione (TZD, n=737), or dipeptidyl peptidase 4 inhibitor (DPP4i, n=3405). We used linear and logistic regression to analyze temporal trends of second-line drug choice, of hemoglobin A1c (HbA1c) at metformin initiation and at initiation of add-on therapy, and of the time to initiating second-line therapy. Over the 6 years, SU use declined (86 to 78%, p=0.003), and INS (9 to 14%, p&lt;0.001) and DPP4i (1.8 to 7.2%, p=0.02) use increased. In the full sample, mean HbA1c remained 7.6% at metformin initiation from 2010-2015 (p=0.2 for trend), but time to add a second drug rose (2.6 to 3.7 years) as did HbA1c at the time of add-on therapy (7.8 to 8.1%) (both p&lt;0.001). Mean HbA1c at initiation of add-on therapy was higher in SU (7.9%) and INS (8.9%) users than in TZD (7.1%) and DPP4i (7.2%) users (p&lt;0.001 for difference between groups). HbA1c at initiation of add-on therapy increased from 2010-2015 among SU (7.8 to 8.0%, p&lt;0.001), INS (8.7 to 8.9%, p&lt;0.001), and DPP4i users (6.8 to 7.4%, p&lt;0.001). The time to treatment intensification increased from 2010 to 2015 for users of each medication class (2.5 to 3.7 years for SU; 2.5 to 3.5 years for INS; 2.9 to 4.0 years for TZD; 3.1 to 4.1 years for DPP4i; all p&lt;0.001).
Conclusions: Inertia in diabetes treatment intensification may be worsening in real-world care potentially blunting the impact of accumulating clinical trial evidence to guide optimal second-line diabetes treatment.

Disclosure
S. Raghavan: None. L. S. Phillips: Other Relationship; Self; Diasyst Inc., Research Support; Self; AbbVie Inc., Eli Lilly and Company, GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Kowa Pharmaceuticals America, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Pharma Ltd., Pfizer Inc., Sanofi-Aventis. L. Caplan: None. J. E. Reusch: Advisory Panel; Self; Medtronic.

Funding
U.S. Department of Veterans Affairs (IK2-CX001907-01)
1099-P: Association between Variability in Body Mass Index and Development of Type 2 Diabetes: Panasonic Cohort Study
Authors: OKADA HIROSHI , HAMAGUCHI MASAHIDE , FUKUI MICHIAKI 
Published: June 2021

Objective: Contrasting results have been reported for the association between the variability in body weight and development of diabetes. No study has elucidated the association between the variability in body weight and the development of type 2 diabetes in a population without obesity and without body weight gain or loss during the study period. In the present study, we evaluated the association between the variability in body mass index (BMI) and development of type 2 diabetes in 19,412 Japanese participants without obesity and without body weight gain or loss during the study period.
Methods: We recorded body weight of the participants consecutively each year in Panasonic Corporation, Osaka, Japan from 2008 to 2014 to evaluate the variability of BMI. The participants with obesity (BMI ≥ 25 kg/m2) at baseline and body weight gain or loss from 2008 to 2014 (delta BMI ≥ ± 1 kg/m2) were excluded from the study. We used coefficient of variation (CV) to represent the variability in BMI during 6 years of the study period.
Results: In total, 416 participants among all participants (315 participants among those without IFG at baseline) developed type 2 diabetes from 2015 to 2018. The risk of developing type 2 diabetes was higher in the fourth quartile of CV of BMI than that in the lowest quartile (first quartile; reference) of CV of BMI in all participants and in those without IFG at baseline (hazard ratio, 1.33; 95% CI, 1.01-1.75 and hazard ratio, 1.51; 95% CI, 1.10-2.08, respectively). The risk for developing diabetes increased by 11.1% and 15.0% per 1% increase in CV of BMI in all participants and in those without IFG at baseline, respectively. Age, BMI at baseline, HDL cholesterol, glucose, current smoking habit, and fast eaters were also associated with the increased odds of developing type 2 diabetes.
Conclusions: In conclusion, the variability in BMI is a risk factor for the development of diabetes in the Japanese population.

Disclosure
H. Okada: None. M. Hamaguchi: Research Support; Spouse/Partner; AstraZeneca K. K. M. Fukui: None.
110-OR: MDA5-Dependent Responses Can Influence Spontaneous and Virus-Accelerated T1D Onset
Authors: BLUM SAMUEL I. , CHEN YI-GUANG , TSE HUBERT M. 
Published: June 2021

Coxsackievirus B3 (CVB3) infection promotes the activation of proinflammatory immune cells and is associated with triggering type 1 diabetes (T1D). We previously demonstrated that CVB3 infection of Non-Obese Diabetic (NOD) mice accelerates T1D, partly due to the activation of melanoma differentiation-associated protein 5 (MDA5)-dependent antiviral responses including IFN-α/β synthesis. Mutations within human IFIH1, the gene encoding MDA5, are correlated with T1D risk. Yet, the role of MDA5 on immune cells during T1D remains unknown. By utilizing mice that lack (KO) or contain an in-frame deletion within the helicase 1 domain of MDA5 (ΔHel1), we can test the hypothesis that reduced MDA5 responses delay T1D by decreasing IFN-α/β synthesis and immune cell activation. NOD and KO mice develop T1D similarly, but ΔHel1 mice have delayed spontaneous and CVB3-accelerated T1D. At 12 weeks of age during spontaneous T1D, ΔHel1 mice have a significant reduction in IFNγ+ CD4+ T cells (6.2-fold), perforin+ CD8+ T cells (13.2-fold), and TNF+ F4/80+ macrophages (MΦ) (1.7-fold) compared to NOD and KO mice. CVB3-infected ΔHel1 mice at day 3 exhibited a significant decrease in pancreatic IFN-α (2.2-fold) and IFN-β (3.1-fold) synthesis compared to NOD mice. At day 7 post-infection, ΔHel1 mice had a significant reduction in pancreatic TNF+ F4/80+ MΦ (2-fold) compared to NOD and KO mice. ΔHel1 and KO mice had reduced pancreatic IFNγ+ CD4+ T cells (1.9-fold) and perforin+ CD8+ T cells (2.6-fold) compared to NOD mice following CVB3 infection. This data demonstrated that the ΔHel1 mutation elicits a decrease in basal and CVB3-responsive MΦ and T cells within the pancreata to delay T1D. However, KO mice have impaired T cell responses to CVB3 and failed to delay spontaneous and CVB3-accelerated T1D indicating MDA5-dependent responses may be necessary for tolerance induction. Future studies will examine the mechanism of ΔHel1 T1D protection and whether MDA5 ATPase activity and/or dsRNA binding can modulate T1D development.

Disclosure
S. I. Blum: None. Y. Chen: None. H. M. Tse: None.

Funding
DK099550, DK127497, DK1264565, T32GM1097805, T32AI007051