bluuebunny/crossref_metadata_2025_split huggingface dataset:
42-OR: The Impact of GSNOR-Mediated Nitroso-Redox Signaling on Immuno-Metabolic Interaction in the Brown Adipose Tissue
Authors: SEBAG SARA , QIAN QINGWEN , ZHANG ZEYUAN , LI MARK , LIRA VITOR A. , POTTHOFF MATTHEW J. , YANG LING 
Published: June 2020

The thermogenic function of brown adipose tissue (BAT) is tightly regulated by cellular redox status, however, the molecular mechanism underlying this regulation is largely unknown. S-nitrosoglutathione reductase (GSNOR, Adh5) is a major denitrosylase that balances intracellular nitroso-redox status. Although GSNOR dysregulation has been implicated in the pathogenesis of many chronic diseases, the pathophysiological role of GSNOR in the BAT is completely unknown. We found cold exposure increased murine BAT GSNOR while diet-induced obesity (DIO) suppressed it, indicating a potential role for GSNOR in metabolic adaptation in the BAT. Mechanistically, we found that the transcription factor heat shock factor 1 (HSF1) occupies the Adh5 promoter activating Adh5 expression, while DIO inhibited the HSF1-GSNOR axis in the BAT. Notably, administration of a HSF1 enhancer to mice with DIO significantly improved glucose intolerance and BAT mitochondrial dysfunciton. Furthermore, GSNOR deletion in the BAT (GSNORBKO) suppressed UCP1-dependent respiration under both thermoneutral and cold acclimation conditions, as well as elevated immune cell infiltration in the BAT. This was in part mediated by increased BAT nitrosative stress and UCP1 S-nitrosylation induced by GSNOR deletion. Moreover, GSNORBKO mice have worsened DIO-induced glucose intolerance and decreased UCP1-mediated oxygen consumption. In contrast, gain-of GSNOR function in the BAT improved DIO-associated glucose intolerance, increased UCP1-dependent oxygen consumption and decreased DIO-induced inflammation. These data provide novel evidence that GSNOR plays a protective role in BAT against metabolic stressors. Ultimately, insights into the mechanisms by which dysregulation of nitroso-redox signaling impairs BAT metabolic homoestasis and drives the pathologies associated with obesity are expected to accelerate the development of novel therapeutic targets for metabolic diseases.

Disclosure
S. Sebag: None. Q. Qian: None. Z. Zhang: None. M. Li: None. V.A. Lira: None. M.J. Potthoff: None. L. Yang: None.

Funding
American Diabetes Association (1-18-IBS-149 to L.Y.)
420-P: Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists: A Systematic Review and Meta-analysis
Authors: ALEXANDER JASON , STAAB ERIN M. , WAN WEN , FRANCO MELISSA , KNITTER ALEXANDRA C. , THOMAS CELESTE C. , PRESS VALERIE G. , ZEYTINOGLU MELTEM , SKANDARI REZA , GUNTER KATHRYN E. , BINDON BRITTANY , JUMANI SANJAY , BOLEN SHARI D. , MARUTHUR NISA M. , HUANG ELBERT , PHILIPSON LOUIS H. , LAITEERAPONG NEDA 
Published: June 2020

Background: Several large randomized trials suggest GLP-1RAs may reduce mortality in addition to lowering A1c in patients with T2D. Treatment algorithms from the ADA/EASD now recommend a GLP-1RA be initiated in patients with T2D who either have or are at high risk of atherosclerotic cardiovascular (CV) disease, regardless of A1c level. To better quantify the efficacy and safety of GLP-1RAs, we conducted a systematic review and meta-analysis of all randomized trials of this drug class.
Methods: We searched PubMed and Scopus (inception to June 2019) for randomized trials of at least 52 weeks duration enrolling adults with T2D that compared GLP-1RAs with placebo. Outcomes included microvascular/macrovascular complications, mortality, change in cardiovascular risk factors, and adverse events. Continuous outcomes were calculated with standardized mean differences, and binary outcomes were calculated using odds ratios. Pooled analyses were performed with fixed and random effects models. Heterogeneity was assessed using the I2 statistic.
Results: See Table for results.
Conclusions: Patients with T2D who received GLP-1RAs when compared to placebo had a significantly lower rate of major adverse CV events and A1c. These findings support the current ADA/EASD treatment recommendations. Subsequent cost effectiveness analyses will help further inform healthcare policy decisions.

Disclosure
J. Alexander: None. E.M. Staab: None. W. Wan: None. M. Franco: None. A.C. Knitter: None. C.C. Thomas: None. V.G. Press: Consultant; Self; Humana, Vizient Inc. M. Zeytinoglu: None. R. Skandari: None. K.E. Gunter: None. B. Bindon: None. S. Jumani: None. S.D. Bolen: None. N.M. Maruthur: Other Relationship; Self; Johns Hopkins HealthCare Solutions. E. Huang: None. L.H. Philipson: None. N. Laiteerapong: None.

Funding
American Diabetes Association (1-18-JDF-037 to N.L.); National Institutes of Health (P30DK092949)
421-P: Efficacy and Safety of Sodium–Glucose Cotransporter-2 Inhibitors: A Systematic Review and Meta-analysis
Authors: ALEXANDER JASON , STAAB ERIN M. , WAN WEN , FRANCO MELISSA , KNITTER ALEXANDRA C. , THOMAS CELESTE C. , PRESS VALERIE G. , ZEYTINOGLU MELTEM , SKANDARI REZA , GUNTER KATHRYN E. , BINDON BRITTANY , JUMANI SANJAY , BOLEN SHARI D. , MARUTHUR NISA M. , HUANG ELBERT , PHILIPSON LOUIS H. , LAITEERAPONG NEDA 
Published: June 2020

Background: Several large randomized trials suggest SGLT2Is may reduce mortality in addition to lowering A1c in patients with T2D. Treatment algorithms from the ADA and EASD now recommend a SGLT2I be initiated in patients with T2D who have chronic kidney disease or heart failure, regardless of A1c level. To better quantify the efficacy and safety of SGLT2Is, we conducted a systematic review and meta-analysis of all randomized trials of this drug class.
Methods: We searched PubMed and Scopus (inception to June 2019) for randomized trials of at least 52 weeks duration enrolling adults with T2D that compared SGLT2Is with placebo. Outcomes included microvascular/macrovascular complications, mortality, change in cardiovascular (CV) risk factors, and adverse events. Continuous outcomes were calculated with standardized mean differences, and binary outcomes were calculated using odds ratios. Pooled analyses were performed with fixed and random effects models. Heterogeneity was assessed with the I2 statistic.
Results: See Table for results.
Conclusions: Patients who received SGLT2Is when compared to placebo had significantly lower rates of heart failure and A1c. These findings support the current ADA/EASD treatment recommendations. Subsequent cost effectiveness analyses will help further inform healthcare policy decisions.

Disclosure
J. Alexander: None. E.M. Staab: None. W. Wan: None. M. Franco: None. A.C. Knitter: None. C.C. Thomas: None. V.G. Press: Consultant; Self; Humana, Vizient Inc. M. Zeytinoglu: None. R. Skandari: None. K.E. Gunter: None. B. Bindon: None. S. Jumani: None. S.D. Bolen: None. N.M. Maruthur: Other Relationship; Self; Johns Hopkins HealthCare Solutions. E. Huang: None. L.H. Philipson: None. N. Laiteerapong: None.

Funding
American Diabetes Association (1-18-JDF-037 to N.L.); National Institutes of Health (P30DK092949)
428-P: Fatty Liver Disease Is Associated with Arterial Stiffness in Type 2 Diabetic Patients
Authors: HIGA MARIKO , HIJIKATA MAI , YAMASHITA KAORU , SUZUKI TAKAYUKI , SAITO MANABU , MICHISHITA MOE , IKEHARA KAYOKO , ICHIJO TAKAMASA 
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD), which is currently the most prevalent liver disorder, not only leads to chronic liver disease but is also associated with cardiovascular mortality. Several studies have conclusively established that increased arterial stiffness is an independent risk factor for cardiovascular events and that the brachial-ankle pulse velocity (baPWV) is a useful clinical indicator of arterial stiffness for early evaluation of functional and structural changes in vessel walls. The aim of this study was to assess whether ultrasonographically diagnosed fatty liver disease is associated with arterial stiffness and carotid intima-media thickness (CIMT) in type 2 diabetic patients. The subjects were 294 type 2 diabetic patients (age: 66.4±10.3 years). Patients with and without fatty liver (FL) were categorized into the FL group (n=155), and non-FL group (n=139), respectively. The baPWV was measured as an index of arterial stiffness, and structural changes in vessel walls were assessed using the CIMT obtained with B-mode ultrasonography. BMI, waist circumference, blood pressure, serum LDL-C, triglyceride (TG), and HbA1c levels, as well as the baPWV and CIMT levels were significantly higher in the FL than in the non-FL group. Serum levels of TG, hepatic AST, age, waist circumference and systolic blood pressure showed significant positive correlations with baPWV, respectively. However, no significant association was observed between the CIMT and serum hepatic AST levels. Multiple regression analysis showed that serum hepatic AST and ALT were independently associated with increased baPWV. Our findings suggest that NAFLD is associated with increased arterial stiffness. This is a clinically significant observation because it implicates arterial stiffness in the pathogenesis of NAFLD, suggesting that abdominal obesity and low-grade inflammation might be key etiopathogenetic contributors to both hepatic steatosis and macrovascular disease in type 2 diabetic patients.

Disclosure
M. Higa: None. M. Hijikata: None. K. Yamashita: None. T. Suzuki: None. M. Saito: None. M. Michishita: None. K. Ikehara: None. T. Ichijo: None.
430-P: Macrovascular Complications and the Diabetes Early Readmission Risk Indicator (DERRI) Predict Risk for Hospital Readmission at 90 Days
Authors: PINKHASOVA DIANA , SWAMI JANYA , PATEL NEETI , DONIHI AMY , SIMINERIO LINDA M. , DELISI KRISTIN , HLASNIK DEBORAH S. , RUBIN DANIEL J. , KORYTKOWSKI MARY T. 
Published: June 2020

Several risk factors for hospital readmission in patients with diabetes (DM) have been identified. The Diabetes Early Readmission Risk Indicator (DERRITM) is a tool that identifies patients at high risk for readmission within 30 days of hospital discharge, but does not incorporate several DM specific factors such as type of DM and pre-discharge glycemic measures. The purpose of this investigation was to prospectively examine DM specific factors and DERRI scores as predictors of readmission risk at 90 days in participants in the Readmission and Comprehension of Discharge Education in Diabetes (RECODED) study. Among the 126 patients, (age mean (STD) 61(12) yrs, BMI 32.9 (9.6) kg/m2, A1c 8.0 (2.2%), 45% women, 22% Black, 85% type 2 DM), readmission occurred in 54 (42.9%) of patients within 90 days of discharge. Factors identified as predicting risk for hospital readmission included the presence of known macrovascular (CAD, p = 0.039; CHF, p = 0.029; CVA, p = 0.054) but not microvascular complications. DERRI scores were higher in those with a readmission compared to those without (27 ± 12% vs. 20 ± 11%, p = 0.006).No differences were observed for age, BMI, type of diabetes, eGFR, history of DM self-management education, inpatient DM service consultation, education level, employment history, A1c, pre-discharge hypoglycemia, hyperglycemia or glycemic variability, or hospital length of stay among those with and without a readmission.
In summary, these results reinforce the complexity of identifying risk factors for hospital readmission in DM patients. Certain macrovascular complications, which are collectively components of the DERRI, individually demonstrate an association with readmission risk at 90 days, as does DERRI. This is the first demonstration of DM related macrovascular complications and DERRI score as a predictor of readmission beyond 30 days of hospital discharge.

Disclosure
D. Pinkhasova: None. J. Swami: None. N. Patel: None. A. Donihi: None. L.M. Siminerio: Research Support; Self; Becton, Dickinson and Company. K. Delisi: None. D.S. Hlasnik: None. D.J. Rubin: None. M.T. Korytkowski: None.

Funding
National Institutes of Health (UL1TR001857)
458-P: Resveratrol Attenuates Diabetic Cardiomyopathy by Inhibiting Asymmetric Dimethylarginine-Induced PGC-1a Acetylation
Authors: XIONG YAN , FANG WEI-JIN , HE ZHI-MIN 
Published: June 2020

The cardiac protection of resveratrol may due to improvement of mitochondrial function through SIRT1 activation and PGC-1α deacetylation. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, is associated with diabetic cardiovascular complications and reported to have cross-talk with lysine acetylation in cells. This study was to determine the role of ADMA in the pathogenesis of diabetic cardiomyopathy, whether resveratrol could revise ADMA-induced pathological changes and elucidate the underlying mechanisms in rat model of type 2 diabetes mellitus (T2DM). Resveratrol was orally administered (50mg/kg/d) to T2DM rats for 16w. Echocardiography was performed to detect cardiac function. Contents of myocardial ATP and mitochondrial DNA were measured to evaluate mitochondrial function and biogenesis. Elevated endogenous ADMA content and its signal disorders were associated with cardiac and mitochondrial dysfunction in the myocardium of T2DM rats compared with control rats. Treatment with resveratrol significantly attenuated endogenous ADMA accumulation and cardiac dysfunction, increased myocardial mitochondrial DNA and ATP contents, as well as upregulated PGC-1α expression in the myocardium of resveratrol-treated diabetic rats compared with untreated diabetic rats. A positive feedback was observed in vitro that elevated ADMA return promoting its synthetic enzyme PRMT1 expression, reducing its metabolic enzymes DDAH2 expression, reproducing myocardial hypertrophy and mitochondrial dysfunction. Resveratrol treatment could reverse these pathological changes. More importantly, ADMA could enhance PGC-1α acetylation and reduced SIRT1 expressions, all of which were antagonized by resveratrol in cardiomyocytes. These results suggest that ADMA-induced PGC-1α hyperacetylation may serve as potential therapeutic targets for resveratrol to improve diabetic cardiomyopathy.

Disclosure
Y. Xiong: None. W. Fang: None. Z. He: None.

Funding
National Natural Science Research Foundation of China (81570751); Natural Science Foundation of Guangdong Province (2016A030311050)
459-P: Liver-Targeted Mitochondrial Uncoupling by CRMP Improves Whole-Body Insulin Sensitivity and Attenuates Atherosclerosis in A LDLR-/- Mouse Model of Metabolic Syndrome
Authors: GOEDEKE LEIGH , ROTLLAN NOEMI , TOUSSAINT KESHIA , NASIRI ALI , ZHANG XINBO , LEE JI EUN , ZHANG XIAN-MAN , FERNÁNDEZ-HERNANDO CARLOS , SHULMAN GERALD I. 
Published: June 2020

Progress in preventing cardiovascular disease (CVD) has been stalled by the growing epidemic of type 2 diabetes, which increases the relative risk of developing atherosclerosis four-fold compared to nondiabetic individuals. We recently developed an orally available, liver-targeted controlled release mitochondrial protonophore (CRMP) that promotes oxidation of hepatic triglycerides by promoting a subtle sustained increase in hepatic mitochondrial inefficiency and shown that this agent safely reverses dyslipidemia, fatty liver, and insulin resistance in rodents and nonhuman primates. While these studies suggest that CRMP may be a novel therapy for the major components of metabolic syndrome, its therapeutic utility for the treatment of CVD remains unknown. To assess the effect of CRMP on atherogenesis, we performed progression studies in Ldlr-/- mice fed a high-fat cholesterol diet and treated with CRMP (30 mg/kg-day) or vehicle control for 12 weeks. Here, we show that CRMP-treated mice display a 30% reduction in fasting plasma triglycerides (which could be attributed to a 20% decrease in VLDL-production) and a significant improvement in both hepatic and peripheral insulin sensitivity, due to reductions in hepatic and muscle ectopic lipid content. Importantly, CRMP-mediated decreases in hypertriglyceridemia and improvements in whole-body insulin sensitivity were associated with a 30% reduction in aortic root plaque area and neutral lipid accumulation (P&lt;0.05). More detailed analysis of these plaques revealed that CRMP treatment also significantly lowered markers of plaque vulnerability, as evidenced by a 30% reduction in necrotic core area and increase in fibrous cap area (P&lt;0.05).
Conclusion: Taken together, these results support an anti-atherogenic role for CRMP and suggest the therapeutic potential of liver-targeted mitochondrial uncouplers for the treatment of cardiometabolic disorders.

Disclosure
L. Goedeke: None. N. Rotllan: None. K. Toussaint: None. A. Nasiri: Employee; Spouse/Partner; Medtronic. X. Zhang: None. J. Lee: None. X. Zhang: None. C. Fernández-Hernando: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, LLC, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Consultant; Self; Novo Nordisk A/S. Consultant; Spouse/Partner; Novo Nordisk A/S. Other Relationship; Self; Gilead Sciences, Inc., iMetabolic Biopharma Corporation. Other Relationship; Spouse/Partner; iMetabolic Biopharma Corporation. Other Relationship; Self; Maze Therapeutics.

Funding
National Institutes of Health (R01DK119968, R01DK116774, P30DK045735 to G.I.S.), (K99 HL150234 to L.G.)
46-OR: The Transcriptional Coregulator Ldb1 Directly Regulates Brown Adipose Thermogenic Function
Authors: KEPPLE JESSICA , LIU YANPING , KIM TEAYOUN , HABEGGER KIRK M. , YOUNG MARTIN , HUNTER CHAD S. 
Published: June 2020

Brown adipose tissue (BAT) is critical for mammalian thermogenesis. BAT utilizes fatty acids and glucose for heat production via mitochondrial uncoupling and is thus an attractive therapeutic target for combatting obesity. Exploiting the energy uncoupling capacity of this tissue will require a greater understanding of underlying BAT transcriptional mechanisms. Our prior work using a global deficiency model supported a novel role for the LIM domain-binding protein 1 (Ldb1) transcriptional co-regulator in regulating BAT function. However, direct roles for Ldb1 expressed in brown adipocytes has not been tested. Ldb1 acts as a scaffold to promote the assembly of transcriptional complexes and is important for the development and function of several metabolic tissues. We hypothesized that Ldb1 maintains BAT thermogenic function through direct regulation of thermogenic genes, like Ucp1. Loss of Ldb1 in primary brown adipocytes resulted in reduced expression of BAT-selective genes including Ucp1 and Elovl3 and the inability to induce Ucp1 expression upon Beta-3 adrenergic receptor agonism. This result was replicated using a siLdb1-transfected Ucp1-expressing cell line. To test Ldb1 roles on systemic thermogenesis, we developed a mouse model, termed Ldb1ΔBAT, where Ldb1 was reduced in thermogenic adipocytes using a Ucp1-driven Cre recombinase. Similar to our in vitro observations, Ldb1ΔBAT mice had reduced mRNAs of key BAT genes, including Ucp1 and Cidea. Through indirect calorimetry and a cold challenge, we uncovered significant impairments in energy expenditure and cold intolerance in Ldb1ΔBAT mice. To assess the transcriptional mechanisms underlying Ldb1 impacts on BAT thermogenesis, we conducted chromatin immunoprecipitation and found Ldb1 occupied upstream regulatory domains of Ucp1 in chromatin prepared from a BAT cell line and primary tissue. Overall, this work supports that Ldb1 is required for the thermogenic function of brown adipocytes.

Disclosure
J. Kepple: None. Y. Liu: None. T. Kim: None. K.M. Habegger: Consultant; Self; Glyscend, Inc. Research Support; Self; Daiichi Sankyo, Novo Nordisk Inc. M. Young: None. C.S. Hunter: None.

Funding
National Institutes of Health (R01DK111483, F31DK121414, T32GM109780)
471-P: Transplantation of Apoptosis Resistant Endothelial Progenitor Cells (EPC) May Improve Renal Function in Both Type 1 and 2 Diabetic Kidney Disease (DKD)
Authors: KUNDU NABANITA , ASICO LAUREANO D. , JOSE PEDRO A. , SEN SABYASACHI 
Published: June 2020

Introduction: DKD is associated with glomerulosclerosis and poor perfusion. Transplanting apoptosis resistant p53 silenced (p53sh) EPCs may help to increased vascularization and renal perfusion. EPCs are known to improve perfusion and could be more beneficial than mouse mesenchymal stromal cell (mMSC) transplantation.
Method: Hyperglycemia and proteinuria were confirmed at 10 weeks in STZ induced type 1 diabetic C57BL mice and db/db mice for type 2 diabetes mellitus (DM). We transplanted 0.3 million p53sh-EPCs, Null EPCs (control), MSC or saline under each kidney capsule. For type 2 DM model, we also transplanted supernatant of p53sh EPC. Urine was collected weekly for creatinine and protein estimation. Perfusion was measured by renal ultrasound at week 4 post transplantation. Kidneys were harvested for qRT PCR.
Results: In type 1 DM model, reduction of protein/creatinine was observed in p53sh EPC transplantation group compared to null and mMSC (1.8 and 1.6 folds, p=0.03. 0.04 respectively) significantly. KDR expression was increased (1.2 fold, p=0.04) on p53sh EPC transplantation compared to null. We observed increased mean and peak renal blood velocity (1.3 folds, p= 0.01, 1.3 fold p=0.001 respectively) in p53sh EPC transplant group compared to null. In type 2 model, 2 fold reduction of protein concentration was noted in p53sh transplanted group compared to null and mMSC groups. Reduction of plasma TNFa, a marker for systemic inflammation was decreased by 2.7 and 1.6 folds in p53sh EPC group in comparison to null-EPC and mMSC respectively. We also noticed that blood glucose level decreased post treatment in all cell therapy groups including the supernatant group, compared to saline, indicating a possible paracrine systemic effect of the cell and supernatant therapy.
Conclusion: Transplantation of p53sh EPC improves renal perfusion and renal function in both type 1 and type 2 DM and it is more beneficial than transplantation of mMSC.

Disclosure
N. Kundu: None. L.D. Asico: None. P.A. Jose: None. S. Sen: None.