bluuebunny/crossref_metadata_2025_split huggingface dataset:
218-LB: Age, Sex, and Fat Mass Affects Erythropoietin Metabolic Response in Mice
Authors: ROGERS HEATHER , NOGUCHI CONSTANCE T. 
Published: June 2021

Erythropoietin (EPO) is required for erythrocyte production. However, EPO receptor (EpoR) extends beyond erythroid tissue and ΔEpoR mice with EpoR restricted to hematopoietic tissue show an increase in fat mass. At 3 months of age, ΔEpoR mice show no difference in body weight compared with wild type (WT, C57BL/6) mice. By 6 months of age, male body weights of ΔEpoR mice are greater than WT mice, and at 8+ months body weights of male and female ΔEpoR mice are greater than their WT counterparts. To assess EPO activity on glucose homeostasis and fat mass, mice were fed a high fat diet (HFD, 60% kCal fat) and treated with EPO (3000U/kg 3X per week) or saline for 3 weeks at age 3, 6, and 8+ months. EPO increased hematocrit in all mice. EPO treatment in male WT mice reduces weight and fat mass at 6 and 8+ months of age, when their fat mass is 35% or greater with saline treatment. Female WT mice treated with EPO do not show significantly less weight or fat mass at any age. EPO treatment does not affect weight or fat mass in ΔEpoR mice. With HFD feeding and EPO treatment in 3 month old mice, body weights are not different between WT and ΔEpoR mice although fat mass is significantly higher in ΔEpoR mice. At 6 months, body weight and fat mass in males are greater in ΔEpoR than WT, while ΔEpoR females show no difference in body weight but significantly more fat mass compared with WT females. In the older mice (8+ months old), both sexes of ΔEpoR mice are significantly heavier and fatter than WT mice. EPO treatment improves glucose tolerance in female ΔEpoR mice at 3 and 6 months but not at 8+months, whereas male ΔEpoR mice only showed improvement at 3 months, not at 6 and 8+months. In male and female WT mice, EPO improves glucose metabolism at 3 and 6 months, and to a lesser extent at 8+ months with greater improvement in mice with &lt;35% fat mass. These data show that EPO regulates metabolism in a sex and age dependent manner mediated via EpoR expression in non-hematopoietic tissue and is influenced by level of fat mass.

Disclosure
H. Rogers: None. C. T. Noguchi: None.
22-OR: Exploring the Association between Physical Activity Levels and Sedentary Behaviors with Risk of T2DM from Childhood to Adolescence: A Causal Inference Analysis
Authors: HARNOIS-LEBLANC SOREN , VAN HULST ANDRAEA , BARNETT TRACIE A. , MATHIEU MARIE-EVE , PARADIS GILLES , SYLVESTRE MARIE-PIERRE , HENDERSON MÉLANIE , GROUP QUALITY RESEARCH 
Published: June 2021

Background and Objective: Causal inference methods were developed to emulate repeated randomized trials in observational studies, notably by controlling for time-varying confounders. Using these methods, we examined the complex relationship between physical activity, sedentary behaviors and T2DM accounting for interrelations between time-varying lifestyle habits and their reciprocal effects on T2DM across childhood.
Methods: We used longitudinal marginal structural models (with inverse probability of treatment and censoring weighting) on prospective data of Caucasian children with a parental history of obesity (QUALITY Cohort) evaluated at 8-10 years (n=630), 10-12 years (n=564) and 15-17 years (n=377). At each visit, participants underwent an OGTT (1.75g/kg glucose, max 75g). ISI-Matsuda estimated insulin sensitivity. Area under the curve of glucose to insulin estimated 1st (0-30 min) and 2nd phase (0-120 min) insulin secretion. ADA cut points determine IFG, IGT and T2DM. Moderate to vigorous physical activity (MVPA) and sedentary behaviors were assessed with 7-day accelerometry and leisure screen time by questionnaire. Confounders included age, sex, BMI z-score, pubertal stage, diet quality index-international, energy intake, sleep, fitness, parental BMI, and income.
Results: Every additional 10-min of daily MVPA across 8-10 to 15-17 years was associated with a 5.4% (95% CI: -8.8; -2.0) reduction in 2nd-phase insulin secretion at 15-17 years. Every additional 1-h of daily screen time across 8-10 to 15-17 years was associated with an 8.4% (95% CI: -14.1; -2.7) reduction in insulin sensitivity and a 6.4% (95% CI: 0.3; 12.5) and 8.1% (95% CI: 1.5; 14.7) increase in 1st- and 2nd-phase insulin secretion at 15-17 years. No associations were observed with IFG/IGT/T2DM.
Conclusion: Even small increases in MVPA or slight reductions in screen time in childhood/adolescence may play a role in T2DM prevention.

Disclosure
S. Harnois-leblanc: None. A. Van hulst: None. T. A. Barnett: None. M. Mathieu: Research Support; Self; CAPSANA, FitSpirit, Research Support; Spouse/Partner; Caboma, Medicus. G. Paradis: None. M. Sylvestre: None. M. Henderson: None. Quality research group: n/a.

Funding
Canadian Institutes of Health Research (OHF-69442, NMD-94067, MOP-97853, MOP-119512); Heart and Stroke Foundation of Canada (PG-040291); Fonds de Recherche du Québec - Santé
222-OR: High Glucose Level Increases Expression of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Receptors
Authors: NANDULA SESHAGIRI RAO , JANAPALA RAJESH NAIDU , SEN SABYASACHI 
Published: June 2021

Introduction: Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by a novel coronavirus, SARS-CoV-2. The SARS-CoV-2 virus infects the host human cells through its surface receptors human angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2). This study aims to investigate the effects of high glucose on the expression of ACE2 and TMPRSS2 receptors using macrophage (CD14+ve cells) as a biomarker in vivo and human endothelial cells in vitro.
Methods: Mononuclear cells were isolated by Ficoll density centrifuge method from whole blood. CD14 cells were isolated from MNCs by MACS kit. The migratory capacity of CD14 cells was evaluated using the CytoSelect Migration Assay kit. CFU-Hill colony formation assay was also done on MNCs. In vitro studies using HUVEC were done by culturing the cells in normal glucose (NG, 5.5mmol/L) or high glucose (HG, 20 mmol/L), followed by mRNA assays at day 3 and 7.
Results: All the COVID patients had high glucose levels (&gt;300 mg/dl). The migratory function of CD14 cells show moderately increased migration compared to similar hematopoietic cells from nondiabetic COVID negative patients. In general, CD14 cells showed low expression of ACE2 and/or TMPRSS2 in all samples. For our in-vitro experiments using cultured HUVEC mRNA expression of ACE2 and/or TMPRSS2 receptors were higher in HG compared to NG at day 7. No expression was observed at day 3 either in NG or HG. An elevated gene expression of inflammatory marker, IL-6 and apoptosis marker, P53 were observed in HG at both days 3 and 7.
Conclusions: A low expression of SARS-CoV-2 receptors were observed on CD14 macrophage cells from patients which may indicate poor recognition of the virus particle by CD14 cells. Higher expression of the SARS-CoV-2 receptors were noted when HUVEC cells were cultured in HG for 7 days.
Conclusion: Longer exposure of human endothelial cells in high glucose condition increase the SARS-CoV-2 receptor expression.

Disclosure
S. Nandula: None. R. Janapala: None. S. Sen: None.

Funding
Clinical and Translational Science Institute at Children’s National
230-LB: Differential Roles of Beta-Cell IP3R and RyR ER Ca2+ Channels in Tunicamycin-Induced Disruption of Beta-Cell Ca2+ Homeostasis
Authors: ZHANG IRINA , PAREKH VISHAL S. , LEON JUAN J. , SATIN LESLIE S. 
Published: June 2021

Pancreatic beta cells maintain glucose homeostasis by secreting insulin following a rise in plasma glucose. Insulin secretion is pulsatile, which is brought about because of oscillations in the concentrations of beta-cell cytosolic Ca2+. The endoplasmic reticulum (ER) helps to regulate the cytosolic Ca2+ level, thereby playing a role in Ca2+-induced insulin release. ER stress, triggered by the accumulation of unfolded proteins in the ER, can lead to the ER Ca2+ depletion, which in turn can contribute to beta-cell deterioration and an increased risk of type-2 diabetes. We sought to determine the effects of tunicamycin (TM)-induced ER stress on ER Ca2+ channels, inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs) and ryanodine receptors (RyRs), and subsequent alterations in beta-cell Ca2+ homeostasis that result from these alterations. To determine the roles of these receptors in TM-induced beta-cell dysfunction, we treated mouse pancreatic islets with the RyR1 inhibitor dantrolene (Dan) or the IP3R inhibitor xestospongin C (XeC) along with TM. Beta cells treated with TM exhibited altered cytosolic and mitochondrial Ca2+ when in sub-threshold glucose compared to vehicle controls. As TM treatment also reduced ER Ca2+, this raised the possibility that the mitochondrial and cytosolic Ca2+ oscillations seen in stressed cells resulted from increased ER Ca2+ efflux mediated by RyRs and/or IP3Rs. We found that TM-induced ER Ca2+ depletion, as well as cytosolic and mitochondrial Ca2+ oscillations were inhibited by co-treatment with Dan, whereas the inclusion of XeC had little or no effect. Taken together, these results suggest that RyRs, and more specifically RyR1 plays a critical role in mediating the disturbed cellular Ca2+ homeostasis seen in response to the induction of ER stress.

Disclosure
I. Zhang: None. V. S. Parekh: None. J. J. Leon: None. L. S. Satin: None.

Funding
National Institutes of Health (R01DK46409); University of Michigan; JDRF (2-SRA-2018-539-A-B)
240-OR: Mortality, MACE, and Diabetic Complications in Men with Hypogonadism and Type 2 Diabetes (T2DM) Receiving Long-Term Treatment with Testosterone Undecanoate Injections (TU): An Update of 12-Year Real-World Data
Authors: HAIDER KARIM S. , HAIDER AHMAD , SAAD FARID 
Published: June 2021

Background: Men with hypogonadism are at increased risk of MACE and mortality. Studies in men with T2DM show that testosterone therapy (TTh) reduces both MACE and mortality.
Methods: Of 361 men with hypogonadism and T2DM, 183 received testosterone undecanoate injections (TU) 1000 mg/12 weeks (T-group), 178 opted against treatment (CTRL). MACE, mortality, and diabetic complications were recorded and compared between groups.
Results: Mean baseline age in the T-group and CTRL was 60.7±5.5 and 63.0±4.9 years. Mean follow-up in T-group vs. CTRL was 8.2 and 9.2 years. 70 patients (38.3%) in the T-group and 70 (39.3%) in CTRL had a history of cardiovascular disease (myocardial infarction MI, stroke, or coronary artery disease diagnosis) (p=0.8341). Baseline smoking prevalence was 41.0% (75 men) in the T-group and 38.2% (68 men) in CTRL (p=0.5161). The T-group had significantly worse baseline risk factor profile than CTRL: BMI (36.5±4.5 vs. 33.4±5.3 kg/m2), systolic blood pressure (163.0±13.5 vs. 145.6±14.6 mmHg), LDL (4.7±0.9 vs. 4.1±1.4 mmol/L), HbA1c 9.4±1.4 vs. 7.8±0.7% (p&lt;0.0001 for all). Mortality: during the entire observation period, 15 patients (8.2%) died in the T-group vs. 61 (34.3%) in CTRL (p&lt;0.0001). Major adverse cardiovascular events (MACE): in the T-group, there were no cases of MI or stroke. In CTRL, there were 56 cases of MI (31.5%) and 56 cases of stroke (31.5%). 35 patients (19.7%) suffered a MI and a stroke. Diabetic complications: in the T-group vs. CTRL, the incidence of retinopathy was 6 (3.3%) vs. 30 (16.9%) (p&lt;0.0001), nephropathy 1 (0.01%) vs. 5 (2.8%) (p&lt;0.05), polyneuropathy 11 (6.0%) vs. 97 (54.5%) (p&lt;0.0001), diabetic foot syndrome 0 (0%) vs. 10.1% (p&lt;0.0001).
Conclusions: Long-term treatment with TU in men with hypogonadism and T2DM significantly reduces mortality, compared to untreated controls.

Disclosure
K. S. Haider: Other Relationship; Self; Bayer AG. A. Haider: Other Relationship; Self; Bayer AG. F. Saad: Consultant; Self; Bayer AG, Stock/Shareholder; Self; AbbVie Inc., Bayer AG, Novo Nordisk.

Funding
Bayer AG
26-OR: Meta-analyses of Genome-Wide Association Studies for Proinsulin Provide Insight into Glycemic Trait Dysregulation
Authors: BROADAWAY K. ALAINE , YIN XIANYONOG , WILLIAMSON ALICE , WILSON EMMA , INVESTIGATORS MAGIC 
Published: June 2021

Proinsulin, a prohormone precursor to insulin, is synthesized and processed before secretion from pancreatic islet beta cells. Increased plasma proinsulin levels relative to insulin levels may predict insulin resistance and type 2 diabetes (T2D), and the genes involved in proinsulin processing are incompletely understood. Previous genome-wide association studies (GWAS) have identified 13 loci associated with proinsulin levels. To identify additional loci, we conducted a meta-analysis of GWAS results of fasting proinsulin from 16 European-ancestry studies of 45,826 individuals. Each cohort analysis controlled for age, sex, population structure, fasting insulin, and BMI. We identified 35 independent association signals at 30 loci (1 Mb, p&lt;5E-8), including 22 signals not reported previously for proinsulin, 11 of which also were not reported in four recent large GWAS meta-analyses for T2D or four glycemic traits. We identified 14 additional nominally significant proinsulin signals (P&lt;5E-5) that colocalized with at least one known glycemic trait signal. Using Bayesian colocalization methods and expression quantitative trait locus (eQTL) data from the InsPIRE islet eQTL consortium, we identified at least one gene colocalized with 17 proinsulin signals. One set of new loci may influence proinsulin processing, including signals near PCSK2, DLC1, and a low-frequency, missense variant at ELAPOR1, a transmembrane protein localized in the plasma membrane-late endosome-lysosome compartments. Another subset of new loci may influence proinsulin and insulin secretion, including TLE1, BCL11A, and RNF6. We further find a proinsulin-increasing allele at the SIX3 locus that has previously only been associated with glucose and T2D in East Asians, demonstrating that the glycemic trait associations at SIX3 are not population-specific. Our results provide additional insight into the biology underlying glycemic trait dysregulation and etiology of T2D.

Disclosure
K. Broadaway: None. X. Yin: None. A. Williamson: None. E. Wilson: None. Magic investigators: n/a.
273-OR: Association of an Integrated Component of Maternal Glycemic Regulation in Pregnancy with Epigenome-Wide Cord Blood DNA Methylation
Authors: JUVINAO-QUINTERO DIANA L. , CARDENAS ANDRES , PERRON PATRICE , BOUCHARD LUIGI , LUTZ SHARON , HIVERT MARIE-FRANCE 
Published: June 2021

Background: Abnormal maternal glucose regulation in pregnancy has been associated with future cardiometabolic diseases in the offspring. Previous studies suggest that fetal programming is due to modulation of DNA methylation (DNAm), but they have been limited in their maternal glycemic characterization.
Methods: In Gen3G, a prospective prebirth cohort, we investigated associations between an integrated component of maternal glucose regulation in pregnancy and cord blood DNAm levels in an epigenome-wide analysis at 719,558 CpG sites among 430 mother-child pairs. We used a principal component (PC) analysis to create a linear combination of multiple glucose and insulin values measured during a second trimester (24-30 weeks) oral glucose tolerance test (OGTT). We adjusted linear regression models for maternal age, parity, smoking during pregnancy, gestational week at OGTT, child sex, gestational age at delivery, and the estimated proportion of cord blood cells.
Results: The first component (PC1) explained 47% of the total variation in maternal glucose and insulin values from the OGTT and was associated with methylation at cg26974062 (TXNIP) at genome-wide level significance (Bonferroni corrected P&lt;6.95x10-8). Two additional CpG sites were suggestively associated with PC1 (P&lt;1.0x10-6). For these three CpG sites, associations of cord blood DNAm were stronger with PC1 compared to associations with the individual glucose or insulin values.
Conclusions: Among adults, blood DNAm at TXNIP has been previously associated with type 2 diabetes. Our findings suggest that an altered prenatal glucose metabolism may program dysregulation of DNAm at TXNIP across the life-course.

Disclosure
D. L. Juvinao-quintero: None. A. Cardenas: None. P. Perron: None. L. Bouchard: None. S. Lutz: None. M. Hivert: None.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-15-ACE-26 to M-F.H.)
281-OR: Endothelial Cell Cd36 Regulates Systemic Glucose and Lipid Metabolism
Authors: GOEDEKE LEIGH , SON NI-HUIPING , LAMOIA TRACI E. , NASIRI ALI , KAHN MARIO , ZHANG XIAN-MAN , CLINE GARY , GOLDBERG IRA J. , SHULMAN GERALD I. 
Published: June 2021

The transmembrane protein, cluster of differentiation 36 (CD36), facilitates tissue fatty acid uptake and is highly expressed in a variety of different cell types, including endothelial cells (ECs). Loss of EC Cd36 reduces parenchymal long-chain fatty acid uptake and improves whole-body glucose tolerance and insulin sensitivity; however, the mechanisms by which this occurs remain unclear. Here, we report that EC-specific deletion of Cd36 in chow-fed male mice (EC-Cd36-/-) leads to significant reductions in whole-body fat utilization during fasting, subsequently increasing plasma non-esterified fatty acid levels by 30% (P&lt;0.05 vs. Cd36fl/fl). We performed hyperinsulinemic-euglycemic clamp studies, using [13C6]glucose as the infusate, and found that loss of EC Cd36 improved whole-body insulin sensitivity by 15% (P&lt;0.05 vs. Cd36fl/fl) due to a 40-50% increase in insulin-stimulated glucose uptake in heart and brown adipose tissue (both P&lt;0.05 vs. Cd36fl/fl). Consistent with enhanced rates of glucose transport, EC-Cd36-/- mice displayed a significant 20% increase in relative rates of myocardial pyruvate dehydrogenase oxidation to citrate synthase flux (VPDH/VCS) compared to Cd36fl/fl controls; in contrast, mitochondrial VPDH/VCS was unaffected in liver and skeletal muscle. Interestingly, improvements in whole-body insulin sensitivity due to loss of EC Cd36 was also associated with 20% reductions in fasting plasma glucose concentrations and hepatic glucose production (both P&lt;0.05 vs. Cd36fl/fl), which could be attributed to a significant 20% decrease in hepatic acetyl-CoA content.
Conclusion: Taken together, these results demonstrate a key role for EC Cd36 in regulating parenchymal fuel selection and hepatic glucose production and provide insight into the mechanisms by which EC Cd36 controls systemic glucose and lipid metabolism.

Disclosure
L. Goedeke: None. N. Son: None. T. E. Lamoia: None. A. Nasiri: Employee; Spouse/Partner; Medtronic. M. Kahn: None. X. Zhang: None. G. Cline: None. I. J. Goldberg: Advisory Panel; Self; Akcea Therapeutics, Arrowhead Pharmaceuticals, Inc., Consultant; Self; Esperion. G. I. Shulman: Consultant; Self; 89bio, Inc., BridgeBio, Ionis Pharmaceuticals, Maze Therapeutics, Novo Nordisk, Other Relationship; Self; AstraZeneca, Esperion Therapeutics, Inc, Generian Pharmaceuticals, Inc., Gilead Sciences, Inc., iMetabolic Biopharma Corporation, Janssen Research & Development, LLC, Merck & Co., Inc., The Liver Company.

Funding
National Institutes of Health (HL150234, R01DK113984, R01DK045735)
282-OR: The Effect of Glucagon on Rates of Hepatic Mitochondrial Oxidation and Pyruvate Carboxylase Flux in Man Assessed by Positional Isotopomer NMR Tracer Analysis (PINTA)
Authors: PETERSEN KITT , SHULMAN GERALD I. 
Published: June 2021

Dual GLP-1/glucagon agonists are now in clinical trials for the treatment of T2D and NASH. In addition to promoting further reduction in food intake on top of GLP-1, the glucagon component of these dual agonists may also promote increased rates of hepatic mitochondrial fat oxidation. In order to investigate this possibility we assessed the glucagon-specific effects of a dual agonist on rates of hepatic mitochondrial oxidation (VCS) and pyruvate carboxylase flux (VPC) in humans by infusing glucagon to achieve a physiological increase in plasma glucagon concentrations in combination with a novel 13C PINTA method to assess rates of hepatic VCS and VPC in 15 healthy volunteers using a paired study design. Following an overnight fast a 3-h IV infusion of [3-13C]lactate (4.3 μmol/Kg-min) and [1,2,3,4,5,6,6-2H7]glucose (0.22 μmol/Kg-min) was begun and during the last 2 hours glucagon (GLG) was co-infused [6 ng/(Kg-min)] or no GLG (CON). The GLG infusion resulted in a ~2.4 fold increase in plasma GLG conc. (from 75±11 to 183±20 pg/mL; P&lt;0.0001), which was associated with an ~20% increase in both plasma C-peptide (from 1.89±0.17 to 2.30±0.26 ng/mL; P=0.02) and plasma insulin conc. (from 9.9±2.0 to 12.0±2.4 μU/mL; P=0.06). Plasma glucose conc. increased from 4.90±0.16 to 5.64±0.19 mmol/L (P=0.0001) which was associated with a tendency for increased rates of glucose production (CON:1042±123 vs. GLG:1148±122 μmol/min; p=0.086) despite no change in rates of VPC flux (CON: 403±69 vs. GLG: 373±55 μmol/min; p=NS). In contrast, this physiological increase in plasma GLG concentrations caused an 85% increase in rates of hepatic VCS (P&lt;0.05).
Conclusion: Taken together these studies demonstrate that a physiological increase in plasma glucagon promotes increased rates of hepatic mitochondrial oxidation in humans, which may provide additional benefits to the anorexic effects of dual GLP-1/glucagon agonists to reduce hepatic steatosis.

Disclosure
K. Petersen: Advisory Panel; Spouse/Partner; AstraZeneca, iMetabolic Biopharma Corporation, Janssen Research & Development, LLC, Merck & Co., Inc., Consultant; Spouse/Partner; Aegerion Pharmaceuticals Inc., Novo Nordisk, Research Support; Self; Gilead Sciences, Inc., Merck & Co., Inc. G. I. Shulman: Consultant; Self; 89bio, Inc., BridgeBio, Ionis Pharmaceuticals, Maze Therapeutics, Novo Nordisk, Other Relationship; Self; AstraZeneca, Esperion Therapeutics, Inc, Generian Pharmaceuticals, Inc., Gilead Sciences, Inc., iMetabolic Biopharma Corporation, Janssen Research & Development, LLC, Merck & Co., Inc., The Liver Company.

Funding
Merck & Co., Inc. (MISP583402); National Institutes of Health (R01DK113984)