bluuebunny/crossref_metadata_2025_split huggingface dataset:
ICA6150349, a Highly Selective Glucagon Agonist, in Combination with Exenatide Significantly Reduces Weight and Glucose in Obese and Diabetic Rats
Authors: PAULIK MARK , TLUSTY TOM , GRIZZLE MARY K. , COPELAND MARCI , WENG SHARON , BLACKWELL WILLIAM C. , SRIVASTAVA VED , WAY JAMES , ROLLER SHANE , ZANE DORIS , HODGE REBECCA , YOUNG ANDREW A. , FELDMAN PAUL L. 
Published: June 2018

ICA6150349, a 38-amino acid analog of glucagon, is peptidase resistant and highly selective for the glucagon receptor. ICA6150349 continuously infused SC at 50 mcg/kg/d (ED50) in DIO LE rats reduced weight (21%), fat mass (37%), and food intake (17%) and normalized triglycerides and cholesterol to lean control levels. ICA6150349 (50 mcg/kg/d) in combination with exenatide (10 mcg/kg/d) further reduced weight (38%), fat mass (70%), and food intake (52%) and also normalized glucose and lipids to lean control levels. ICA6150349 continuously infused at 50 mcg/kg/d in ZDF rats increased HbA1c (1.3%), reduced weight (29%), fat mass (42%), and food intake (13%) and normalized triglycerides (66%) and cholesterol (38%) to lean control levels. ICA6150349 (50 mcg/kg/d) in combination with exenatide (10 mcg/kg/d) decreased HbA1c (1.5%), off-setting the increase seen with ICA6150349 monotherapy. The ICA6150349 and exenatide combination reduced weight (19%), fat mass (25%), food intake (29%) cholesterol (27%) and triglycerides (41%). In rodent models of obesity/T2D, ICA6150349 in combination with exenatide can significantly reduce weight, fat mass, glucose and lipids, sometimes normalizing these parameters to lean control levels.

Disclosure
M. Paulik: Employee; Self; Intarcia Therapeutics, Inc.. T. Tlusty: None. M.K. Grizzle: None. M. Copeland: None. S. Weng: None. W.C. Blackwell: Employee; Self; Intarcia Therapeutics, Inc. V. Srivastava: Employee; Self; Intarcia Therapeutics, Inc. J. Way: Employee; Self; Intarcia Therapeutics, Inc. S. Roller: Employee; Self; Intarcia Therapeutics, Inc.. D. Zane: None. R. Hodge: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc. A.A. Young: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; GlaxoSmithKline plc. P.L. Feldman: Employee; Self; Intarcia Therapeutics, Inc..
Obesity-Associated Family with Sequence Similarity 13 Member A Gene Regulates Adipocyte Differentiation
Authors: TANG JIAZHEN , ZHOU HONGYI , YANG JING , CHEN WEIQIN 
Published: June 2018

Obesity and its associated morbidities represent the major and most rapidly expanding health epidemic in the world. Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphism (SNP) variants in Family with Sequence Similarity 13, Member A (FAM13A) gene to be highly associated with waist-hip ratio (WHR) with adjustment for body mass index (BMI) (WHRadjBMI). However, the exact function of this gene in adipose tissue development and obesity remains largely uncharacterized. We for the first time identified Fam13A as an adipose tissue abundant gene whose expression was highly regulated by fasting/refeed and dramatically reduced in epididymal and subcutaneous fat depots in murine models of genetic obesity and diet-induced obesity (DIO). Its expression was enriched in mature adipocytes and significantly upregulated during murine and human adipogenesis potentially through a PPARγ-dependent mechanism. However, FAM13A-/- mice only exhibited a tendency of higher adiposity and maintained normal glucose clearance and insulin resistance. They are also not protected from high fat diet-induced obesity and metabolic perturbation. The dispensable role of FAM13A was further supported by normal adipogenesis in FAM13A-/- Stromal vascular cells (SVCs). Interestingly, overexpression of FAM13A in 3T3-L1 preadipocytes downregulated beta-catenin expression, impaired preadipocyte survival and enhanced its susceptibility to serum starvation-induced apoptosis. Furthermore, FAM13A-overexpressing preadipocytes failed to differentiate into mature adipocytes through interfering early-stage C/EBPα/PPARγ-mediated adipogenesis. These data for the first time reveal new details of an obesity-associated FAM13A gene in mediating beta-catenin action and adipocyte differentiation, providing novel insight into a relationship between FAM13a and adipose biology.

Disclosure
J. Tang: None. H. Zhou: None. J. Yang: None. W. Chen: None.
Self-Assembled Hyaluronic Acid Nanoparticles Ameliorate Adipose Tissue Inflammation and Insulin Resistance in Diet-Induced Obese Mice
Authors: RHO JUN GI , LEE WANGHEE , LEE EUNYOUNG , KIM CHONGTAE , LEE EUN KYUNG , KIM WOOK 
Published: June 2018

Self-assembled hyaluronic acid nanoparticles (HA-NPs), consisting of hydrophobic cores surrounded by a hydrophilic HA shell, have been extensively investigated for biomedical and pharmaceutical applications because of their biocompatibility and receptor-binding properties. Here, we report that an empty HA-NP itself not bearing any drug has therapeutic effects on adipose tissue inflammation and insulin resistance. HA-NPs inhibit not only the receptor-mediated internalization of low-molecular-weight (LMW) free HA but also LMW free HA-induced pro-inflammatory gene expression in mouse primary bone marrow-derived macrophages (BMDMs) isolated from wild type mice. Following systemic administration of Cy5.5-labeled HA-NPs, in vivo biodistribution assay and immunofluorescent staining indicate the distribution of HA-NPs and their co-localization with CD44 in adipose tissues including epididymal white adipose tissue (eWAT). However, these effects are largely reduced or rarely observed in BMDMs isolated from CD44-deficient mice. In addition, diet-induced obese (DIO) mice fed a high-fat diet (HFD) show elevated CD44 expression and HA-NP accumulation in eWAT compared to mice on standard diet. Treatment with HA-NPs in HFD-fed DIO mice suppresses macrophage infiltration into adipose tissue and adipose tissue inflammation, leading to improved insulin sensitivity and glycemic control. It is revealed that HA-NP itself can be a therapeutic agent for the treatment of type 2 diabetes.

Disclosure
J. Rho: None. W. Lee: None. E. Lee: None. C. Kim: None. E. Lee: None. W. Kim: None.
Empagliflozin and Linagliptin Administered in Combination or as Serial Add-On Therapy Decreases Macrovascular and Microvascular Stiffening and Microalbuminuria in a Mouse Model of Diabetic Nephropathy
Authors: AROOR ANNAYYA R. , HABIBI JAVAD , JIA GUANGHONG , KLEIN THOMAS , MAYOUX ERIC , DEMARCO VINCENT 
Published: June 2018

Diabetic individuals are at increased risk for progression of proteinuria and renal fibrosis. There is an urgent need for more effective therapeutic strategies since conventional anti-hyperglycemic therapies may not sufficiently reduce renal injury. Combinations of newer anti-hyperglycemia therapies, such as, DPP-4 and SGLT2 inhibitors, which improve glycemia by differing mechanisms and exhibit cardiovascular and renal protections may show promise in this regard. We tested the hypothesis that targeting SGLT2 and DPP-4 improves aortic and renal vascular stiffening as well as suppression of renal tissue injury. Eleven week old female db/db mice were fed a diet containing LINA (2mg/kg/day) or EMPA (10mg/kg/day) monotherapy for 10 weeks. Additional groups received add-on therapy after 5 weeks on monotherapy (LINA added to EMPA or EMPA added to LINA. One group received LINA and EMPA combination therapy for the entire 10 week test period. A control group received no therapy. Both EMPA and LINA monotherapies decreased diabetes associated aortic and renal vascular stiffening and albuminuria. Improvement by LINA was observed without any significant improvement in glycemic control whereas EMPA significantly reduced both fasting glucose and HbA1c levels accompanied by decrease vascular stiffening and albuminuria. Like the monotherapies, combination therapy or serial add-on therapies afforded cardiovascular and reno-protection, however, these dual therapies had marginal advantage over monotherapy. Taken together, suppression of macrovascular and microvascular stiffening by DPP-4 and SGLT2 inhibitors contribute significantly to vascular health in diabetic patients by both glycemic-dependent and -independent mechanisms.

Disclosure
A.R. Aroor: None. J. Habibi: None. G. Jia: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. E. Mayoux: None. V. DeMarco: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc..
Metabolic Markers Predictive of Prediabetes in the Korean Population
Authors: LEE HEUN-SIK , PARK TAE-JOON , KIM BONG-JO 
Published: June 2018

Background: Prediabetes (PD) is a high-risk state for type 2 diabetes (T2D), but the risk of progression from PD to T2D can be prevented by early diagnosis and intervention. Metabolomics studies suggest that metabolic biomarkers can shed insight into etiological mechanisms and improve the accuracy of prediction of disease onset.
Objectives: We aimed to identify serum metabolic biomarkers and verify their predictive performance for PD in the Korean population, as compared to the performance of known clinical risk factor (CRF) as well as previously reported metabolites (PRM) in other population studies.
Methods: A targeted metabolomics was carried out to quantify serum metabolites for 1,723 participants from the Korea Association REsource (KARE) cohort from which 500 individuals were followed-up to 6-years. PD-related metabolites were identified at baseline by statistical methods including multivariable regression analysis, and tested their association to incidence of PD during follow-up.
Results: The 12 metabolites were significantly altered in PD (adjusted P&lt;4.07E-04). These metabolites predicted incidence of PD with an area under curve (AUC) of 0.71. The AUC of the metabolic markers was significantly higher than that of the two PRM models (0.56 and 0.64, P&lt;0.005) and the CRF (0.64, P&lt;0.01). The performance of the metabolic markers compared to glucose model was significantly higher among the obese (BMI &gt;= 25 kg/m2, 0.79 vs. 0.58, P&lt;0.001), significantly lower among the female (0.73 vs. 0.85, P&lt;0.002) and the lean (BMI&lt;25 kg/m2, 0.68 vs. 0.78, P&lt;0.01), and not significantly different among the age and the male. The full model with metabolic markers, CRF, glucose yielded the best prediction (AUC=0.84).
Conclusion: Our results revealed that the novel metabolic markers are not only associated with the risk of PD, but also improve the prediction performance in combination with classical approaches. These findings may help understanding causality of diabetes progression and developing preventive strategies for T2D.

Disclosure
H. Lee: None. T. Park: None. B. Kim: None.
Dipeptidyl Peptidase-4 Inhibition with Linagliptin Promotes Angiogenesis/Vasculogenesis in the Hearts of Female Diabetic db/db Mice
Authors: TOEDEBUSCH RYAN , AROOR ANNAYYA R. , HABIBI JAVAD , KLEIN THOMAS , PULAKAT LAKSHMI , DEMARCO VINCENT 
Published: June 2018

We have previously reported that the DPP-4 inhibitor linagliptin (LINA) prevents diastolic dysfunction and myocardial fibrosis in a mouse model of diet-induced obesity, a pre-clinical model of prediabetes. LINA suppressed WD-induced pro-inflammatory mediators, such as TRAF3IP2 and downstream signaling intermediates, NF-κB, AP-1 and p38-MAPK in the heart. Herein, we extend that study by testing whether LINA slows progression of diastolic dysfunction in diabetic db/db mice, and improves the underlying maladaptive immune/inflammatory response. To accomplish this, we fed db/db mice normal mouse chow with or without linagliptin (38 mg/kg chow). After performing echocardiography on mice treated or not for 10 weeks, we analyzed expression of 200 cytokines in myocardial extracts and performed Ingenuity Pathway Analysis (IPA) in an effort to determine what signaling pathways are predicted to be differentially activated in the heart. Mice treated with linagliptin had improved diastolic function indicated by lower LV filling pressure compared to untreated mice (E/E’; 35 vs. 50; p&lt;0.05). IPA predicted that LINA activates pathways contributing to cardiovascular development of the vasculature (32 molecules, Activiation z-score = 3.7), angiogenesis (31 molecules, Activation z-score = 3.7) and vasculogenesis (27 molecules, Activation z-score = 3.7). Cardiomyocyte size (i.e., cross-sectional area) was reduced by 23% (533±30 vs. 411±18 μm2; p&lt;0.05) and myocardial capillary density was two-fold higher with LINA treatment compared to untreated mice (p&lt;0.05). In addition, the proteome analysis showed a significant decrease in TNF-α related apoptosis inducing ligand, a cytokine that induces endothelial nitric oxide, in untreated mice, however, this deficiency was prevented by LINA. These data suggest that linagliptin exerts a beneficial immune/inflammatory response in the diabetic heart that confers myocardial vasculoprotection.

Disclosure
R. Toedebusch: None. A.R. Aroor: None. J. Habibi: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. L. Pulakat: None. V. DeMarco: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc..
Identification of Novel Transcriptional Regulators of Uncoupling Protein 1 Using a Modified CRISPR-Cas9 Methodology
Authors: DARCY JUSTIN , WANG CHIH-HAO , LUNDH MORTEN , SHAMSI FARNAZ , LYNES MATT , EMANUELLI BRICE , TSENG YU-HUA 
Published: June 2018

Obesity is an epidemiological dilemma due to its associated comorbidities such as diabetes, cancer, and heart disease. Because traditional weight loss strategies such as diet and exercise are thus far ineffective at curtailing the growing prevalence of obesity, new therapeutic approaches are being sought after. In this regard, brown adipose tissue (BAT) has garnered attention due to its ability to burn fat as fuel during thermogenesis, which is carried out by the mitochondrial uncoupling protein 1 (UCP1). Since UCP1 is mainly regulated at the level of transcription, our laboratory sought to identify novel transcriptional regulators of UCP1 using a modified CRISPR-Cas9 methodology termed engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) (Fujii and Fujita, 2015). enChIP takes advantage of dCas9, which lacks endonuclease activity while maintaining functional DNA binding activity, fused to a 3xFLAG tag that can be used for immunoprecipitation. For our study, we delivered five guide RNAs (gRNAs) targeting the Ucp1 promoter region in a mouse-derived mature brown adipocyte line that had been modified to endogenously express the dCas9-3XFLAG fusion protein. Following treatment with either vehicle or CL316,243, we immunoprecipitated the resulting Ucp1/dCas9/3XFLAG complex using an anti-FLAG antibody. We then utilized tandem liquid chromatography-mass spectrometry for an unbiased proteomic screen to evaluate proteins enriched by β3-adrenergic stimulation. Three biological replicates revealed 17 enriched proteins in mature adipocytes following β-adrenergic stimulation. These included histone variants and proteins involved in transcriptional regulation, such as H2A.Z and CRIP2, respectively. These identified proteins have the potential to be manipulated to regulate the expression of UCP1, thereby affecting the thermogenic function of BAT and systemic metabolism.

Disclosure
J. Darcy: None. C. Wang: None. M. Lundh: None. F. Shamsi: None. M. Lynes: None. B. Emanuelli: None. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd.. Research Support; Self; MedImmune.
Diet-Induced Adipose Tissue Inflammation and Hypoxia Are Reversed by GLP-1 Potentially via Improved Microcirculation
Authors: XU FEN , CHEN ZONGLAN , XIAN YINGXIN , DENG HONG R. , XU WEN , LIANG HUA , WENG JIANPING 
Published: June 2018

Obesity is considered as an inflammatory disease. A proposed trigger of the inflammation is hypoxia, which occurs when the enlargement of vascular network is not sufficient to support the expanding adipocytes. Exenatide, a GLP-1 receptor agonist, plays an anti-inflammatory role in obesity, but the mechanisms are poorly understood. The current study investigated the effects of exenatide on inflammation, hypoxia and microcirculation in epididymal fat of high-fat diet induced obese mice. Here, 8-week-old male C57BL/6 mice were randomly divided into 2 groups: NC group (normal control) and HF group (high-fat diet). After 12 weeks diet induction, HF group was further divided into 2 groups: HF group (HF+saline) and HF+EX group (HF+exenatide, 24nmol/kg/day). Compared with NC group, HF group showed significant increases in weight gain and impaired glucose tolerance; serum inflammatory cytokine levels (IL-6, TNF-α, MCP-1) were elevated. Immunohistochemistry staining of F4/80 showed that macrophage infiltration increased in adipose tissue. The mRNA expressions of hypoxia-induced gene (HIF-1a, eNOS) were significantly upregulated. However, laser confocal microscopy showed that capillary density was reduced in HF group. After 4 weeks exenatide treatment, all the obese induced immune disorder (e.g., inflammatory cytokine levels, macrophage infiltration) and hypoxia were significantly ameliorated, leading to an improved energy homeostasis in HF mice when compared with those receiving saline treatment. Proteins levels of PECAM-1 and VEGF-R2 which are indicators of angiogenesis were obviously elevated and capillary density measured by confocal was dramatically increased by exenatide in epididymal fat tissues. As insufficient vasculature may trigger hypoxia and inflammation in obesity, our results indicated that inflammation and hypoxia in obesity could be reversed by GLP-1 potentially via improved angiogenesis and microcirculation in adipose tissue.

Disclosure
F. Xu: None. Z. Chen: None. Y. Xian: None. H.R. Deng: None. W. Xu: None. H. Liang: None. J. Weng: None.
Weight Loss Outcomes with Species-Specific Dual GLP-1R/GCGR Agonists in Animal Models
Authors: ELVERT RALF , BOSSART MARTIN , ZHANG BOB , KANNT AIMO , WAGNER MICHAEL , HAACK TORSTEN , EVERS ANDREAS , DUDDA ANGELA , LORENZ MARTIN , KEIL STEFANIE , LARSEN PHILIP J. 
Published: June 2018

Dual agonism of glucagon-like peptide-1 receptor and glucagon receptor (GLP-1 R/GCGR) was shown to reduce body weight. Species-specific dual GLP-1 R/GCGR agonist peptides (SSDA), structurally based on exendin-4 and carrying a fatty acid side-chain for half-life extension, or the selective GLP-1 R agonist liraglutide (lira) were administered to diet-induced obese (DIO) mice twice daily for 32 days, and to DIO and diabetic cynomolgus monkeys once daily for 43 days. Potencies of the SSDA and lira on mouse and monkey GLP-1 receptors were in the single-digit picomolar range. Body weight change was greater with SSDA than with lira in mice (-21.1 ± 2.1% vs. -12.9 ± 1.4%) and monkeys (-8.2 ± 1.2%; p&lt;0.001 vs. -5.1 ± 1.1%; p&lt;0.001; Figure). Indirect calorimetry in mice showed increased total energy expenditure (TEE) in those treated with SSDA, caused not only by increased fat oxidation but also by increased oxidation of carbohydrates. Lira significantly increased TEE, but significantly less than SSDA. These data support the mechanistic view that weight loss with SSDA does not result exclusively from reduced food intake but also from increased energy expenditure induced by GCGR activity. In murine and primate models, dual GLP-1 R/GCGR agonism with SSDA led to greater body weight loss than GLP-1 R alone. This represents a novel dual mechanism of action with potential for the treatment of obesity.

Disclosure
R. Elvert: Employee; Self; Sanofi. M. Bossart: Employee; Self; Sanofi. B. Zhang: None. A. Kannt: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. M. Wagner: Employee; Self; Sanofi. T. Haack: Employee; Self; Sanofi-Aventis Deutschland GmbH. A. Evers: Employee; Self; Sanofi. A. Dudda: Employee; Self; Sanofi. M. Lorenz: None. S. Keil: Employee; Self; Sanofi. P.J. Larsen: Employee; Self; Sanofi.
The Presence of Cerebral White Matter Lesions and Lower Skin Microvascular Perfusion Predict Decline in General Cognitive Ability in Type 1 Diabetes Patients but Not in Healthy Controls
Authors: EMANUEL ANNA L. , DUINKERKEN EELCO VAN , WATTJES MIKE P. , KLEIN MARTIN , BARKHOF FREDERIK , SNOEK FRANK J. , ERINGA ETTO C. , IJZERMAN RICHARD , SERNE ERIK H. 
Published: June 2018

Objective: Cognitive impairments in type 1 diabetes may result from hyperglycemia-associated cerebral microangiopathy. In this study we aimed to identify cerebral microangiopathy and skin microvascular dysfunction - as surrogate marker for generalized microvascular function - as predictors of cognitive decline over time.
Research Design and Methods: Twenty-five type 1 diabetes patients and 25 matched healthy controls underwent neurocognitive testing at baseline and after follow-up (mean duration of 3.8±0.8 years). At baseline, 1.5 T cerebral magnetic resonance imaging was used to detect white matter lesions (WML) and cerebral microbleeds. In addition, skin capillary perfusion was assessed by means of capillary microscopy. Multiple linear regression analysis was performed to examine if cerebral microangiopathy and capillary perfusion were associated with changes in cognitive performance.
Results: In type 1 diabetes patients, but not in healthy controls, the presence of WML (ß=-0.419;p=0.037) as well as lower skin capillary perfusion (baseline: ß=0.753;p&lt;0.001; peak hyperemia: ß=0.743;p=0.001; venous occlusion: ß=0.675;p=0.003; absolute capillary recruitment: ß=0.549;p=0.022) at baseline were associated with decline in general cognitive ability over time, independent of age and sex, HbA1c and severe hypoglycemic events. The relationship between WML and cognitive decline was significantly reduced to non-significant levels after adjusting for capillary perfusion.
Conclusions: In type 1 diabetes patients, presence of WML and lower skin capillary perfusion predict poorer general cognitive ability over time. The relationship between WML and cognitive decline was significantly reduced when adjusting for capillary perfusion, suggesting that generalized microvascular dysfunction at least partly underlies WML-associated cognitive decline.

Disclosure
A.L. Emanuel: None. E. van Duinkerken: None. M.P. Wattjes: Consultant; Self; Biogen. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Roche Pharma, Sanofi Genzyme. M. Klein: None. F. Barkhof: None. F.J. Snoek: None. E.C. Eringa: None. R. Ijzerman: Research Support; Self; AstraZeneca. E.H. Serne: None.