bluuebunny/crossref_metadata_2025_split huggingface dataset:
238-LB: Erythropoietin Receptor–Mediated Erythropoietin Regulation of Energy Metabolism in Mice
Authors: YIN WEIQIN , ROGERS HEATHER , RAJVANSHI PRAVEEN K. , AN XIULI , GASSMANN MAX , NOGUCHI CONSTANCE T. 
Published: May 2022

EPO receptor (EPOR) expression in white adipose tissue (WAT) mediates EPO metabolic activity and mitochondrial biogenesis. Mice that lack EPOR in adipose tissue have increase fat mass accumulation, increased susceptibility to diet induced obesity and decreased WAT mitochondrial activity. Here we assess the potential for EPO to promote a metabolic response in liver, brown adipose tissue and skeletal muscle by assessing the extent of EPOR expression using the EpoR-dtTomato-Cre mouse. We quantified EPOR in liver, brown adipose tissue and soleus muscle compared with EPOR expression in subcutaneous and epididymal WAT and found the highest level in WAT by mRNA, protein and immunohistochemical analyses. Elevated EPO by intraperitoneal injection or by transgene over expression resulted in tissue specific changes in gene expression. In liver, EPO decreased expression of genes involved in gluconeogenesis and triglyceride secretion. In brown adipose tissue, EPO increased expression of thermogenic genes. In subcutaneous WAT, EPO decreased genes involved in lipogenesis. In soleus muscle, EPO decreased expression of lipolytic genes. These findings indicate that increased EPO decreases lipogenesis gene LPI, ACC1, ACC2 and Fas expression in the BAT, skeletal muscle, ScWAT, liver and eWAT and increases lipolysis gene Atgl and Hsl expression in the BAT, ScWAT, skeletal muscle, and Atgl expression in the liver and eWAT. Measurements of energy metabolism did not detect any changes associated with EPO treatment in energy expenditure, respiratory exchange ratio, locomotor activity and total activity. However, as observed in WAT, we also find that EPO promotes mitochondria activity in liver, brown adipose tissue and skeletal muscle indicated by elevated gene expression of CytC, Idh3α, Cpt1, Pgc-1α and Cox7a1. Together, these data support the hypothesis that EPO promotes lipolysis and inhibits fat synthesis to regulate body weight and fat mass. In addition, EPO may regulate glucose metabolism via inhibition of gluconeogenesis.

Disclosure
W. Yin: None. H. Rogers: None. P. K. Rajvanshi: None. X. An: None. M. Gassmann: None.
242-LB: Roux-en-Y Gastric Bypass and Vertical Sleeve Gastrectomy Showed Similar Efficacy in Achieving Cardiometabolic Composite Target in Subject with Type 2 Diabetes Undergoing Bariatric Surgery
Authors: MONTE LAVINIA , TUCCINARDI DARIO , ROSSINI GIOVANNI , WATANABE MIKIKO , POZZILLI PAOLO , NAPOLI NICOLA , MANFRINI SILVIA 
Published: May 2022

Introduction: The ADA produced a triple composite outcome that summarizes the therapeutic targets of the three most prevalent complications of obesity: type 2 diabetes (T2D) , hypertension and dyslipidemia (HbA1c &lt;7.0%; LDL cholesterol&lt;100 mg/dL and systolic blood pressure &lt;130 mmHg) . The present study primarily investigates the difference between Vertical Sleeve gastrectomy (VSG) and Roux-en-Y Gastric Bypass (RYGB) in achieving the composite target one year after the surgery. The secondary outcome assessed the success rate in achieving the separate components' target at months 6, 12 and 24 post-surgery.
Methods: This retrospective observational study evaluated 103 patients with obesity and T2D. At each visit, anthropometric measurements were recorded, and the metabolic and lipid profile was evaluated before surgery and subsequently during the follow-up visits at 6, 12 and 24 months post-surgery.
Results: Twelve months after surgery, patients undergoing RYGB did not show a significant difference compared to those undergoing VSG in achieving the composite target (P =.57) . Patients undergoing RYGB showed greater LDL target achievement at 6 months post-surgery than the VSG (P=.005) . Total cholesterol and LDL cholesterol were significantly reduced over time in the RYGB compared to the VSG (P=.023 and P=.010 respectively) .
Conclusion: RYGB and VSG showed similar efficacy in reaching the cardiometabolic ADA composite target in subjects with T2D undergoing bariatric surgery. Patients undergoing RYGB showed a significant reduction over time in LDL and total cholesterol compared to the VSG group. More extended randomized studies are needed to evaluate the effectiveness of the two surgical procedures in the improvement and remission of cardiovascular risk factors associated with obesity.

Disclosure
L. Monte: None. D. Tuccinardi: None. G. Rossini: None. M. Watanabe: Consultant; Novo Nordisk. P. Pozzilli: Advisory Panel; Dompé, Consultant; Abbott, Speaker's Bureau; Dompé, Lilly Diabetes, Medtronic, Sanofi. N. Napoli: Advisory Panel; Novo Nordisk, Consultant; Lilly Diabetes. S. Manfrini: None.
244-LB: GPR75 Ablation Protects against Diet-Induced Obesity, Inflammation, and Insulin Resistance
Authors: HOSSAIN SAKIB , DIRICE ERCUMENT 
Published: May 2022

Obesity related conditions including atherosclerosis and type 2 diabetes mellitus (T2DM) have a profound effect on cardiovascular health and morbidity. Recent reports by Akbari et. al. indicate that truncated loss of function variants of the orphan G-protein coupled receptor, GPR75, are associated with 5.3 kg lower bodyweight and 54% lower odds of obesity in heterozygous individuals (Science, 2021) . Based on these findings, we hypothesized that whole body deletion of Gpr75 protects against diet-induced obesity (DIO) and the resulting insulin resistance. Wild-type and Gpr75 null mice were subjected to 14 weeks of regular chow or high-fat diet (HFD) feeding. Body weight, intraperitoneal glucose and insulin tolerance tests, and pro-inflammatory cytokine gene expressions were measured initially and at week 14. There were no significant differences in body weight, glucose homeostasis, and tumor necrosis factor alpha (TNF-α) expression between wild-type (WT) and Gpr75 -/- (KO) mice at baseline. However, WT mice obtained a diabetogenic phenotype after HFD-feeding while the KO counterparts were protected as indicated by reduced body weight, (45.32 ± 1.387 grams vs. 28.29 ± 1.47 grams) and increased sensitivity to insulin (blood glucose 30 min after insulin injection as percent change, -28.5 ± 4.41% vs. -50.68 ± 4.15%, p&lt;0.0001) . This correlated with a 1.98-fold decrease in brown adipose tissue (BAT) and 2.31-fold decrease in subcutaneous adipose tissue (SAT) TNF-α mRNA expression in KO compared to WT mice. Furthermore, there was a 3.19-fold reduction in circulating chemokine ligand 5 (CCL5) in KO compared to WT mice. This data may provide a potential novel target for the control of obesity-driven disorders such as inflammation and insulin resistance.

Disclosure
S. Hossain: None. E. Dirice: None.

Funding
NIH123203
244-OR: Moderate Intensity Endurance Exercise Training Improves Late-Phase ß-Cell Function in Humans with Type 2 Diabetes
Authors: ZHANG HUI , MIDDELBEEK ROELAND , SIMPSON LAURA , CARBONE NICHOLAS P. , GOODYEAR LAURIE J. 
Published: May 2022

Type 2 diabetes (T2D) is associated with β-cell dysfunction. Although exercise is considered beneficial in T2D, the effects of moderate intensity endurance exercise training on β-cell function in humans with T2D are not known. GWAS uncovered Ras-Responsive Element Binding Protein 1 (RREB1) as a risk factor for T2D and in vitro studies suggest RREB1 impairs β-cell function; no studies have investigated exercise effects on RREB1. Here, we determined the effects of moderate intensity exercise training on β-cell function, RREB1, insulin, glucagon, and amylin in humans with T2D (7F/3M, 49±5y, BMI 30±3kg/m2) . Subjects completed 10-weeks of supervised exercise (Wks 1-3: 20-30min/day; 3X/wk; ∼50% VO2peak and Wks 4-10: 45-60min/day; 4X/wk; ∼70% VO2peak) . Fasting blood samples for OGTT, HbA1c, and hormones were obtained pre- and post-training (48hr) . Serum RREB1 was measured pre- and post-training and also in response to a single bout of maximal exercise. Training decreased HbA1c (7.7% to 7.2%, P=0.01) , pro-insulin (-18%, P=0.03) , pro-insulin/c-peptide ratio (-8%, P=0.03) , and glucose (OGTT: 90min, -18%, P=0.01; 120min, -15%, P&lt;0.001) . Both β-cell function (late-phase disposition index, +38%, P=0.01) and insulin sensitivity (Stumvoll Index, +25%, P=0.01) improved. Body weight and composition, VO2peak, glucagon, amylin, c-peptide, and insulin were unchanged. Baseline RREB1 negatively correlated with the exercise-induced increase in late-phase disposition index (R= -0.71, P=0.03) , consistent with an inhibitory role of RREB1. Training did not alter serum RREB1, but interestingly, acute exercise decreased RREB1 both before (-51%, P&lt;0.01) and after training (-11%, P=0.04) . Thus, RREB1 is an exercise-regulated serum factor whose decrease may function to improve β-cell function with exercise.
In conclusion, moderate intensity exercise training, in the absence of increased VO2peak, improves late phase β-cell function and glucose control in humans with T2D.

Disclosure
H.Zhang: None. R.Middelbeek: Research Support; Novo Nordisk. L.Simpson: None. N.P.Carbone: None. L.J.Goodyear: None.

Funding
National Institutes of Health (K23-DK114550, R01-DK112283, 5P30DK36836, 5P30DK057521-20)
249-LB: PAX4 Loss of Function Alters Human Endocrine Cell Development and Influences Diabetes Risk
Authors: KRENTZ NICOLE , HUI LAU HWEE , ABAITUA FERNANDO , PEREZ-ALCANTARA MARTA , WEI CHAN JUN , AJEIAN JILA N. , CHAMPON BENOITE , SUN HAN , JHA ALOKKUMAR , HOON SHAWN , GARDNER DAPHNE , LING KAO SHIH , SHYONG TAI E. , GLOYN ANNA L. , TEO ADRIAN 
Published: May 2022

In an effort to identify disease-causing mechanisms, numerous genome-wide studies across different ancestries have discovered genetic variants influencing type 2 diabetes (T2D) risk. Amongst identified diabetes-associated loci, a PAX4 coding variant (p.Arg192His) is uniquely and reproducibly associated with altered T2D-risk in East Asian populations. PAX4 encodes a transcription factor, and in mice Pax4 is essential for beta cell development. Whether PAX4 plays a similar role in humans and how diabetes associated PAX4 variants impact beta cell development and/or function is unknown. We combined in vivo studies in human variant carriers with disease modelling in human stem cell models to address these questions. Carriers of the PAX4 p.Arg192His allele have reduced islet cell function compared to non-carriers (AIRg: p.Arg192 756.9 vs. p.His192 530.8 p&lt;0.002) . Deletion of PAX4 by CRISPR-Cas9 genome-editing in isogenic human induced pluripotent stem cell (hiPSC) -derived beta-like cells caused de-repression of alpha cell gene expression, suggesting decreased function in carriers of PAX4 variants may be due to altered beta cell development. hiPSCs derived from carriers of either the PAX4 p.Arg192His or a novel p.Tyr186X allele identified in a proband with early onset diabetes, had increased polyhormonal endocrine cell formation and reduced insulin content following in vitro differentiation towards beta-like cells; correction of the diabetes-associated PAX4 alleles reversed these phenotypic changes. Our in vitro and in silico molecular studies of diabetes associated alleles support reduced PAX4 expression and/or function. PAX4 knockdown in the EndoC-βH1 human beta cell model altered hormone gene expression, reduced total insulin content, and impaired insulin secretion.
In conclusion, we have demonstrated the importance of PAX4 for human endocrine cell development and provide a potential mechanism for diabetes-associated alleles through de-repression of alpha cell gene expression.

Disclosure
N. Krentz: None. S. Hoon: None. D. Gardner: None. S. Kao: None. E. Tai: Advisory Panel; Amgen Inc., Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk, Stock/Shareholder; Abbott, AbbVie Inc. A. L. Gloyn: Other Relationship; Genentech, Inc., Roche Pharmaceuticals. A. Teo: Stock/Shareholder; BetaLife Pte Ltd. H. Lau: None. F. Abaitua: Employee; Vertex Pharmaceuticals Incorporated. M. Perez-alcantara: None. J. Chan: None. J. N. Ajeian: None. B. Champon: None. H. Sun: None. A. Jha: None.

Funding
Wellcome (200837) ; National Institutes of Health (U01-DK105535, U01-DK085545, UM1DK126185, U01DK123743, U24DK098085, P30DK116074) ; Lee Foundation Grant (SHTX/LFG/002/2018) Paris-NUS 2021-06-R/UP-NUS (ANR-18-IDEX-0001)
250-OR: Role of Ezh2 in Hepatic Inflammation and Developmental Programming of Liver Disease
Authors: RUEBEL MEGHAN L. , JAMBAL PUREVSUREN , CHINTAPALLI SREE V. , CHEN JIN-RAN , SHANKAR KARTIK 
Published: May 2022

Maternal obesity predisposes offspring to the development of fatty liver and nonalcoholic steatohepatitis. Using a well-established mouse model (C57BL6/J) of maternal high-fat, high sucrose diet (HFD) exposure, we characterized epigenomic alterations in adult offspring liver. ChiP-seq for six histone modifications were performed on offspring livers from dams fed either a AIN93G (CON, 7% fat calories, n=11) or HFD (45% fat calories, n=9) for 12 wk prior to pregnancy and through weaning. Offspring of HFD dams, showed a robust gain in repressive H3K27me3 modification mediated by the histone methyltransferase, Ezh2. Since Ezh2 has been implicated in modulating inflammatory signaling we examined if Ezh2 in macrophages contributes to hepatic inflammation following a high-fat palmitate/cholesterol (FPC) diet. We generated myeloid cell-specific Ezh2-knockouts (Ezh2-CKO) by crossing Ezh2-floxed (Ezh2f/f) mice to LysM-Cre expressing mice. At 5 weeks of age Ezh2-CKO and flox-control litter mates were provided ad libitum CON (n=22) or FPC diet (52% fat calories, n=22) for 14 days. At 7 weeks of age, body and liver weights were collected and liver tissue was flash frozen for RNA-seq analyses. Two-way ANOVA of liver to body weight ratios showed a significant diet effect (p&lt;0.0001) , with increased ratios in the FPC group without effects of genotype. Transcriptomic analyses showed that the effects of FPC diet were diminished in CKO mice relative to flox controls (223 vs.132 DEGs in flox and CKO, respectively) with 2DEGs shared between genotypes. Ingenuity Pathway Analysis revealed signaling pathways and processes related to inflammation, macrophage and leukocyte activation, reactive oxygen species, and PPARα that were increased in the flox with FPC diets compared to CKO animals. Collectively, these findings reveal a role for Ezh2 in developmental programing of liver disease and hepatic inflammation, uncovering a novel epigenetic process influencing hepatic disease risk in offspring.

Disclosure
M.L.Ruebel: None. P.Jambal: None. S.V.Chintapalli: None. J.Chen: None. K.Shankar: None.

Funding
U.S. Department of Agriculture-ARS-CRIS (6251-51000-005-00D) NIH (P30DK048520-27, R01HD102726-01A1) Funds from the Department of Pediatrics, University of ColoradoAnschutz Medical Campus and the Anschutz Health and Wellness Center.
259-LB: Inhibition of the Polyamine-Hypusine Circuit Delimits Islet ß-Cell Stress in the Context of T1D via Suppression of IRE-1a Signaling
Authors: ANDERSON ANDY , KULKARNI ABHISHEK , MIRMIRA RAGHAVENDRA G. 
Published: May 2022

Recent data suggest that stress-induced molecular pathways in the β cell may trigger the display of neoantigens that initiate autoimmunity in type 1 diabetes (T1D) . Polyamines (putrescine, spermidine, and spermine) are biogenic amines that participate in stress-induced mRNA translation, in part, through the posttranslational hypusine modification of eIF5A. Rate-limiting enzymes in this circuit include the ODC, which converts Arg to polyamines, and DHPS, which controls eIF5A hypusination. Previously, we showed that inhibition of ODC or DHPS in non-obese diabetic mice using either DFMO or GC7, respectively, resulted in preserved β-cell function, enhanced β-cell mass, and significantly reduced T1D incidence. DFMO treatment subjects with recent-onset T1D was suggestive of reductions in β cell stress. We hypothesized that polyamine depletion with DFMO reduces inflammatory stress in β cells and the consequent accumulation of unhypusinated eIF5A limits stress-related protein production. To test the hypothesis, we treated the human islets with proinflammatory cytokine (PIC) cocktail to mimic T1D in presence or absence of 5 mM DFMO. We observed induction of ER stress as shown by increased expression of unfolded protein response proteins within 24 h of PIC treatment. Treatment with DFMO reduced protein levels of IRE1α and downstream XBP1. Gene expression analysis showed significant downregulation of genes in the IRE1α pathway (CHOP, TNXIP, and XBP1s) . To clarify a mechanism underlying suppression of stress protein production by unhypusinated eIF5A, we treated HEK cells with DFMO or GC7, both of which enhanced the association of unhypusinated eIF5A with GCN2, an eIF2α kinase, suggesting a non-ER stress mediated mechanism of mRNA translational blockade. Collectively, these data suggest that inhibition of the polyamines-hypusine circuit suppresses ER stress via IRE1α signaling and enhances non-ER stress mediated suppression of mRNA translation.

Disclosure
A. Anderson: None. A. Kulkarni: None. R. G. Mirmira: None.
268-OR: Impact of the COVID-Pandemic on Antihyperglycemic Prescription Patterns in Canada
Authors: CHENG ALICE Y. , GOLDENBERG RONALD , KRAWCHENKO IRIS E. , TYTUS RICHARD , HAHN JINA , LIU AIDEN R. , LAN TOMMY , MILLSON BRADLEY , HARRIS STEWART B. 
Published: May 2022

Background: COVID-public health measures may have impacted diabetes care through delayed care and reduced medication access. This study describes antihyperglycemic medication prescription patterns among adults with type 2 diabetes (T2D) before and during the COVID-pandemic in Canada.
Methods: Using IQVIA’s longitudinal pharmacy based prescription data, antihyperglycemic prescriptions from March 1, 2018 to February 28, 2021 were analyzed among adults who had ≥1 prescription for a non-insulin antihyperglycemic drug. The number of people who: 1) had antihyperglycemic prescriptions,2) were newly started on antihyperglycemic drugs, and3) were newly diagnosed with T2D (inferred from prescriptions) were reported.
Results: The number of people who had ≥1 antihyperglycemic prescription was comparable in the year of the COVID-pandemic (March 2020 to February 2021) and the year prior (March 20to February 2020) . The number of people who newly initiated a GLP-1RA, SGLT2i or second-generation basal insulin analogue decreased for the first few months of the pandemic (April to September 2020) with recovery thereafter. The number of people who were newly diagnosed with T2D decreased by 7% in the COVID-year.
Conclusion: Fewer people initiated newer antihyperglycemic medications and fewer people were newly diagnosed with T2D in the first few months for the pandemic which may reflect reduced health care access.

Disclosure
A.Y.Cheng: Advisory Panel; Abbott, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Dexcom, Inc., Eli Lilly and Company, HLS Theraoeutics, Insulet Corporation, Janssen Pharmaceuticals, Inc., Medtronic, Novo Nordisk, Sanofi, Board Member; Type 1 Diabetes Think Tank Network, Other Relationship; Diabetes Canada, Speaker's Bureau; Bausch Health, Canada, Merck & Co., Inc. R.Goldenberg: Consultant; IQVIA Inc., Speaker's Bureau; Amgen Canada, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Canada Inc., Sanofi. I.E.Krawchenko: Speaker's Bureau; Janssen Pharmaceuticals, Inc. R.Tytus: Other Relationship; Banty , Boehringer Ingelheim International GmbH, Canadian Health Research Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc. J.Hahn: Employee; Novo Nordisk Canada Inc. A.R.Liu: Employee; Novo Nordisk A/S, Novo Nordisk Canada Inc. T.Lan: Other Relationship; Novo Nordisk Canada Inc. B.Millson: Other Relationship; Novo Nordisk Canada Inc. S.B.Harris: Consultant; Abbott, AstraZeneca, Eli Lilly and Company, Novo Nordisk, Sanofi, Other Relationship; Abbott, AstraZeneca, Bayer Inc., Dexcom, Eli Lilly and Company, HLS Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Research Support; Applied Therapeutics Inc., AstraZeneca, Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation (JDRF) , Novo Nordisk, Sanofi, The Lawson Foundation.
269-OR: No BMI Increase during the COVID-Pandemic in Children and Adults with T1D in Three Continents: Joint Analysis of ADDN, T1DX, and DPV Registries
Authors: NARAYAN KRUTHIKA , AUZANNEAU MARIE , NOOR NUDRAT , ROMPICHERLA SAKETH , EBEKOZIEN OSAGIE , GLASTRAS SARAH , SMART CARMEL E. , BACHMANN SARA , WELP REINHARD , MAAHS DAVID M. , HOLL REINHARD W. , CRAIG MARIA E. 
Published: May 2022

The COVID-pandemic necessitated worldwide lockdowns in 2020, with restrictions on physical activity and changes in eating habits. We investigated temporal trends in BMI in three international T1D registries between 2018-2020. Data were extracted from DPV (Germany/Austria/Luxembourg/Switzerland) , T1D Exchange (T1DX, US) , and Australasian Diabetes Data Network (ADDN) . The period affected by the COVID-pandemic was defined as Mar to Dec 2020 and compared with the 9-mth periods in 2018 and 2019. Median age and median BMI were aggregated for each individual per year. Mean BMI was aggregated by year, sex, and age groups (stratified by 2 yearly intervals to age 20 years, and yearly until age 60. Study population: ADDN (n=29,875, mean age 21.9 years, 51% male) ; DPV (n=118,580, 21.2 years, 53% male) ; T1DX (n=47,122, 21.3 years, 51% male) . BMI stratified by age group and sex are shown in the figure. There were no apparent BMI differences across the three years. Females aged 30-40 years and 40-50 years in ADDN only demonstrated a slightly higher BMI in 2020. Conclusion: At a population level, mean BMI was not different before and during the pandemic in people with T1D. In some individuals, a healthier lifestyle or more regulated nutritional intake may have counteracted potential adipogenic effects of lockdown measures.

Disclosure
K.Narayan: None. D.M.Maahs: Advisory Panel; Abbott Diabetes, Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Consultant; Aditx Therapeutics, Inc., Biospex. R.W.Holl: None. M.E.Craig: None. M.Auzanneau: None. N.Noor: None. S.Rompicherla: None. O.Ebekozien: None. S.Glastras: None. C.E.Smart: None. S.Bachmann: None. R.Welp: None.