bluuebunny/crossref_metadata_2025_split huggingface dataset:
1964-P: Slug Epigenetically Represses Adipose Thermogenic Programs
Authors: KANG QIANQIAN , JIANG LIN , RUI LIANGYOU 
Published: June 2020

Thermogenic fat, such as brown adipose tissue (BAT) and beige fat, gains increasing attention due to its ability to protect against obesity and type 2 diabetes. Brown adipocytes and beige adipocytes contain dense mitochondria that burn glucose and free fatty acids to produce heat, and mitochondrial Ucp1 mediates heat production. Coactivator PGC1α is a master regulator of mitochondrial biogenesis and Ucp1 expression, and profoundly influences the energy expenditure capability of thermogenic fat. We attempted to delineate transcriptional regulators that govern thermogenic fat activity through PGC1α, and identified transcriptional repressor Slug. Both human and mouse PGC1α promoters contain multiple Slug binding motifs. Slug potently suppressed the activity of PGC1α promoter luciferase reporters but not mutant PGC1α promoters lacking Slug motifs. Consistently, Slug physically bound to the PGC1α promoter and decreased the levels of PGC1α promoter H3K9 acetylation, a transcriptionally-active epigenetic mark, presumably by recruiting HDAC1/2 to the promoter. In line with this notion, treatment with HDAC1/2 inhibitor trichostatin A abrogated the ability of Slug to suppress PGC1α promoter luciferase reporters. Remarkably, deletion of Slug substantially increased expression of PGC1α and Ucp1 in both BAT and inguinal fat in mice, and increased H3K9 acetylation levels on the PGC1α promoter in BAT. Slug-deficient BAT had increased O2 consumption rates and thermogenesis capability. Slug knockout mice were resistant to high fat diet-induced obesity, insulin resistance, glucose intolerance, and fatty liver disease. Likewise, adipocyte-specific deletion of Slug also ameliorated HFD-induced glucose intolerance. Unlike global Slug knockout mice, adipocyte-specific Slug knockout mice displayed mild metabolic phenotypes.
In conclusion, our data suggest that Slug regulates thermogenic fat energy expenditure at least in part by epigenetically suppressing the PGCα-mitochondria axis.

Disclosure
Q. Kang: None. L. Jiang: None. L. Rui: None.
1976-P: Cardiovascular Safety of Sulfonylureas in Type 2 Diabetes: Effect Modification by Obesity?
Authors: SUISSA KARINE , DOUROS ANTONIOS , AZOULAY LAURENT , FILION KRISTIAN B. , SCHNEEWEISS SEBASTIAN 
Published: June 2020

Background: Pharmacokinetic studies suggest that adiposity may modify antidiabetic (AD) medication efficacy and safety via altered drug distribution. While sulfonylureas (SU) have been linked to a higher cardiovascular (CV) risk, with inconsistent results, the role of obesity remains unclear. We evaluated the effect of obesity on CV risk with SU as first-line therapies for type 2 diabetes in a clinical practice. Methods: Using the UK’s Clinical Practice Research Datalink, we conducted a cohort study of patients initiating AD treatment. Initiators of SU monotherapy were matched with initiators of metformin (MET) monotherapy on a high-dimensional propensity score. Patients were censored at the time of discontinuation or addition of another AD drug. We used Cox proportional hazards models within body mass index (BMI) categories (&lt; 25 kg/m2 (normal weight; 26%), 25-30 kg/m2 (overweight; 42%), ≥ 30 kg/m2 obese; 32%)) to estimate hazard ratios (HR) of major adverse cardiovascular events (MACE), individual components of MACE, and all-cause mortality, comparing SU with MET.
Results: A total of 94,750 patients with type 2 diabetes initiated SU or MET. We matched 13,999 initiators of SU with 13,999 MET initiators. The overall HR of MACE comparing SU with MET was 1.23 (95% CI: 1.08-1.39); the HR was 1.33 (95% CI: 1.02-1.74) among obese patients, 1.27 (95% CI: 1.04-1.55) for overweight patients, and 0.99 (95% CI: 0.77-1.28) among normal weight patients. Similarly, the risk of all-cause mortality, CV death and ischemic stroke with SU was highest in obese individuals, with evidence of interactions for all-cause mortality and stroke.
Conclusion: Sulfonylureas as a first-line monotherapy for type 2 diabetes is associated with a higher risk of MACE compared with MET. Our data suggest that this effect might be strongest in obese patients, with no increased risk in normal weight patients. To ensure the best response to treatment, BMI level may be considered when choosing MET over SU for first-line treatment.

Disclosure
K. Suissa: None. A. Douros: None. L. Azoulay: Consultant; Self; Janssen Pharmaceuticals, Inc., Pfizer Inc. K.B. Filion: None. S. Schneeweiss: None.
1981-P: Impaired Exercise Lipid Oxidation Is Associated with Poor Metabolic Health, Not Excess Body Fat Per Se
Authors: ARAD AVIGDOR D. , DIMENNA FREDERICK J. , KITTRELL HANNAH D. , KISSILEFF HARRY R. , ALBU JEANINE 
Published: June 2020

Introduction: It is not clear whether impaired exercise lipid oxidation is associated with excess body-fat or changes in metabolic health often associated with the overweight/obese state. Mixed findings may reflect lack of control for key variables including: 1) acute energy balance and macronutrient composition of the diet; 2) intensity and duration of exercise; and 3) subject characteristics including fat-free mass (FFM), fitness and, perhaps most importantly, metabolic health (e.g., insulin resistance).
Purpose: To determine whether excess body-fat or loss of metabolic health is associated with altered fuel metabolism during exercise.
Methods: Eight metabolically healthy (FH- and ≤1 MetSyn) normal-weight (BMI, 19-24 kg∙m-2) (MHNW) and 8 overweight/obese (26-35 kg∙m-2) (MHO) sedentary adults, and 7 metabolically unhealthy (FH+ and ≥ 2 MetSyn) normal-weight (MUNW) and 7 overweight/obese (MUO) sedentary adults, controlled for age (18-45 yr), sex, and fitness level (≤ “average”), completed a 10-day weight-stable (controlled feeding) testing protocol that included measurement of V?O2peak, RMR, body-fat %, OGTT and lipid oxidation during 45 min of moderate-intensity cycling. ANCOVA with adjustment for rate of O2 consumption (ml∙min-1∙kgBW-1) was used with contrasts to compare indices of lipid oxidation among the four groups.
Results: Adjusted means over both sexes for lipid oxidation during exercise, expressed as rate (mg∙min-1∙kgFFM-1), RER and percent total energy expenditure were significantly different between groups (p&lt;0.05). There was a significant difference between MHNW vs. MUO for all indices (p&lt;0.05), and between MUNW vs. MHO for rate (p&lt;0.025). Tukey post-hoc also revealed a significant difference between MHNW vs. MUNW for all indices.
Conclusion: We found that impaired exercise lipid oxidation previously ascribed to the overweight/obese state was specifically associated with the loss of metabolic health as opposed to the overweight/obese state per se.

Disclosure
A.D. Arad: None. F.J. DiMenna: None. H.D. Kittrell: None. H.R. Kissileff: None. J. Albu: None.
1991-P: Intensive Lifestyle Intervention Does Not Reduce Racial and Ethnic Disparities in Achievement of Optimal Glycemic Control
Authors: HAYES JACQUELINE F. , BERTONI ALAIN , PILLA SCOTT J. , WING RENA R. 
Published: June 2020

African Americans and Hispanics with type 2 diabetes have worse glycemic control relative to non-Hispanic whites. The Look AHEAD randomized trial demonstrated that an intensive lifestyle intervention for weight loss (ILI), versus diabetes support and education (DSE), improved HbA1c among overweight/obese adults with type 2 diabetes. We examined whether ILI reduced racial/ethnic disparities in achieving optimal glycemic control (HbA1c &lt;7%). We used a GEE model to examine the effects of race/ethnicity, treatment arm, and their interaction on achieving HbA1c &lt;7% over 8 years. Among 4,889 participants (16% African American, 14% Hispanic), more achieved HbA1c &lt;7% in ILI vs. DSE in years 1-4 (p&lt;0.001). However, significantly fewer Hispanic and African Americans achieved HbA1c &lt;7% (p&lt;0.001). The race by treatment interaction was not significant at any time point. These findings demonstrate persistent racial/ethnic disparities in glycemic control in a clinical trial population over eight years, which were not reduced by an effective lifestyle intervention. More research is needed to develop interventions that improve diabetes outcomes while reducing disparities.

Disclosure
J.F. Hayes: None. A. Bertoni: None. S.J. Pilla: None. R.R. Wing: None.

Funding
National Institutes of Health
1999-P: Intranasal Oxytocin Improves Lean Muscle Mass in Older Adults with Sarcopenic Obesity: A Pilot Study
Authors: ESPINOZA SARA E. , LEE JESSICA , WANG CHEN-PIN , MACCARTHY DANIEL J. , GANAPATHY VINUTHA , PASCUCCI CHIARA , MUSI NICOLAS 
Published: June 2020

Obesity leads to sarcopenia and poor physical function with aging. Evidence in animals and in middle-age humans suggests that the pituitary hormone oxytocin reduces appetite, promotes weight loss, and improves glucose tolerance while preserving lean muscle mass. We studied oxytocin’s effect on body mass index (BMI), glucose tolerance, muscle mass, and physical function in an older adult population with sarcopenic obesity. Twenty-one older (≥60 yrs), obese (30-43 kg/m2), sedentary (&lt;2 exercise/week) adults with slow gait (&lt;1 m/sec) were randomized to either intranasal oxytocin (24 IU QID) or placebo for 8 wks. Those with diabetes, mod-severe chronic diseases, and cognitive impairment (Mini-Cog &lt;3) were excluded. Pre and post BMI, oral glucose tolerance test (OGTT), Hemoglobin A1c (HbA1c), physical function (short physical performance battery [SPPB]), and whole body lean and fat mass (via DXA) were assessed. Generalized linear mixed effects models were used to evaluate the effect of oxytocin on these measures. Age was 67.5 ±5.4 yrs, 71% were female, BMI was 36.0 ±3.6 kg/m2, fasting plasma glucose (FPG) was 92.0 ±8.9 mg/dL, HbA1c was 5.7 ±0.4%, 2-hour OGTT glucose was 140.8 ±4.1 mg/dL, SPPB was 9.2 ±1.9, fat mass was 45429.1 ±7037.4 g, and lean mass was 49892.4 ±10470.9 g. At 8 wks, total lean mass increased significantly (2,250 g) in the oxytocin group (pre- vs. post-treatment difference of -690.5 g in placebo and +1,559.5 g in the oxytocin group, p&lt;0.01). Oxytocin did not lead to significant changes in BMI, FPG, HbA1c, 2-hour OGTT glucose, fat mass or SPPB.
In conclusion, this preliminary data suggests that oxytocin leads to improvement in whole body lean mass. Future studies are needed in a larger population to determine whether older adults with sarcopenic obesity may benefit from treatment with oxytocin to improve lean muscle mass. Further work is needed to determine whether these improvements ultimately lead to improved physical function and other parameters of healthspan with aging.

Disclosure
S.E. Espinoza: None. J. Lee: None. C. Wang: None. D.J. MacCarthy: None. V. Ganapathy: None. C. Pascucci: None. N. Musi: None.

Funding
Claude D. Pepper Older Americans Independence Centers (University of Texas Health Science Center at San Antonio; University of Texas Medical Branch Galveston); Clinical Translational Science Award Programs (University of Texas Health Science Center at San Antonio; University of Texas Medical Branch Galveston); University of Texas Health Science Center at Houston
20-LB: Time since Diagnosis Is Associated with Subclinical Cardiovascular Disease in Adults with Type 1 Diabetes
Authors: RODRIGUEZ FATIMA M. , RIVAS BERNARDETTE , LARA CAROLINA , URIBE DANIEL , MARTAGON ALEXANDRO J. , ALMEDA-VALDES PALOMA , GARAY MORA JUAN A. , PEDRAZA NATALIA RAMIREZ 
Published: June 2020

Individuals with type 1 diabetes have increased morbidity and mortality due to cardiovascular disease (CVD), being the cause of death in 40% of these patients. A high proportion develop CVD before 50 years. Objective of this study was to explore factors associated with subclinical cardiovascular disease using aortic stiffness markers including pulse wave velocity (APWv), aortic augmentation index (AIx) and carotid intima-media thickness (cIMT).
Material and Methods: Cross-sectional study carried out in the Type 1 Diabetes Clinic of a tertiary center in Mexico City. Demographic and biochemical variables were evaluated. Anthropometric and body composition analysis was performed using bioelectrical impedance. Assessment of the APWv and cIMT was carried out using ultrasound and AIx with aortic tonometry. Statistical analyses were performed using SPPS version 21, a P value &lt; 0.05 was considered significant.
Results: 49 patients have been included, 25(51%)women. Mean age of the participants was 38.1±11.9 years. Mean age at diagnosis was 17± 8.8 years and time median time since diagnosis 20(range 6 to 43) 17± 8.8 years. A positive correlation was found between APWv and time since diagnosis, total cholesterol and visceral adipose tissue and a negative association with eGFR. The AIx showed positive correlation with time since diagnosis, age, body mass index (BMI) and systolic blood pressure. The cIMT showed a positive correlation with time since diagnosis, BMI and a negative association with eGFR. We did not find associations between the stiffness markers and A1c or albuminuria. In the linear regression analysis only time since diagnosis remained significantly and independently associated with the AIx after adjusting for age, BMI and systolic blood pressure.
Conclusions: This preliminary report shows that time since type 1 diabetes diagnosis is positively and independently associated with markers of aortic rigidity (AIx) in this population of young adults with type 1 diabetes.

Disclosure
F.M. Rodriguez: None. B. Rivas: None. C. Lara: None. D. Uribe: None. A.J. Martagon: None. P. Almeda-Valdes: None. J.A. Garay Mora: None. N. Ramirez Pedraza: None.
2033-P: In Vitro Analysis of Bisphenol A Effects on Beta-TC-6 Cells Function
Authors: ANASTASIOU IOANNA , ELEFTHERIADOU IOANNA , TENTOLOURIS ANASTASIOS , ANGELOPOULOU ANDRIANI , KOSTA OURANIA , MOUROUZIS IORDANIS , TENTOLOURIS NIKOLAOS 
Published: June 2020

Bisphenol A (BPA) is an organic compound that is widely used in plastic products. It acts as an endocrine disruptor capable of mimicking or modifying the activity of endogenous hormones. Recent data have shown that exposure to BPA increases the risk of type 2 diabetes. The aim of this study was to examine the effects of BPA on beta-TC-6 mice cells. Cells were incubated with serial dilutions of BPA: control group, 0.002μM, 0.02μM, 0.1μM, and 0.2μM for 12, 24, 48 and 72 hours. Cell viability and proliferation levels were determined by measuring intracellular ATP levels. BPA effects on beta-TC-6 cells were investigated by studying gene expression regulated at the transcriptional RNA level by real time PCR technique (citrate synthase and ATP synthase 6) and protein concentrations regulated at the translational levels by western blot analysis. The aging rate of cells was studied using SenTraGor TM. Exposure of beta-TC-6 cells to all BPA concentrations resulted in significant decreases of intracellular ATP levels when compared with the control group (all p&lt;0.05). Moreover, exposure of beta-TC-6 cells to 0,2μM BPA concentration for 24 and 48 hours resulted in significant increases in the relative gene expression levels and in increased expression of proteins involved in apoptosis. The percentage of aging cells was &gt;20% of total number of cells 24 hours after incubation at the 2 higher concentrations of BPA and was significantly increased when compared with the control group and the lower concentration of BPA. BPA affects viability, function and aging of beta-TC-6 cells. BPA presumably increases apoptosis rate and induces mitochondrial dysfunction on beta-TC-6 cells in a dose-dependent manner.

Disclosure
I. Anastasiou: None. I. Eleftheriadou: None. A. Tentolouris: None. A. Angelopoulou: None. O. Kosta: None. I. Mourouzis: None. N. Tentolouris: None.
2035-P: Involvement of Circular RNAs in Proinflammatory Cytokines-Mediated Beta-Cell Dysfunction
Authors: WANG ZHEN , ZHENG YING , ZHOU ZHIGUANG 
Published: June 2020

Background: Exposure of pancreatic β-cell to proinflammatory cytokines released by islet-infiltrating immune cells will lead to impaired insulin production and secretion as well as β-cell apoptosis during the initial phase of type 1 diabetes (T1D). Circular RNAs (circRNAs) were newly discovered as a novel class of non-coding RNAs that are involved in many diseases. As little is known about their role in insulin-secreting cells, this study aimed to evaluate their contribution to inflammation-induced β-cell dysfunction.
Methods: CircRNA expression proﬁle in MIN6 cells stimulated with a mix of cytokines, including IL-1β, IFN-γ, and TNF-α, was detected by circRNA microarrays. The diﬀerentially expressed circRNAs were validated by qRT-PCR. The involvement of selected circRNAs was tested after their inhibition in MIN6 cells. MicroRNA target prediction software and multiple bioinformatic approaches were used to construct a map of circRNA-microRNA-mRNA interactions and predict possible functions and pathways of the circRNAs.
Results: 1020 upregulated and 902 downregulated circRNAs were detected in cytokines-treated β-cells with a set filter fold-change ≧1.5. By qRT-PCR, circRNA 006029 and 013053 were furtherly proved to be increased by 2.1 fold and 3.7 fold, while circRNA 000286 and 017277 were downregulated by 3.4 fold and 1.9 fold. Inhibition of circRNA 000286 and 017277 in β-cells, with or without stimulation of cytokines, could promote β-cell apoptosis and affect glucose-induced insulin secretion. GO analysis enriched terms such as anatomical structure development and intracellular, and the top pathways included Pathways in cancer and MAPK signaling pathway. It was also speculated that the two circRNAs may regulate the key genes involved in β-cell apoptosis and function, such as Bcl2 and Vamp2.
Conclusion: Our data showed circRNAs as novel regulators in proinflammatory cytokines-mediated β-cell dysfunction, and suggested the involvement of circRNAs in the development of T1D.

Disclosure
Z. Wang: None. Y. Zheng: None. Z. Zhou: None.

Funding
National Natural Science Foundation of China (81502359)
2038-P: The Somatostatin Analog Pasireotide Reduces Pancreatic ß-Cell Function and Survival, and Both Incretin-Based Drugs and Irisin Revert These Effects
Authors: NATALICCHIO ANNALISA , BIONDI GIUSEPPINA , MARRANO NICOLA , VINCENTI LEONARDO , CIGNARELLI ANGELO , PERRINI SEBASTIO , LAVIOLA LUIGI , GIORGINO FRANCESCO 
Published: June 2020

Pasireotide is a new-generation somatostatin analog used for the treatment of acromegaly, Cushing’s disease and neuroendocrine tumors. However, due to its high affinity for somatostatin receptors (SSTR) 2 and 5, highly expressed in enteroendocrine- and pancreatic β-cells, it can reduce insulin, GLP-1 and GIP release and increase glucagonemia, causing marked hyperglycemia in some patients. The diabetogenic effects of pasireotide are significantly reduced in vivo by the co-administration of liraglutide or vildagliptin. The aim of this study was to evaluate the effects of pasireotide on β-cell survival and function, and the ability of molecules with known beneficial action on β-cells (incretin-based drugs and irisin, a myokine with β-cellular trophic properties) to prevent these effects. In INS-1E cells, both acute and chronic administration of pasireotide 10-50 nM reduced glucose-induced insulin secretion by 30% and 50% respectively and proinsulin mRNA levels by 20%, without altering cellular insulin content. Furthermore, pasireotide induced apoptosis in INS-1E cells and human pancreatic islets. Pretreatment with both incretin-based drugs (exendin-4, lixisenatide, liraglutide, saxagliptin) and irisin prevented pasireotide-induced apoptosis in INS-1E cells. In addition, pasireotide increased the protein levels of SSTR2 (2-fold) but not of SSTR5. Among the protective molecules examined, only irisin was able to prevent this increase.
In conclusion, pasireotide can induce hyperglycemia and diabetes via direct effects on β-cells, resulting in reduced insulin secretory capacity and survival. Both GLP-1 receptor agonists and DPP-4 inhibitors and irisin can reduce the proapoptotic effects of pasireotide, acting through partially different molecular mechanisms. These results demonstrate for the first time a functional antagonism between SSTR2/5 activation and incretin-based drugs or irisin in pancreatic β-cells.

Disclosure
A. Natalicchio: Consultant; Self; AstraZeneca, Novo Nordisk Inc., Sanofi-Aventis. G. Biondi: None. N. Marrano: None. L. Vincenti: None. A. Cignarelli: None. S. Perrini: None. L. Laviola: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Medtronic. F. Giorgino: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., LifeScan, Inc., MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Development Centre Europe Ltd.

Funding
Novartis
2042-P: Loss of Apoptosis Repressor with Caspase Recruitment Domain Promotes High-Fat Diet Induced Hyperglycemia In Vivo
Authors: TEMPLIN ANDREW T. , SCHMIDT CHRISTINE R. , HOGAN MEGHAN F. , ESSER NATHALIE , KITSIS RICHARD N. , HULL REBECCA L. , ZRAIKA SAKENEH , KAHN STEVEN E. 
Published: June 2020

Apoptosis repressor with caspase recruitment domain (ARC) is an endogenous inhibitor of apoptosis signaling. We previously showed ARC is expressed in β cells and ameliorates amyloid-induced β-cell death in vitro. More recently, we found that wild type (WT) and whole-body ARC knockout (KO) mice on an FVB background fed a normal chow diet exhibit no differences in islet area, β-cell area, or α-cell area at 16 (n=5) or 35 weeks (n=7-8) of age. In the present study, we sought to determine whether ARC plays a role in maintaining glycemia in response to the challenge of high fat diet (HFD, 60% kcal from fat) feeding in vivo. At 12 weeks of age, just prior to starting 24 weeks of HFD, ARC KO mice displayed lower body weight than WT mice (0 wks: 26.2±0.6 vs. 30.6±0.8 g; p&lt;0.01; n=13), and this weight difference persisted throughout the HFD study (24 wks: 44.7±2.5 vs. 51.9±1.0 g; p=0.04, n=4-9). Random plasma glucose (PG) was not different between genotypes prior to HFD feeding. With HFD challenge, PG increased significantly in ARC KO but not WT mice (see Table). This elevation in PG in ARC KO mice was observed after 4 weeks of HFD and remained throughout the study. These data indicate that loss of ARC promotes hyperglycemia in response to HFD feeding in vivo. Whether this hyperglycemia in ARC KO mice arises from impaired β-cell compensation due to reduced β-cell mass or function remains to be determined.

Disclosure
A.T. Templin: None. C.R. Schmidt: None. M.F. Hogan: None. N. Esser: None. R.N. Kitsis: None. R.L. Hull: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc.

Funding
U.S. Department of Veterans Affairs (I01-BX001060, IK2-BX004659); National Institutes of Health (P30DK017047)