bluuebunny/crossref_metadata_2025_split huggingface dataset:
Research into the Effect of Sodium-Glucose Linked Transporter 2 Inhibition on Left Ventricular Remodeling in Patients with Heart Failure and Diabetes Mellitus
Authors: SINGH JAGDEEP S.S. , MORDI IFY , MOHAN MOHAPRADEEP , GANDY STEPHEN J. , PEARSON EWAN , HOUSTON JOHN G. , STRUTHERS ALLAN D. , LANG CHIM C. 
Published: June 2018

Introduction: DM and heart failure (HF) are lethal, with limited diabetic therapy options. Sodium-glucose linked transporter 2 (SGLT2) inhibitors have been reported to have CV benefits in at risk DM patients. We are the first to study the CV effects of SGLT2 inhibition in patients with DM and HF.
Methods: In this randomized double-blind placebo controlled trial, 56 patients (mean age: 67.1 years, males: 66%) with DM and echocardiographically confirmed HF with reduced ejection fraction (HFrEF) on regular diuretic therapy were assigned to dapagliflozin 10mg OD or placebo for one year. Primary endpoint was the difference in left ventricular (LV) volumes between both groups using cardiac MRI. Secondary endpoints include LV mass, LV ejection fraction (EF), weight, BP and diuretic use. Outcomes were analysed using linear regression controlling for baseline values, age, sex and renal function.
Results: There was no difference between dapagliflozin and placebo in the primary endpoints of LV end diastolic volume (LVEDV) or LV end systolic volume (LVESV); +4.71mls; 95% CI: -17.to 26.50 and +1.52mls; 95% CI: -15.68 to 18.72 respectively. However, when an interaction term for starting LVEF was added to the model, dapagliflozin significantly lowered LVEDV, LVESV and LV mass in those with starting LVEF ≥ 45%; -15.59mls; p=0.019, -15.20mls; p=0.016 and -4.87gm/m2; p=0.026. Patients on dapagliflozin had weight reduction; -1.90kg; 95% CI: -3.83 to +0.04; p=0.054, lower diastolic BP; -6.34mmHg; 95% CI: -11.35 to -1.32; p=0.014 and higher hemoglobin; +1.23 g/dl; 95% CI: 0.65 to 1.82; p&lt;0.001. They were also more likely to stop or reduce loop diuretics; 50.0% vs. 8.7%; p=0.005.
Conclusions: Our data show dapagliflozin treatment resulted in weight and blood pressure reduction among patients with DM and HFrEF. There was evidence to suggest that dapagliflozin may cause LV reverse remodelling in DM patients with mild, but not with more severe HFrEF.

Disclosure
J.S.S. Singh: None.I. Mordi: None.M. Mohan: None.S.J. Gandy: None. E. Pearson: Speaker's Bureau; Self; Eli Lilly and Company.J.G. Houston: None. A.D. Struthers: Research Support; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca.C.C. Lang: None.
Dapagliflozin plus Saxagliptin Shows Noninferior A1C Reduction vs. Insulin Glargine in Patients with Type 2 Diabetes Inadequately Controlled by Metformin With or Without Sulfonylurea
Authors: VILSBØLL TINA , EKHOLM ELLA , JOHNSSON EVA K. , DRONAMRAJU NALINA , JABBOUR SERGE , LIND MARCUS 
Published: June 2018

This international, multicenter, randomized, open-label phase 3b trial (NCT02551874) evaluated the efficacy and safety of dapagliflozin (DAPA) 10 mg/day plus saxagliptin (SAXA) 5 mg/day vs. titrated insulin glargine (INS) in patients with type 2 diabetes (T2D) poorly controlled by metformin (MET) ≥1500 mg/day ± sulfonylurea (SU) ≥50% maximum dose (A1C levels 8-12%). The primary end point was change in A1C from baseline to week 24; DAPA + SAXA was tested for non-inferiority vs. INS. Secondary end points were: change in body weight; proportions of patients a) with hypoglycemia, b) achieving A1C &lt;7% without hypoglycemia, c) achieving A1C &lt;7% at week 24; and change in 24-hour glucose at week 2 assessed by continuous glucose monitoring. Mean±SD baseline data were age 55.5±9.6 years; A1C 9.1±1.0%; BMI 32.2±5.3 kg/m2, and were similar in both arms. DAPA + SAXA resulted in non-inferior reductions in A1C without weight gain, reductions in mean 24-hour glucose, and was associated with a lower prevalence of hypoglycemia and a greater proportion of patients achieving A1C &lt;7% without hypoglycemia vs. INS (Table); there were no additional safety concerns. DAPA + SAXA therapy resulted in similar glycemic control, prevented weight gain and reduced risk of hypoglycemia compared with titrated INS in patients with T2D poorly controlled by MET ± SU.

Disclosure
T. Vilsbøll: None. E. Ekholm: None. E.K. Johnsson: Employee; Self; AstraZeneca. N. Dronamraju: None. S. Jabbour: None. M. Lind: Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eli Lilly and Company. Advisory Panel; Self; MSD K.K.. Research Support; Self; Pfizer Inc.. Consultant; Self; Medtronic.
Integrative Analysis of Human Plasma Proteome/Metabolome Reveals Central Role for Phospholipid, Retinol, and Histidine Metabolism after Gastric Bypass
Authors: DREYFUSS JONATHAN , YUCHI YIXING , PAN HUI , SIMONSON DONALD C. , VERNON ASHLEY H. , ARYAL PRATIK , KAHN BARBARA , FOSTER KATHLEEN , KASIF SIMON , GOLDFINE ALLISON , PATTI MARY E. 
Published: June 2018

Bariatric surgery has emerged as a potent approach to improve obesity-related metabolic comorbidities including type 2 diabetes (T2D). However, molecular mechanisms responsible for metabolic improvement after bariatric surgery remain incompletely understood. We profiled and integrated the fasting plasma proteome (aptamer-based Somalogic platform) and metabolome (MS, Metabolon) from patients with T2D at baseline and up to 3 years after randomization to either gastric bypass (GB) or nonsurgical diabetes/weight management (DMW) within the SLIMM-T2D longitudinal clinical trial (random subset, n=19 per group). To identify top-ranking pathways encompassing both proteomic and metabolomic data, we developed a systems approach employing two interdependent programs: ezlimma (for differential analysis) and Pathway Analysis via Network Smoothing (PANTS). PANTS smooths differential statistics over a large network of interacting proteins/metabolites, calculating significance by permutation. Top-ranking pathways were phospholipid (e.g., choline), retinol (e.g., retinol-binding protein 4, RBP4), and histidine metabolism (e.g., carnosine dipeptidase 1, CNDP1). Quantitative Western blot confirmed 26% reduction in RBP4 in GB vs. DWM; ELISA confirmed 66% reduction in CNDP1 in GB vs. DWM (both p&lt;0.05, 3 months). CNDP1 change at 3 months was associated with improved metabolism at 1 year (BMI r=0.67, p&lt;10-5; HbA1c r=0.61, p&lt;10-4). Causal inference analysis in the entire cohort identified CNDP1 change at 3 months as the most likely protein to cause improved HbA1c at 1 year (p=0.01). Decreased CNDP1 occurred before significant weight loss, suggesting weight-independent impact on glycemia. Investigating modulation of CNDP1 activity, its enzymatic products Ala/His, and related metabolites will be important to determine if these pathways may serve as targets for T2D therapy.

Disclosure
J. Dreyfuss: None. Y. Yuchi: None. H. Pan: None. D.C. Simonson: Advisory Panel; Self; GI Windows, Inc.. Stock/Shareholder; Self; GI Windows, Inc.. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. A.H. Vernon: None. P. Aryal: None. B. Kahn: Advisory Panel; Self; Janssen Research & Development. Research Support; Self; Janssen Research & Development. Advisory Panel; Self; Alterna Biotech. K. Foster: None. S. Kasif: None. A. Goldfine: Employee; Self; Novartis AG. M.E. Patti: Research Support; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. Research Support; Self; Ethicon US, LLC., Coviden, MedImmune. Other Relationship; Self; Novo Nordisk Inc., XOMA Corporation, AstraZeneca, Nestlé. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eiger BioPharmaceuticals.
HLA-C Position 275, a Novel HLA Locus Identified in Autoantibody-Positive Type 1 Diabetes of Chinese Han Population Based on a Genome-Wide Association Study
Authors: XU KUANFENG , CHEN YANG , GU YONG , ZHU MENG , ZHANG MEI , SUN MIN , XU XINYU , HSU HSIANG-TING , CHEN HENG , SHI YUN , CAI YUN , DAI HAO , ZHENG SHUAI , ZHENG XUQIN , ZHOU HONGWEN , YU LIPING , HU ZHIBIN , ZHOU ZHIGUANG , WENG JIANPING , SHEN HONGBING , YANG TAO 
Published: June 2018

Type 1 diabetes (T1D) is a highly heritable autoimmune disease. Although more than 50 non-HLA risk loci have been identified, the strongest associations were observed in HLA regions in Caucasian populations. The aim of this study is to identify T1D risk HLA loci in Chinese Han population and explore the risk prediction models based on these loci. A two-stage genome-wide association study (GWAS) of T1D (at least one autoantibody positive) was performed in Chinese Han population, the GWAS scan was conducted by the Illumina Human OmniZhongHua platform and included 1,045 T1D cases and 1,3controls, and the replication included 1,378 cases and 3,774 controls. Promising associations were further validated by combining with the data from the Wellcome Trust Case Control Consortium (WTCCC). Association analyses for T1D used logistic regression models assuming additive effects. Results from different stages were combined with fixed effects model in meta-analysis. In the GWAS scan stage, we identified 18 distinct genomic regions with P-values &lt;1.00×10-5. As expected, the strongest associations with T1D were located in the HLA region, and rs1770 at MHC (OR=4.54, P&lt;1.00×10-324), a previously identified Caucasian T1D risk locus, showed the strongest association after combining the results from different stages. Further fine mapping in the HLA region identified five independent risk loci, a novel Chinese specific locus HLA-C position 275 (P=9.78×10−12) was discovered except for rs1770, HLA-DRB1 position 11, HLA-DRB1 position74, and HLA-A position 9. Risk prediction model based on these five independent loci of HLA can achieve an AUC of 0.85 (0.84-0.87). A s the primary T1D GWA study in Asian population to date, the results identified a Chinese specific HLA locus and would be the basis of precision medicine of Chinese T1D by risk prediction based on the identified HLA loci.

Disclosure
K. Xu: None. Y. Chen: None. Y. Gu: None. M. Zhu: None. M. Zhang: None. M. Sun: None. X. Xu: None. H. Hsu: None. H. Chen: None. Y. Shi: None. Y. Cai: None. H. Dai: None. S. Zheng: None. X. Zheng: None. H. Zhou: None. L. Yu: None. Z. Hu: None. Z. Zhou: None. J. Weng: None. H. Shen: None. T. Yang: None.
Unraveling the Athlete’s Paradox—Higher Insulin Sensitivity and Lower PKC? Activation Despite Higher Bioactive Lipids in Endurance-Trained Athletes
Authors: PESTA DOMINIK , ANADOL-SCHMITZ EVRIM , GANCHEVA SOFIYA , MARKGRAF DANIEL F. , ZAHARIA OANA P. , KATSUYAMA HISAYUKI , KUPRIYANOVA YULIYA , HWANG JONG-HEE , ZHANG DONGYAN , SHULMAN GERALD I. , RODEN MICHAEL 
Published: June 2018

High intramyocellular lipid (IMCL) content associates negatively with insulin sensitivity (IS) in insulin resistant, but not in endurance-trained humans. It has been hypothesized that different cellular distribution of bioactive lipids such as diacylglycerols (DAG) and ceramides (CER) could interfere with insulin action and underlie this “athlete’s paradox.” We examined endurance-trained athletes (ATH; n=9) and sedentary individuals (SED; n=12) with comparable total IMCL, as measured by 1H-magnetic resonance spectroscopy, who underwent spiroergometry and hyperinsulinemic-euglycemic clamps to assess maximal oxidative capacity and IS, respectively. In skeletal muscle biopsies, translocation of protein kinase C (PKC) θ and ε were determined by Western blotting and concentrations of DAG and CER were measured using targeted LC-tandem mass spectrometry upon separating fractions of cellular membranes, lipid droplets and cytosol by ultracentrifugation. Maximal oxidative capacity and IS were 46% and 47% higher in ATH than in SED (both p&lt;0.01), respectively. The membrane:cytosol ratio of PKCθ, which reflects PKCθ activity, was 62% lower in ATH consistent with their increased IS (p&lt;0.01), while there was no group difference for PKCε. Total and membrane DAG (40% and 48%, both p&lt;0.01) as well as membrane CER (15%, p&lt;0.05) were higher in ATH while the respective concentrations in lipid droplets and cytosol did not differ. In SED, IS correlated inversely with all stereoselective subspecies of lipid-droplet DAG. On the other hand, cytosolic sn-1,2 (C16:0-C18:2) and sn-1,3 (C18:1-C18:0) DAG correlated positively with IS in ATH.
In conclusion, higher IS in endurance-trained ATH can be explained by lower muscle PKCθ activation, which may be due to differences in the stereoselectivity and/or subcompartmentation of cellular DAG between ATH and insulin resistant SED.

Disclosure
D. Pesta: None. E. Anadol-Schmitz: None. S. Gancheva: None. D.F. Markgraf: None. O.P. Zaharia: None. H. Katsuyama: None. Y. Kupriyanova: None. J. Hwang: None. D. Zhang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi.
HuR Influences Metabolic Flexibility in Skeletal Muscle
Authors: WARFEL JAYCOB D. 
Published: June 2018

Metabolic Flexibility allows for the oxidation of fuels based on their availability. Respiratory Quotient (RQ) values from subjects with type 2 diabetes mellitus in both basal and insulin stimulated states remain consistent, indicating a decreased ability to switch between available substrates. The molecular mechanisms governing defects in this switching ability are unclear at present. We therefore compared global gene expression in skeletal muscle between obese subjects classified by their sleep and 24 hour RQ as either metabolically flexible or inflexible. From this data we identified a number of transcripts stabilized by the RNA binding protein, HuR, which were enriched in metabolically flexible subjects. This finding prompted us to generate mice with a skeletal muscle specific knockout of Elavl1, the gene encoding HuR (HuRm-/-). HuRm-/- mice have a metabolically inflexible phenotype with mild obesity and impaired glucose tolerance compared to control littermates. HuRm-/- mice have an increase in RER; and decreased expression of genes involved in oxidative phosphorylation, fatty acid transport, and mitochondrial fatty acid metabolism, suggesting a decreased ability to use fats as an energy source. HuRm-/- mouse skeletal muscle also shows decreases in protein levels of important modulators of the mTOR signaling pathway, and compensatory increases in transcript levels of HuR target mRNAs. These data highlight the importance of HuR function in skeletal muscle metabolism; and suggest HuR as a mediator of metabolite selection.

Disclosure
J.D. Warfel: None.
Reprograming of Human Adipocytes to a Briter Phenotype—Enhanced Fatty Acid Oxidation and Lipid Droplet Remodeling
Authors: LEE MI-JEONG , JASH SUKANTA , PURI VISHWAJEET , FRIED SUSAN K. 
Published: June 2018

Converting energy storing white adipocytes to energy wasting ‘brite’ ones is now recognized to be feasible and may confer protection against obesity and its related cardiometabolic diseases. Fragments of omental and subcutaneous human adipose tissues were cultured for 7 days with insulin and dexamethasone with or without rosiglitazone (rosi) to induce britening. Rosi caused a metabolic reprograming of the adipocytes including increased rates of basal FA oxidation and the expression of mRNAs and proteins in multiple pathways that modulate FA metabolism, triacylglycerol synthesis, cellular FA trafficking, and mitochondrial oxidative capacity (PGC1a, UCP1, CIDEA, PLIN5, FABP3). Furthermore, these changes were associated with a dramatic remodeling of the surface of the adipocyte lipid droplet (LD) such that clusters of small LDs decorated with mitochondria were formed. Formation of these small LDs was blocked by inhibition of lipolysis and required FA activation and reesterification. Surprisingly, both omental and subcutaneous adipocytes were similarly ‘britened’. A similar remodeling was induced in primary cultures of newly-differentiated human adipocytes and these cells showed higher rates of basal and maximally-stimulated oxygen consumption. Consistent with transcriptome changes in both systems, lipidomics showed increased levels of unsaturated FAs, phospholipid species, and cardiolipins in brite cells. Taken together, these results identify a coordinated metabolic and structural reprogramming of mature human adipocytes toward a more oxidative phenotype. Although rosi has unacceptable clinical side effects, knowledge of the downstream effectors of this metabolic improvement may lead to development of targeted approaches to improve adipocyte and metabolic health and prevent type 2 diabetes in human obesity.

Disclosure
M. Lee: None. S. Jash: None. V. Puri: None. S.K. Fried: None.
Effects of Acute Experimental Hyperglycemia on Oxidative Markers and AGE-RAGE Dynamics in Obese Humans
Authors: PERKINS RYAN , MIRANDA EDWIN R. , KARSTOFT JR. KRISTIAN , BEISSWENGER PAUL J. , SOLOMON THOMAS P. , HAUS JACOB M. 
Published: June 2018

Chronic hyperglycemia promotes oxidative stress and advanced glycation end product (AGE) formation, leading to recognition by the AGE receptor (RAGE). AGE-RAGE binding and inflammation perpetuates diabetic complications, however the study of these phenomenon present inherent challenges in vivo. Therefore, our purpose was to evaluate the effects of acute experimental hyperglycemia on AGEs, oxidative markers, and RAGE expression in healthy, obese subjects (n=10; 31.2±1.2 kg/m2; 56±3 y) subjected to hyperglycemic clamps (+5.4 mM above basal). Plasma was assayed at baseline, 2, and 24 h post glucose-infusion for well-known AGE-free adducts (CML, CEL, G-H1, MG-H1, 3DG-H) and oxidative markers (MethSO, AAA) via LC-MS/MS as well as soluble RAGE (sRAGE) isoforms via ELISA. Urine was also assayed (basal and 24 h) for AGEs and oxidative markers (normalized to creatinine) and skeletal muscle biopsies were used to study RAGE expression via Western blot. Most circulating factors (MethSO, AAA, CEL, MG-H1, and G-H1) decreased (p&lt;0.05) over time, while CML increased (p&lt;0.05) and 3DG-H remained unchanged (p&gt;0.05). In urine, only MethSO was seen to increase at 24 h (p&lt;0.05). Plasma:Urine ratios were decreased (p&lt;0.05) for MethSO, AAA, CML, MG-H1, while ratios were increased (p&lt;0.05) for CML. All species of sRAGE isoforms (total, cleaved and esRAGE) were unchanged (p&gt;0.05). In skeletal muscle tissue, there was a trend (p&lt;0.1) for decreased RAGE protein expression at 2 h which returned to baseline at 24 h. This study demonstrates AGEs and oxidative markers are sensitive to the physiological dynamics of acute hyperglycemia in obese, but otherwise healthy humans. The differential findings presented here were surprising and may be explained by increased AGE-RAGE binding or AGE sequestration, osmotic diuresis and/or oxidative defense mechanisms. These findings are relevant for postprandial glucose excursions and highlights the importance of appropriate glucose management.

Disclosure
R. Perkins: None. E.R. Miranda: None. K. Karstoft: None. P.J. Beisswenger: Employee; Self; PreventAGE Health Care, LLC.. T.P. Solomon: None. J.M. Haus: None.
Targeting the Amyloid Precursor Protein (APP) to Mitochondria of White Adipose Tissues Triggers Mitochondrial Dysfunction and Obesity
Authors: AN YU A. , SCHERER PHILIPP E. 
Published: June 2018

The role of mitochondrial dysfunction in white adipose tissues (WAT) under different metabolic conditions is not well understood. Here, we report that under high fat diet (HFD) conditions, endogenous production of APP is significantly induced and, instead of being secreted, the protein is highly enriched in WAT mitochondria. To better understand the role of APP, we established an inducible model by directing the full-length APP with a mitochondrial targeting presequence quantitatively to mitochondria, selectively in adipocytes. We validated that APP mRNA and protein levels were significantly elevated in subcutaneous WAT, and the protein was markedly accumulated in isolated mitochondria from sWAT. EM imaging suggested widespread loss of mitochondrial cristae. Respiratory measurements on a Seahorse instrument revealed a rapid impairment in mitochondrial functions in sWAT, concomitant with an increase in adipocyte size within a few days. APP transgenic mice displayed significantly enhanced fat mass, along with impaired glucose tolerance and reduced insulin sensitivity under a long term HFD challenge. By H and E staining, we observed widespread inflammatory cell infiltration in WAT, and consistent with the adipose tissue dysfunction, we also noticed massive hepatic steatosis. Adiponectin levels in plasma and sWAT were significantly reduced. We specifically eliminated endogenous APP in WAT through a conditioned knock-out mouse model (Appflox/flox) to demonstrate that adipocyte-specific deletion of APP can ameliorate high fat diet-induced mitochondrial dysfunction.
In summary, accumulated APP in WAT mitochondria significantly induces mitochondrial dysfunction in adipocytes, leading to unhealthy adipose tissue expansion and eventually resulting in obesity and systemic insulin resistance.

Disclosure
Y.A. An: None. P.E. Scherer: None.
HOXC10 Maintains White Adipose Tissue Identity and Its Loss Leads to Enhanced Browning of White Adipose Tissues
Authors: TAN ANGELINE H.Y. , GUN SINYEE , HAN WEIPING 
Published: June 2018

Increased thermogenesis via increased beige fat development enhances energy expenditure and improves glucose homeostasis. However, thermogenic mechanisms regulating beige adipogenesis within white adipose tissue (WAT) are less understood. The homeobox-containing transcription factor, HOXC10, is traditionally thought to regulate musculoskeletal and patterning of limb development in mammals. We found that HOXC10 is expressed in subcutaneous WAT. Ectopic expression of HOXC10 in adipocytes suppressed brown markers genes, while knockdown of HOXC10 upregulates brown genes expression. To investigate the functional role of HOXC10 in adipose tissue, we generated adipose-specific HOXC10 knockout (AHKO) mice using adiponectin-Cre mice. We show that development of functional beige adipocytes within subcutaneous WAT is enhanced in AHKO mice, contributing to decreased white fat in the lean AHKO mice kept at room temperature. Furthermore, AHKO mice show reduced weight gain, lower fat mass and improved glucose tolerance compared to wild type (WT) mice when fed on high fat diet. Interestingly, AHKO mice exhibit enhanced thermogenic response to cold exposure. These mice also show increased energy expenditure, alongside increased in brown fat markers in subcutaneous WAT, with no effect on classical BAT. These data indicate that HOXC10 plays a critical role in maintaining white adipose tissue identity, and loss of HOXC10 promotes browning in WAT.

Disclosure
A.H.Y. Tan: None. S. Gun: None. W. Han: None.