bluuebunny/crossref_metadata_2025_split huggingface dataset:
1807-P: MR-Based Assessments Better Capture Pathophysiologic Profiles in Nonalcoholic Fatty Liver Disease
Authors: KIM YOOMI , LEE DAEHO , LEE KIYOUNG 
Published: June 2020

Aims/Introduction: Several non-invasive tools are available for the assessment of steatosis and fibrosis in nonalcoholic fatty liver disease (NAFLD) including clinical scoring systems, serum markers, transient elastography (TE), and magnetic resonance imaging (MRI) techniques, such as MRI-proton density fat fraction (MRI-PDFF) and MR elastography (MRE). In the present study, we aimed to evaluate whether MRI-based examinations better reflected the pathophysiology and metabolic features of NAFLD and outperformed other non-invasive methods.
Materials and Methods: A total of 120 subjects (31 healthy volunteers and 89 NAFLD patients) were subjected to anthropometric and laboratory tests, TE, and MRI-based examinations in this cross-sectional study, including liver biopsy in some patients (n=39).
Results: MRI-PDFF correlated with hepatic fat measured by MR spectroscopy (r=0.978, p&lt;0.001) and was superior to the TE controlled attenuation parameter (CAP) (r=0.741, p&lt;0.001). In addition, MRI-PDFF showed stronger correlations with various pathophysiologic parameters for cellular injury, glucose and lipid metabolism, and inflammation, than the CAP. The MRI-PDFF and CAP cutoff levels associated with abnormal elevation of serum alanine aminotransferase were 9.8% and 269 dB/m, respectively. The MRE liver stiffness measurement (LSM) showed stronger correlations with liver enzymes, platelets, complement component 3, several clinical fibrosis scoring systems, the enhanced liver fibrosis (ELF) score than the TE LSM. In an analysis of only biopsied patients, MRE and TE performed better in discriminating significant fibrosis (≥F2) than the ELF test.
Conclusions: Our results suggest that MRI-based assessment of NAFLD is the best non-invasive tool that captures the histologic, pathophysiologic and metabolic features of the disease.

Disclosure
Y. Kim: None. D. Lee: None. K. Lee: None.
1811-P: Induction of Hepatic Steatosis by a Methionine Choline Deficient Diet Promotes FGF21-Induced Insulin Secretion Independent of Diabetes
Authors: KIMURA TOMOHIKO , DE JESUS DARIO F. , FUKUDA KAZUKI , KAHRAMAN SEVIM , SHIBUE KIMITAKA , ORIME KAZUKI , KULKARNI ROHIT 
Published: June 2020

While it is known that patients with nonalcoholic fatty liver disease exhibit enhanced insulin secretion, the factor(s) that contribute to this effect are not fully understood especially in nondiabetic subjects. Our aim was to examine crosstalk between a steatotic liver induced by a diet that is deficient in methionine choline (MCD) and pancreatic islets in the absence of diabetes/insulin resistance. Nine-week old male C57BL/6J mice were fed normal chow (CTL) or the MCD diet for 3 weeks followed by evaluation of glucose homeostasis, liver and pancreas pathology and hepatic gene expression by RNA-sequencing. Three weeks of MCD diet caused simple hepatic steatosis with hepatic triglyceride content 2-fold higher in MCD compared to CTL (n=5; p&lt;0.05). Hepatic FGF-21 mRNA, protein and circulating FGF-21 levels were all significantly increased in MCD (129-fold, 8-fold, 5-fold respectively; n=5; p&lt;0.05). Interestingly, while β-cell mass was not significantly altered between groups, insulin secretion as evaluated by ex-vivo GSIS in freshly isolated islets was significantly increased in MCD (5-fold; p&lt;0.05, n=10). Examination of liver samples from patients with or without steatosis mimicked hepatic MCD data in the mouse model. Thus a significant increase in both mRNA and protein FGF-21 were evident in the steatotic group (3-fold, 5-fold respectively; n=6, p&lt;0.05). Furthermore, 3 days treatment of nondiabetic human islets with recombinant FGF-21 protein led to a significant increase in GSIS compared to control (1.5-fold; p&lt;0.05, n=4). FGF-21 treatment of EndoC-βH1 cells revealed significant activation of AKT and ERK1/2 signaling that likely promoted the enhanced insulin secretion. Taken together, liver steatosis significantly increases circulating FGF-21 to promote enhanced insulin secretion via improved signaling in nondiabetic beta cells.

Disclosure
T. Kimura: None. D.F. De Jesus: None. K. Fukuda: None. S. Kahraman: None. K. Shibue: None. K. Orime: None. R. Kulkarni: None.

Funding
National Institutes of Health (R01DK067536, R01DK103215)
182-LB: Cardiovascular Response to Exercise in T2D
Authors: ENGE DANIEL , REUSCH JANE E. , REGENSTEINER JUDITH G. , SCHÄFER MICHAL , HUNTER KENDALL S. , BARKER ALEX J. , NADEAU KRISTEN J. , SCALZO REBECCA L. , SCHAUER IRENE E. , ABUSHAMAT LAYLA , WHIPPLE MARY O. , RAFFERTY DEIRDRE 
Published: June 2020

Type 2 diabetes (T2D) confers a greater likelihood of heart failure (HF) and hospitalization due to HF. Our group has reported sub-clinical cardiac dysfunction and aortic stiffness in youth and adults with uncomplicated T2D. As aortic stiffening is reported to precede HF and is common in people with uncomplicated T2D, we tested the hypothesis that aerobic exercise training will improve cardiac function and central arterial stiffness in people with T2D compared to participants of similar BMI without T2D. Sedentary adults with (n = 18, age 48±7, 45% female) and without (n = 20, age 45±7, 46% female) T2D, underwent MRI for cardiac function and aortic compliance (aortic relative area change [RAC] and pulse wave velocity [PWV]) before and after 15 weeks of aerobic exercise training. At baseline, both cohorts exhibit subclinical diastolic dysfunction, however, those with T2D had lower end-diastolic volume (EDVN,47.2±9.9 vs. 52.3±9.1 mL/m2) and end-systolic volume (ESVN,21.1±5.4 vs. 23.6±5.2 mL/m2), than controls. The T2D group had higher max thickness of the left ventricular (LV) septal wall (LVMTs, 10.5±1.8 vs. 9.3±1.6 mm) and LV lateral wall (LVMTl, 8.4±1.6 vs. 7.6±1.3 mm) than controls. Those with T2D also had lower RAC (12.7±1.6 vs. 20.2±1.6%) and higher PWV (7.4±1.3 vs. 3.9±0.6 m/s) than controls. Preliminary data in a subset post exercise intervention (n=7 with and n=8 without T2D), revealed increased EDVN(42.8±7.9 to 51.5±11.3 mL/m2) and ESVN(19.7±4.0 to 24.3±6.5 mL/m2) and decreased LVMTs(11.35±1.5 to 9.96±1.3 mm) and LVMTl(8.42±0.81 to 7.74±0.89 mm) in the T2D group, but cardiac endpoints were unchanged in controls. Post-intervention in both groups, ascending aorta RAC increased (control: 16.2±4 % to 18.5±1.7 and T2D: 10.6±1.7 % to 19.6±2.2 %) and PWV decreased (control: 6.3±2.0 to 3.4±0.3 and T2D: 8.0±1.4 to 2.9±0.7). Data from this study in progress suggest that adults with T2D have a greater degree of cardiac dysfunction and arterial stiffness than controls of similar BMI, which improve to a greater degree with exercise than in controls.

Disclosure
D. Enge: None. J.E. Reusch: None. J.G. Regensteiner: None. M. Schäfer: None. K.S. Hunter: None. A.J. Barker: None. K.J. Nadeau: None. R.L. Scalzo: None. I.E. Schauer: None. L. Abushamat: None. M.O. Whipple: None. D. Rafferty: None.

Funding
U.S. Department of Veterans Affairs (CX001532)
1820-P: A Direct AMPK Activator Reduces Liver Steatosis in a Mouse Model of NASH
Authors: MATHER KARLY M. , BOLAND MICHELLE L. , RIVERS EMMA , SRIVASTAVA ABHISHEK , SCHIMPL MARIANNE , ROBINSON JAMES , WAN PAUL T.C. , HANSEN JOSEFINE L. , READ JON A. , TREVASKIS JAMES L. , SMITH DAVID M. 
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD), is associated with metabolic disease and estimated to affect 25% of adults. NAFLD can progress to nonalcoholic steatohepatitis (NASH) which may lead to cirrhosis and hepatocellular carcinoma. There is no current treatment or cure for NASH.
AMPK (5’AMP-activated protein kinase) activators have shown potential for treating NAFLD/NASH due to their effects on fatty acid inhibition and cholesterol synthesis. To evaluate this potential, an AMPK activator (herein known as C455) was selected for a preclinical NASH study. C455 demonstrated potent and selective activation of AMPK (cellular EC50= 85 nM). X-ray crystallography showed the compound binds at the ADaM site, and pharmacokinetics determined a bioavailability of 45% and half-life of 3h.
Mice (male ob/ob on Amylin-NASH diet for 14-weeks or low-fat control) were dosed orally with vehicle or C455 at 3 or 30mg/kg daily. After 6 weeks of treatment, plasma ALT and terminal liver weight were decreased 32% and 22% respectively in mice treated with 30mg/kg C455 vs. vehicle. This dose also decreased liver lipid from 33% to 23%. Fibrosis via collagen staining did not improve with treatment, but significant decreases in mRNA transcripts for Col1a1(62%), Col1a2(59%), Col4a1(56%), and Timp1(55%) were seen with the high dose. Histology showed dose dependent increases in heart weight relative to body weight, and increased expression of genes associated with cardiac hypertrophy. Mice given 30mg/kg C455 also had increased cardiac glycogen storage compared to vehicle treated or LFD control mice.
Our study results show that systemic activation of AMPK in a diet-induced mouse model of NASH reduces plasma ALT, decreases liver lipid, and suppressed hepatic collagen gene expression but shows no histological improvement in fibrosis. Coupled with increased heart weight and glycogen storage, the data suggests that current small molecule activators of AMPK may not be viable therapies for the treatment of NASH-related fibrotic disease.

Disclosure
K.M. Mather: None. M.L. Boland: None. E. Rivers: None. A. Srivastava: None. M. Schimpl: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Robinson: None. P.T.C. Wan: None. J.L. Hansen: None. J.A. Read: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J.L. Trevaskis: Employee; Self; Gilead Sciences, Inc. D.M. Smith: Employee; Self; AstraZeneca.
1821-P: Foz Foz Mice with a Mutation in the Alms1 Gene Model the Metabolic Syndrome with Advanced Stages of Nonalcoholic Steatohepatitis and Fibrosis
Authors: LIU JIANYING , WANG SHENG-PING , D’AQUINO KATHARINE E. , HO GEORGE , WALLACE NATHANIEL H. , RANKIN MATTHEW M. , DU FUYONG , HINKE SIMON A. , ALBARAZANJI KAMAL A. , NAWROCKI ANDREA R. 
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH) is highly prevalent in modern societies frequently consuming diets rich in fats and carbohydrates. NASH is characterized by liver steatosis, inflammation and increased risk for liver fibrosis in human. There is no single animal model available that encompasses the defining features of NASH; therefore, it is of importance to thoroughly characterize available rodent models for NASH research and new drug discovery. Foz/foz mice have a mutation in the Alms1 gene, a ubiquitous protein essential for proper primary cilium function. They have similar defects such as metabolic syndrome, NASH and liver fibrosis to human with the same gene mutation. To better characterize the model, foz/foz mice were fed with western diet (WD, D12079B) for various duration. Compared with WT mice, foz/foz mice on WD had (1) increased BW gain driven by hyperphagia; (2) insulin/leptin resistance with decreased adiponectin levels and hyperlipidemia; (3) increased fat mass and hepatomegaly; (4) increased liver enzymes and elevated TIMP1 in plasma; (5) Liver gene expressions profiles of foz/foz mice showed up-regulation of fibrogenic genes and Lipogenesis, inflammation genes. Histopathology assessment showed foz/foz mice developed severe hepatic steatosis and increased marker of macrophage populations (F4/80 IHC staining). liver collagen content was significantly increased at 16 and 24 wks post WD feeding (PSR staining) compared to wild type mice fed the same diet. Our results suggest that the foz/foz mouse model has robust hallmark features of NASH such as metabolic syndrome, steatohepatitis, and fibrosis. In addition, our data suggest the presence of metabolic complications in other organs as well, as foz/foz mice develop proteinuria over time. The WD-induced foz/foz model exhibits several clinically relevant features and serves as a translational model of NASH.

Disclosure
J. Liu: None. S. Wang: None. K.E. D’Aquino: Employee; Self; Janssen Pharmaceuticals, Inc. Employee; Spouse/Partner; Janssen Pharmaceuticals, Inc. N.H. Wallace: None. M.M. Rankin: Employee; Self; Janssen Pharmaceuticals, Inc. Stock/Shareholder; Self; Johnson & Johnson. F. Du: None. S.A. Hinke: Employee; Self; Janssen Pharmaceuticals, Inc. Stock/Shareholder; Self; Johnson & Johnson. K.A. Albarazanji: None. A.R. Nawrocki: Employee; Self; Janssen Pharmaceuticals, Inc.
1828-P: Diurnal Pattern of Hepatic Insulin Extraction in Healthy and Type 2 Diabetes
Authors: ROMERES DAVIDE , YADAV YOGESH R. , RUCHI FNU , COBELLI CLAUDIO , MAN CHIARA DALLA , BASU ANANDA , BASU RITA 
Published: June 2020

Hepatic extraction of insulin is associated with insulin sensitivity in humans. It is unknown if a diurnal pattern of HE exists and if this differs between nondiabetic (ND) and type 2 diabetes (T2D) subjects. Here are data presented for 10 ND (BMI 29.4±1.3 kg/m2, age 57±3 yrs) and 9 T2D subjects (BMI 33±2 kg/m2, age 58±4 yrs, HbA1c 57±4 mM/mol) studied thus far. They ingested identical mixed meals (75 g carbs; 8 kcal/kg) at either breakfast (B), lunch (L) or dinner (D) in randomized Latin square order on three consecutive days with frequent sampling of plasma glucose (G), insulin (I) and C-peptide (C) concentrations. Fasting and post-meal glucose concentrations were higher while fasting and post-meal insulin, C-peptide concentrations were lower during meals in T2D as compared to ND subjects. Total and basal hepatic insulin extraction (HE and HEb, respectively) were estimated using the Oral Insulin and C-peptide Minimal Models. Differences with B, L and D and between ND and T2D were assessed by N-way ANOVA (a p-value&lt;0.05 was considered statistically significant). Results show that both HE and HEb were significantly lower (p=0.009, p=0.011, respectively) throughout the day in T2D than ND subjects (Fig 1). Our initial results suggest an emerging diurnal pattern of HE in T2D subjects with D being lower than other meals. These observations provide novel insights into the diurnal pattern of hepatic extraction throughout the day in T2D subjects.

Disclosure
D. Romeres: None. Y.R. Yadav: None. F. Ruchi: None. C. Cobelli: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca.

Funding
National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)
1832-P: Palmitic Acid Esters of Hydroxy Stearic Acids Reduce Endogenous Glucose Production through GPR43 Activation
Authors: SANTORO ANNA , ZHOU PENG , ZHU YAN , PERONI ODILE D. , NELSON ANDREW T. , SIEGEL DIONICIO , KAHN BARBARA 
Published: June 2020

Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), bioactive lipids with anti-inflammatory and antidiabetic effects, improve systemic and hepatic insulin sensitivity in insulin-resistant mice. PAHSAs augment insulin action on endogenous glucose production (EGP) through direct and indirect actions involving inter-tissue communication between liver and adipose tissue. The direct effect of PAHSAs to inhibit EGP is mediated through a cAMP dependent pathway involving Gα/i protein-coupled receptors. Here, we investigated which receptor mediates PAHSA effects on EGP. We found that 9-PAHSA activates GPR43 in a Ca+2 flux assay. 4-CMTB (0.4μM), a selective agonist-allosteric modulator of GPR43, reduced basal EGP by 23% and glucagon-stimulated EGP by 20% in primary hepatocytes ex vivo. Acute 9-PAHSA treatment (40μM) inhibited basal EGP to the same extent as 4-CMTB. 9-PAHSA suppression of basal EGP was abolished in primary hepatocytes from whole body GPR43 KO mice. Intravenous infusion of 9-PAHSA (9μg/hr) for 3 hrs decreased ambient EGP in chow-fed mice studied 5 hours after food removal (WT: vehicle= 24.2±1.9 vs. PAHSA= 17.2±0.7 mg/kg/min p&lt;0.05). This effect was absent in GPR43 KO mice (KO: vehicle= 25.3±4.2 vs. PAHSA= 23.4±2.7 mg/kg/min). We also examined whether GPR43 activation is required for the direct effect of 9-PAHSA on WAT lipolysis. Treatment with the β-adrenergic agonist isoproterenol increased FFA release from WAT explants by 3.8-fold, and 9-PAHSA inhibited isoproterenol-induced lipolysis by 21% which was similar to the effects of insulin and 4-CMTB. In WAT explants from GPR43 KO mice, 9-PAHSA suppression of isoproterenol-induced FFA release was abolished while insulin still suppressed lipolysis.
Sum: 9-PAHSA activates GPR43, which is involved in its direct effects to reduce hepatic glucose production and WAT lipolysis.
Conclusion: We have identified a new receptor that mediates some of the beneficial metabolic effects of PAHSAs.

Disclosure
A. Santoro: None. P. Zhou: None. Y. Zhu: None. O.D. Peroni: None. A.T. Nelson: None. D. Siegel: None. B. Kahn: Advisory Panel; Self; Harrington Discovery Institute, Janssen Pharmaceuticals, Inc., National Institute of Diabetes and Digestive and Kidney Diseases.

Funding
American Diabetes Association (1-18-PDF-134 to P.Z.); National Institutes of Health (DK43051, DK57521, DK106210, DK112622); JPB Foundation; American Heart Association
1833-P: A Novel Genetic Modified and Pegylated FGF21 Analog for the Treatment of Nonalcoholic Steatohepatitis in Nonhuman Primates
Authors: CUI AOYUAN , LI JIAN , JI SHAOHUI , MA FENGGUANG , WANG GENBEI , XUE YAQIAN , LIU ZHENGSHUAI , MA XIAOHUI , LI YU 
Published: June 2020

Nonalcoholic steatohepatitis (NASH) is becoming a major cause of liver diseases with no effective drugs in the clinic. Fibroblast growth factor 21 (FGF-21) has emerged as a potent metabolic regulator with therapeutic prospect to lipids and NASH in animal models and preclinical trials. FGF-21 and the agents mimicking its activity may be developed into the pharmacotherapeutic targets for NASH treatment. Here, we show that B1344, a site-specific PEGylated human FGF-21 analog, shifts physiology of NASH mice or cynomolgus monkeys towards that of the control animals fed with standard diet, and significantly improves their NASH phenotypes. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, methionine and choline deficiency (MCD) diet-fed mouse model of NASH were generated. Both short- and long-term administration of B1344 with the doses of 0.125 mg/kg and 0.2 mg/kg in mice protect against lipotoxicity damage and liver fibrosis. Expression levels of proinflammatory and fibrotic genes are decreased in livers of mice treated with B1344. Moreover, pharmacologic efficacies of B1344 on NASH were evaluated in NAFLD cynomolgus monkeys fed with high-fat diet. Strikingly, administration of B1344 causes a potent reduction of hepatic steatosis and fibrosis as measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF) and Sirius Red staining, and protects the monkeys from the progression of steatohepatitis. In addition, administration of B1344 results in a reduction of body weight and adiposity, and improvement of lipid profile and glycemic control. The biological properties of the novel FGF-21 analog B1344 is identical to human FGF-21. Together, these demonstrate impressive effects of B1344 on NASH and metabolic parameters, and may represent novel therapeutics for treating these diseases in humans.

Disclosure
A. Cui: None. J. Li: None. S. Ji: None. F. Ma: None. G. Wang: None. Y. Xue: None. Z. Liu: None. X. Ma: None. Y. Li: None.

Funding
Tasly Pharmaceutical Co. Ltd.; National Key Research and Development Program of China (2019YFA0802502); National Natural Science Foundation of China (81925008); Chinese Academy of Sciences (XDA12030210); Shanghai Science and Technology Commission (19140903300); National Science and Technology Major Projects (2019ZX09201001-001-001)
184-OR: Liver Fibrosis Scores Do Not Predict Response to Therapy in T2DM
Authors: LAVRYNENKO OLGA , ALATRACH MARIAM , ABDUL-GHANI MUHAMMAD , CERSOSIMO EUGENIO , ALKHOURI NAIM , PUCKETT CURTISS L. , DEFRONZO RALPH A. , ADAMS JOHN M. , VASQUEZ JUAN A. , CLARKE GEOFFREY D. 
Published: June 2020

Patients with NAFLD and T2DM are at high risk of liver fibrosis. Pioglitazone(Pio) and GLP-1RAs have shown efficacy against NAFLD. The EDICT trial assessed Triple (pio/exenatide/metformin(met)) vs. Conventional(Conv) (met/SU/insulin) Therapy.
Aim: Evaluate the effect of these approaches on liver fibrosis scores and hepatic fibrosis, steatosis (FibroScan).
Methods: 144 newly diagnosed T2DM were randomized to receive Triple or Conv Therapy to maintain HbA1c &lt;6.5%. After 2 yrs baseline measurements were repeated and liver fibrosis scores (AST/ALT ratio, APRI, FIB-4, NFS) were calculated.
Results: Patients were well matched for age, BMI, HbA1c (8.8%), LFTs. Neither therapy reduced any liver fibrosis score. Triple, but not Conv, reduced AST/ALT (p&lt;0.001). The greatest AST/ALT reductions with Triple Therapy occurred in subjects in highest AST/ALT tertile at baseline. Only 1 subject receiving Triple Therapy had fibrosis score &gt;0, while 43% of Conv Therapy subjects had fibrosis score of F3/F4 (p&lt;0.0001). 87% of Conv Therapy subjects had steatosis score of S2/S3 vs. to 38% of Triple Therapy (p&lt;0.001) (Table).
Conclusion: Both Triple (6.0%) and Conventional Therapy (6.7%) markedly reduced HbA1c after 2 yrs, but only Triple Therapy reduced AST/ALT. Fibrosis scores did not change in either group and are not useful in predicting response to therapy. Triple Therapy completely prevented fibrosis and reduced steatosis by &gt;50 % vs. Conventional Therapy.

Disclosure
O. Lavrynenko: None. M. Alatrach: None. M. Abdul-Ghani: None. E. Cersosimo: None. N. Alkhouri: Research Support; Self; Allergan plc. C.L. Puckett: None. R.A. DeFronzo: None. J.M. Adams: None. J.A. Vasquez: None. G.D. Clarke: None.