bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mediating Role of Acculturation and Lifestyle Behaviors on Cardiometabolic Risks among Asian Indians in the United States
Authors: JOSEPH NITHA MATHEW , MISRA RANJITA , WANG JING , CRON STANLEY , RAMASWAMY PADMAVATHY 
Published: June 2018

Background: Asian Indians are the 2nd largest Asian immigrants in the U.S. and have higher rates of diabetes, metabolic syndrome, and cardiovascular disease when compared to the general U.S. population and other immigrant groups. Acculturation levels influence the lifestyle practices and studies have reported acculturated individuals have increased risks for chronic diseases.
Aim: Hence, this study explored the mediating role of lifestyle behaviors (physical activity and dietary behavior) between acculturation and cardiometablic risk factors among Asian Indians using the DIA (Diabetes in Indian Americans) national study.
Methods: The sample comprised 1038 randomly selected adult Asian Indians in seven U.S. sites (mean age was 48.54 ±12.8 years). Acculturation was assessed using the English proficiency scores from the Acculturation Scale for Southeast Asians and dietary behavior and physical activity were calculated from the subscales of Health Promotion Lifestyle Profile II. Path analyses with bootstrap methods were used to explore if physical activity or dietary behavior mediates the relationship between acculturation and cardiometabolic risk factors (HbA1c, fasting blood glucose levels, Body Mass Index, systolic and diastolic blood pressure, and lipid profiles [HDL, LDL, total cholesterol, and triglycerides]).
Results: Dietary behavior significantly mediated the relationship between acculturation and HbA1C (β=0.004, p = .047) and physical activity mediated the relationship between acculturation and HDL (β=0.08, p = .011). All other mediation models were not significant (p&gt;.05) based on the nonsignificant indirect effects detected in the models.
Conclusion: Culturally specific dietary education and physical activity interventions for this high risk ethnic group may have potential to reduce cardiometabolic risks. Results provide firm basis for educational program.

Disclosure
N. Mathew Joseph: None. R. Misra: None. J. Wang: None. S. Cron: None. P. Ramaswamy: None.
GCN5l1 Modulates Cross Talk between Mitochondria and Cell Signaling to Regulate Fox01 Stability and Gluconeogenesis
Authors: WANG LINGDI 
Published: June 2018

The mitochondrial enriched GCN5-like 1 (GCN5L1) protein has been shown to modulate mitochondrial protein acetylation, mitochondrial content and mitochondrial retrograde signaling. Here we show that hepatic GCN5L1 ablation reduces fasting glucose levels and blunts hepatic gluconeogenesis without affecting systemic glucose tolerance. PEPCK and G6Pase transcript levels are downregulated in hepatocytes from GCN5L1 liver specific knockout mice and their upstream regulator, FoxO1 protein levels are decreased via proteasome-dependent degradation and via reactive oxygen species mediated ERK-1/2 phosphorylation. ERK inhibition restores FoxO1, gluconeogenic enzyme expression and glucose production. Reconstitution of mitochondrial-targeted GCN5L1 blunts mitochondrial ROS, ERK activation and increases FoxO1, gluconeogenic enzyme expression and hepatocyte glucose production. We suggest that mitochondrial GCN5L1 modulates post-translational control of FoxO1, regulates gluconeogenesis and controls metabolic pathways via mitochondrial ROS mediated ERK activation. Exploring mechanisms underpinning GCN5L1 mediated ROS signaling may expand our understanding of the role of mitochondria in gluconeogenesis control.

Disclosure
L. Wang: None.
Collagen VI-Derived Endotrophin Promotes Hepatic Apoptosis, Inflammation, and Fibrosis in Chronic Liver Disease
Authors: KIM MIN , PARK JIYOUNG 
Published: June 2018

Type VI collagen alpha3 chain (Col6a3) is a biomarker for hepatic fibrosis and poor prognosis of hepatocellular carcinoma (HCC), but its function in liver pathology remains unknown. Analysis of human HCC patients revealed that elevated mRNA levels of COL6A3 in tumor-proximal liver regions were associated with poor prognosis in HCC patients. Here, we show that endotrophin (ETP), a cleaved Col6a3 fragment, significantly augmented hepatocyte apoptosis, inflammation, and fibrosis in chemically induced chronic liver disease models by utilizing either CCl4 or DEN in the background of hepatocyte-specific ETP transgenic mice, nevertheless ETP per se showed a limited phenotypic changes in liver tissues. Notably, both hepatocytes and non-parenchymal cells in liver tissues were responsible for an increase of ETP levels in chronic liver injuries, and inhibition of ETP with neutralizing antibodies (10B6) ameliorated hepatic apoptosis, inflammation, and fibrosis in these cells. Our results mechanistically implicate ETP as a necessary component for sustained JNK activation in early stage of chronic liver diseases; thus, ETP-JNK axis could be a promising therapeutic target, particularly in individuals with high local levels of COL6A3 in chronic liver disease.

Disclosure
M. Kim: None. J. Park: None.
SGLT Inhibitors Enhance Endogenous Glucose Productions (EGP) in a Preclinical Animal Model
Authors: HUANG SHUJUAN , CAI DONGFENG , YUE ZENGPU , YAN HUANG , ZHOU ZHOU , FU XINFA , WANG HONGMEI , TAO YI , HWA JOYCE J. 
Published: June 2018

Aim: SGLT inhibitors was found to paradoxically enhance EGP in type 2 diabetes patients, while reduce EGP in diabetic mice during hyperinsulinemic-euglycemic clamp. In this study, we assess acute and 7-day effects of SGLT inhibitors on EGP in rats by 13C-glucose tracer dilution method to identify a translational rodent model.
Method: SD rats aged 7 weeks were assigned to 3 groups (n=6 each), vehicle, LX4211 (10 mg/kg) and canagliflozin (10 mg/kg). On day 1, rats were fasted for 3 hours and dosed with SGLT inhibitors, LX4211 or canagliflozin before a 13C-glucose IV injection (25 mg/kg) 2 hour post drug administration. Blood were collected at 0, 5, 15, 30, 45, 60, 75, 90, 120, and 150 minutes time points. Plasma 13C-glucose and 12C-glucose levels were detected by LC/MS. EGP was calculated by multiplying fractional glucose turnover rate by pool size. After washout and the same 18 rats were dosed for 7 days, EGP were assessed on day 7.
Results: 13C--glucose IV injection after acute LX4211 and canagliflozin dosing did not significantly changed plasma glucose concentration over time, but led to a rapid rise in plasma 13C-glucose enrichment followed by a time-dependent decrease of 13C-glucose enrichment. The fractional glucose turnover rate and EGP were 3.14±0.35 (SD) percent and 6.28±0.70 (SD) mg.kg-1.minutes-1 in vehicle group. Single dose of LX4211 and canagliflozin significantly increased EGP by 27.5% and 57.1%, respectively. After 7-days of treatment, the fractional glucose turnover and EGP were 3.30±0.28 (SD) percent and 6.59±0.56 (SD) mg.kg-1.minutes-1 in vehicle group, which was highly consistent to the previous EGP measurement. Moreover, 7 days treatment of LX4211 and canagliflozin significantly elevated EGP by 24.8% and 33.4%, respectively.
Conclusion: This study demonstrated that SGLT inhibitors can increase EGP in animal model as in type 2 diabetes patients. Detecting EGP using 13C-glucose tracer dilution method may facilitate the discovery of novel SGLT inhibitors with differential effects on EGP.

Disclosure
S. Huang: None. D. Cai: None. Z. Yue: None. H. Yan: None. Z. Zhou: None. X. Fu: None. H. Wang: None. Y. Tao: None. J.J. Hwa: None.
Vitamin E Supplementation during Nonalcoholic Steatohepatitis (NASH) Pathogenesis in High-Sucrose, High-Fat-Fed Genetically Obese Mice
Authors: HASENOUR CLINTON , YOUNG JAMEY 
Published: June 2018

Nonalcoholic fatty liver disease is characterized by dysregulated hepatic oxidative metabolism which may progress to a state of elevated inflammation and fibrosis (NASH). The lipophilic antioxidant vitamin E (VitE) has shown promise as an effective strategy for treating NASH in some clinical trials. Here we tested whether dietary VitE supplementation is sufficient to prevent NASH development and mitigate aberrant glucose and oxidative liver metabolism during overnutrition. Hyperphagic, melanocortin-4-receptor deficient mice (MC4R-/-) were fed a chow, western diet (WD) or WD+VitE (500IU/kg diet) ad lib starting at 8 or 20 weeks of age. All mice were studied at 28 weeks of age; thus, 5, 28 week-old MC4R-/- groups were investigated: chow, WD or WD+VitE for 20 weeks, and WD or WD+VitE for 8 weeks. This design allowed us to test whether VitE limits NASH pathogenesis after an intermediate or long exposure to WD. Mice (n=8-11, per group) underwent jugular vein and carotid artery catheterization for 13C/2H isotope-based metabolic flux analysis to calculate in vivo liver glucose and citric acid cycle fluxes. Body weight and fat mass were unaffected by WD or WD+VitE feeding for 8 weeks. 20 weeks of WD or WD+VitE, however, increased these parameters relative to chow. Glucose production, gluconeogenesis, and pyruvate cycle fluxes were also elevated by 20 weeks of WD or WD+VitE feeding. Unlike mice fed WD for 8 weeks, WD+VitE for 8 weeks also accelerated gluconeogenesis. All mice fed a WD or WD+VitE had increased hepatocellular steatosis, ballooning, lobular inflammation and activity compared to chow; fibrosis was more extensive in mice fed a WD or WD+VitE for 20 weeks. Thus, the provision of VitE during hyperphagia and WD failed to limit NASH pathogenesis. In fact, shorter term VitE supplementation accelerated WD-mediated changes in glucose production, indicating VitE may actually exacerbate the dysregulation of liver metabolism that occurs in response to chronic overnutrition.

Disclosure
C. Hasenour: None. J. Young: None.
Evaluation of Hepatic Steatosis and Fibrosis Using Transient Elastography in Partial Lipodystrophy Patients
Authors: DOS SANTOS FÁBIO F. , VIOLA LUIZ FELLIPE C. , MATSUURA FELIPE O. , VALERIO CYNTHIA M. , GODOY-MATOS AMELIO F. , COSTA MARCIA H. , ARAUJO-NETO JOAO M. , DIAS MELINA 
Published: June 2018

Introduction: Partial lipodystrophy (PL) is a rare disease associated with insulin resistance and metabolic dysfunctions, including NAFLD. Global prevalence of NAFLD is ±25%. In PL patients NAFDL prevalence and severity remains unclear. AIMS To evaluate the presence of hepatic steatosis and/or fibrosis in PL patients using transient elastography (TE) in comparison to a control group.
Materials and Methods: Fifteen patients (7 with PL of the limbs, 8 with Familiar Partial Lipodystrophy Dunnigan-type) and 15 (13 women) controls paired to BMI and age were included. We recruited participants aged 18-65 years-old and a BMI≥25 and ≤35kg/m², excluding other causes of steatohepatitis. Anthropometric measures, metabolic parameters and the presence of steatosis/fibrosis using TE(Fibroscan®) were evaluated. According to literature, the adopted cut-off values in TE for Controlled Attenuation Parameter (CAP) and Liver Stiffness Measurement (LSM) are ≥238dB/m and ≥5,8kPa, respectively. Student t-test was used for continuous variables. Main results are presented as Mean ± SD.
Results: Mean age was 52.93 and 50.26 years-old in PL and control groups, respectively. BMI was slightly but not significantly higher in control group (30,13kg/m² [SD±2,85] vs. 27,43kg/m² [SD±5,30]). Waist-to-hip ratio did not differ. PL group had higher fasting plasma glucose (116.78mg/dL [SD±39,54] vs. 89,58mg/dL [SD±23,34], p= 0,0476). No differences in hepatic lesion biomarkers or lipid profile was noted, except for a lower HDL-c in PL group (40,64mg/dL [SD±9,45] vs. 49,62mg/dL [SD±12,67], p=0,0432). CAP tended to be higher in PL patients [301,82dB/m (SD±54,88) vs. 262,93dB/m (SD±57,44); p=0,0685] and LSM was significantly higher (7,32kPa [SD±3,71] vs. 4,94kPa [SD±1,58], p=0,0260).
Conclusions: Patients with PL presented a trend for increased hepatic steatosis and showed higher values of fibrosis in TE. Therefore, we suggest PL patients should undergo TE for screening of NAFLD.

Disclosure
L.C. Viola: None. F.O. Matsuura: None. C.M. Valerio: None. A.F. Godoy-Matos: Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation. Other Relationship; Self; Takeda Development Center Americas, Inc., Novo Nordisk Inc.. M.H. Costa: None. J.M. Araujo-Neto: None. M. Dias: None.
Overall Safety of Canagliflozin (CANA) in the CANagliflozin CardioVascular Assessment Study (CANVAS) Program
Authors: HOLLANDER PRISCILLA , MOHAN VISWANATHAN , WOO VINCENT C. , WOO VINCENT C. , OH RICHARD , FULCHER GREG 
Published: June 2018

CANA is an SGLT2 inhibitor that was generally well tolerated in 12 placebo (PBO) and active-controlled phase 3/4 trials (non-CANVAS studies [NCS]) for ≤104 weeks in a broad range of patients with type 2 diabetes (T2D). Here we report the longest-term safety data to date (up to 6.5 years) with CANA in patients with T2D and high CV risk from the CANVAS Program vs. the NCS. Amputation and fracture were novel safety signals in the CANVAS Program (HR [95% CI]: 1.97 [1.41, 2.75] and 1.26 [1.04, 1.52]) that were not seen in the NCS (RR [95% CI]: 0.23 [0.06, 0.89] and HR [95% CI]: 1.13 [0.74, 1.72]). The incidence of labeled AEs (i.e., osmotic diuresis [OD]- and volume depletion [VD]-related AEs, hypoglycemia, urinary tract infection, genital mycotic infection [GMI], renal-related AEs, hypersensitivity, diabetic ketoacidosis) and those that were serious or led to discontinuation in the CANVAS Program and the NCS are reported. In the CANVAS Program, incidence of OD- and VD-related AEs and GMI was higher with CANA vs. PBO, consistent with NCS (Table). There were no imbalances in other labeled AEs including hypoglycemia and renal-related AEs. The rate of serious and discontinuation-related labeled AEs was similar with CANA and PBO. CANA was generally well tolerated for up to 6.5 years in the CANVAS Program with an AE profile (excluding amputation and fracture) consistent with NCS, which included a more general T2D population.

Disclosure
P. Hollander: Advisory Panel; Self; Novo Nordisk Inc., Eli Lilly and Company, Merck & Co., Inc.. V. Mohan: None. V.C. Woo: Advisory Panel; Self; Janssen Pharmaceuticals, Inc., AstraZeneca, Novo Nordisk Inc., Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc. R. Oh: Employee; Self; Janssen Research & Development. G. Fulcher: Other Relationship; Self; Novo Nordisk Inc., Janssen Scientific Affairs, LLC., Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp..
Increased HbA1c Variability May Shorten Time to Microalbuminuria Development in Type 1 Diabetes (T1D)
Authors: CLEMENTS MARK A. , WU MENGDI , FOSTER NICOLE C. , LAFFEL LORI M. , SHAH VIRAL N. , VENDRAME FRANCESCO , KINGMAN RYAN S. , ALONSO GUY T. , CARLSON ANDERS , DESALVO DANIEL J. , BUCKINGHAM BRUCE A. , SHERR JENNIFER , BENJAMIN ROBERT , EYTH EMILY , DUBOSE STEPHANIE 
Published: June 2018

We aim to understand the impact of HbA1c variability, as measured by SD-HbA1c, on risk of microalbuminuria in T1D population. An analysis was performed utilizing data of 8,680 participants in the T1D Exchange Clinic Registry (50% female, 86% non-Hispanic white, mean age 34 years, mean diabetes duration 14 years at enrollment) who met the following criteria: ≥2 clinic visit records, T1D duration ≥1 year at enrollment, age of diagnosis ≥10 years old and no known renal disease (including no microalbuminuria) at the time of registry enrollment. Median number of albuminuria and HbA1c measures were 4 and 21 per participant, respectively. Microalbuminuria was present during follow-up in 562 (6.5%) participants. Median intrapersonal mean HbA1c and SD-HbA1c were 7.8% and 0.6% respectively. Participants with high HbA1c variability had shorter time to first microalbuminuria (p&lt;0.001, Figure 1a.) Those with high (≥50th percentile) mean HbA1c and high SD-HbA1c also had shorter diabetes duration prior to first reported microalbuminuria compared to high mean-HbA1c but low SD-HbA1c (p&lt;0.001, Figure 1b). HbA1c variability relates to risk of microalbuminuria in T1D; its relationship to other outcomes should be studied.

Disclosure
M.A. Clements: Speaker's Bureau; Self; Medtronic. Advisory Panel; Self; Glooko, Inc.. M. Wu: None. N.C. Foster: None. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, LLC.. V.N. Shah: None. F. Vendrame: Consultant; Self; Novo Nordisk Inc.. R.S. Kingman: None. G.T. Alonso: None. A. Carlson: Advisory Panel; Self; Sanofi, Insulet Corporation. Consultant; Self; Merck & Co., Inc.. Research Support; Self; Medtronic, Novo Nordisk A/S. D.J. DeSalvo: Consultant; Self; Dexcom, Inc.. Speaker's Bureau; Self; Insulet Corporation. B.A. Buckingham: Advisory Panel; Self; Novo Nordisk Inc., ConvaTec Inc.. Research Support; Self; Medtronic, Insulet Corporation, Dexcom, Inc., Tandem Diabetes Care, Inc.. Consultant; Self; Tandem Diabetes Care, Inc., Becton, Dickinson and Company. J. Sherr: Consultant; Self; Medtronic MiniMed, Inc.. Advisory Panel; Self; Insulet Corporation, Eli Lilly and Company, Bigfoot Biomedical. R. Benjamin: Speaker's Bureau; Self; Pfizer Inc.. E. Eyth: None. S. DuBose: None.
Beta-Cell Function and Survival Are Modulated Differentially by Type I or Type II Muscle through Specific Myokines
Authors: MIZGIER MARIA L. , RUTTI SABINE , PINGET MICHEL , BOUZAKRI KARIM 
Published: June 2018

Type 2 diabetes has a complex pathophysiology implicating several organs as the adipose tissue the liver, the skeletal muscle and the pancreas. Tissue crosstalk is emerging as a determinant way to coordinate the different organs implicated in glucose homeostasis. Among the inter-organ communication factors, muscle-secreted myokines can modulate the function and survival of pancreatic beta-cells. We establish human primary in vitro models of cells isolated from soleus (type I), triceps brachii (type II) and vastus lateralis (mixte) muscles to study the myokines profile secretion using and antibody-based array, the transcriptome using RNA-sequencing, and their sensitivity to TNF-alpha-induced insulin resistance, by assessing the glucose uptake rate. We then investigate how the muscle type and insulin resistance status impact on beta-cell function (glucose stimulated insulin secretion), survival (proliferation and apoptose) in order to identify new myokines in fiber type specific muscle pancreas crosstalk. We show that type I and type II primary myotubes present specific mRNA and myokine signatures as well as different sensitivity to TNF-alpha induced insulin resistance (TNF-alpha failed to induce insulin resistance in type II muscle). We also report here that the impact of myokines on beta-cells proliferation, apoptosis and insulin secretion, depends on fiber types and their metabolic status. Finally, that angiogenin and osteoprotegerin are triceps specific myokines with beta-cell protective actions against proinflammatory cytokines. These results suggest that type I and II muscles could impact insulin secretion and beta-cell mass differentially in type 2 diabetes through specific myokines secretion.

Disclosure
M.L. Mizgier: None. S. Rutti: None. M. Pinget: None. K. Bouzakri: None.
Perivascular Adipose Tissue Controls Insulin-Stimulated Perfusion and Glucose Uptake in Muscle through Adipomuscular Microvascular Anastomoses
Authors: TURAIHI ALEXANDER H. , SERNE ERIK H. , MOLTHOFF CARLA , GOUMANS MARIE-JOSE T. , JIMENEZ CONNIE J. , YUDKIN JOHN S. , SMULDERS YVO M. , VAN HINSBERGH VICTOR W. , ERINGA ETTO C. 
Published: June 2018

Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls glucose metabolism and vascular function through outside-to-inside communication and through vessel-to-vessel, or “vasocrine” signaling. Here, we studied this hypothesis in mice by examining effects of removal of local intramuscular PVAT on muscle blood flow and glucose metabolism. Using the hyperinsulinemic, euglycemic clamp (HEC) in combination with positron emission tomography, we found that local PVAT removal transiently reduces muscle glucose uptake by ±50 percent. Contrast-enhanced ultrasonography and intravital microscopy of the gracilis artery (GA) during the HEC showed that PVAT removal abolishes insulin-induced increases in GA diameter and abrogated insulin-stimulated muscle blood volume (microvascular recruitment or IMVR). The effect of PVAT on IMVR was mediated by distinct microvessels or anastomoses, which we showed using lightsheet microscopy of mice expressing mCherry in endothelial cells. Proteomics analysis revealed that PVAT removal significantly alters expression of 109 of 1719 detected proteins in muscle. Observed changes in protein expression included reduction of a mitochondrial protein cluster and of vesicle-associated membrane protein 5 (Vamp5), involved in Glut4 trafficking.
In conclusion, we have found that PVAT within muscle regulates muscle perfusion, glucose uptake and muscle protein expression, communicating with the distal microcirculation via microvascular anastomoses. These data highlight the importance of PVAT in vascular and metabolic physiology, and are relevant for type 2 diabetes and associated muscle dysfunction.

Disclosure
A.H. Turaihi: None. E.H. Serne: None. C. Molthoff: None. M.T. Goumans: None. C.J. Jimenez: None. J.S. Yudkin: None. Y.M. Smulders: None. V.W. van Hinsbergh: None. E.C. Eringa: None.
Adipsin Prevents Beta-Cell Failure in a Mouse Model of Type 2 Diabetes by Blocking Dedifferentiation and Cell Death
Authors: GOMEZ-BANOY NICOLAS , CHEN TONG , POIRIER BREANNE , RUBIO-NAVARRO ALFONSO , LO JAMES 
Published: June 2018

Adipsin and its downstream molecule C3a are complement factors that regulate insulin secretion. In order to assess the effects of adipsin in chronic DM2 and beta cell failure, we used adeno-associated virus (AAV) to replenish adipsin in db/db mice. A robust increase in both serum adipsin and C3a was achieved using AAV-Adipsin compared to control AAV-GFP, even 5 months after the injection (Figure 1a). Adipsin treatment significantly ameliorated hyperglycemia and boosted insulin levels (Figure 1b). More importantly, adipsin treatment increased beta cell mass and prevented beta cell loss in the late stages of DM2 (Figure 1c). Mechanistically, adipsin decreased beta cell death and dedifferentiation (Figures 1d and e). Adipsin also augmented expression of key beta cell transcription factors. Using unbiased transcriptomics, we identified that adipsin treatment downregulated the phosphatase Dusp26 in the pancreatic islets. Interestingly, overexpression of Dusp26 in beta cells and primary islets leads to a loss of beta cell transcription factors and an increase in palmitate-induced cell death (Figures 1f and g). Pharmacological inhibition of Dusp26 increased islet survival in palmitate conditions. Collectively these data suggest that adipsin/C3a and dusp26 directed therapies may represent a novel approach to conserve beta cell mass and achieve long term beta cell health for patients with T2D.

Disclosure
N. Gomez-Banoy: None. B. Poirier: None. A. Rubio-Navarro: None. J. Lo: None.