bluuebunny/crossref_metadata_2025_split huggingface dataset:
1793-P: C-Peptide Kinetics: The Van Cauter Population Model May Not Be Applicable to Post–Gastric Bypass Adults with Postprandial Hyperinsulinemic Hypoglycemia
Authors: SCHIAVON MICHELE , HERZIG DAVID , HEPPRICH MATTHIAS , DONATH MARC Y. , STETTLER CHRISTOPH , BALLY LIA , MAN CHIARA DALLA 
Published: June 2020

Insulin secretion is key to understand postprandial hyperinsulinemic hypoglycemia (PHH), an increasingly recognized and potentially debilitating complication of gastric bypass (GB) surgery. To assess it noninvasively, the Oral C-peptide Minimal Model (OCMM) can be used. This requires to know C-peptide (CP) metabolic clearance rate (MCR) usually fixed to the values predicted by the Van Cauter (VC) population model, but this has never been assessed in PHH individuals. Here, the aim is to fill this gap. Two groups of post-GB adults with PHH underwent either a 75g oral glucose (11F/5M; age=43±8 y; BMI=28.2±7.1kg/m2) or a 60g mixed-meal (9F/3M; age=44±10y; BMI=27.4±3.9kg/m2) tolerance test with sampling for plasma glucose and CP over 3.5 and 3h, respectively. The OCMM was used to describe CP concentration with CP kinetics fixed to VC or estimated based on data (DB). Model performance was assessed by its ability to predict CP data. In both groups, the VC approach underestimated CP-peak and overestimated CP-tail, while the DB one well predicted CP data in all subjects (Figure 1A). As a consequence, MCR resulted significantly higher with DB than VC approach (Figure 1B). The present findings question the validity of the VC population model to predict CP kinetics in PHH patients and call for CP bolus experiments to develop a reliable kinetic model in this population.

Disclosure
M. Schiavon: None. D. Herzig: None. M. Hepprich: None. M.Y. Donath: Advisory Panel; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Roche Pharma, Sanofi-Aventis. C. Stettler: None. L. Bally: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH.

Funding
Italian Ministry of Education (232/2016); Swiss National Science Foundation (PCEGP3_186978); University of Padova
1795-P: Proinsulin-Insulin Pancreatic Islets In-situ Expression Mirrors Metabolic Defects Observed in Type 2 Diabetic and Glucose Intolerant Living Donors
Authors: BRUSCO NOEMI , SEBASTIANI GUIDO , LICATA GIADA , GRIECO GIUSEPPINA E. , NIGI LAURA , FIGNANI DANIELA , MOFFA SIMONA , SORICE GIAN PIO , DI GIUSEPPE GIANFRANCO , ASSUNTA CEFALO CHIARA MARIA , MARI ANDREA , DOTTA FRANCESCO , GIACCARI ANDREA , MEZZA TERESA 
Published: June 2020

Increased circulating levels of proinsulin (PI) and proinsulin-to-insulin ratio (PI/INS) is a well-known abnormality in type 2 diabetes (T2D). The exact mechanism behind this increase in T2D, as well as in T1D, is unknown. The aim of this study was to analyze proinsulin and insulin expression in pancreatic islets of tissue biopsies of patients undergoing partial pancreatectomy (PP) with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and T2D, in order to explore the alterations that occur in islets during metabolic stress. Frozen sections of pancreatic tissue biopsies (n=17) classified following OGTT into n=5 NGT, n=9 IGT and n=3 T2D were stained for INS and PI through double immunofluorescence staining. β-cell glucose sensitivity (calculated as the ratio of insulin secretion and glucose increments), basal insulin secretion, and glucose levels 2-hours following OGTT were analyzed. Image analysis was performed on each individual islet through Volocity software. In-situ staining measurements were correlated with patients’ clinical parameters. PI-INS colocalization as well as the area (µm2) of PI positivity and PI/INS ratio gradually increased from NGT to IGT and T2D pancreatic islets (p&lt;0.0001), suggesting an altered localization and processing of PI in INS which potentially cause the release of immature granules with a higher relative content of PI. We demonstrated that the increase of PI/INS ratio was associated with higher basal INS (r=0.65 p&lt;0.004) and glucose levels 2-hours following OGTT (r=0.75 p&lt;0.0008). Finally, we also observed that the reduction of β-cell glucose sensitivity is linked to increase of in-situ PI-INS ratio (r=-0.6 p&lt;0.02).
In conclusion, our results suggest that the increase of PI/INS ratio in pancreatic islets is directly related to metabolic defects in dysfunctional β cells, highlighting the importance of correct PI processing and folding in the maintenance of glucose homeostasis.

Disclosure
N. Brusco: None. G. Sebastiani: None. G. Licata: None. G.E. Grieco: None. L. Nigi: None. D. Fignani: None. S. Moffa: None. G. Sorice: None. G. Di Giuseppe: None. C. Cefalo: None. A. Mari: Consultant; Self; Lilly Diabetes. Research Support; Self; Boehringer Ingelheim International GmbH. F. Dotta: None. A. Giaccari: Speaker’s Bureau; Self; Amgen, AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi-Aventis. T. Mezza: None.

Funding
European Foundation for the Study of Diabetes; AstraZeneca
1797-P: Effect of LCZ696 and Its Components Sacubitril and Valsartan on Insulin Secretion and Glucose Homeostasis in Mice
Authors: ESSER NATHALIE , SCHMIDT CHRISTINE R. , BARROW BREANNE , CRONIC LAURA , HACKNEY DARYL J. , MONGOVIN STEVE M. , HULL REBECCA L. , ZRAIKA SAKENEH 
Published: June 2020

In type 2 diabetes, HbA1c decreases upon treatment of heart failure with the angiotensin receptor-neprilysin (NEP) inhibitor LCZ696 (LCZ). We sought to determine whether the components of LCZ, the NEP inhibitor sacubitril (SAC) and angiotensin receptor blocker valsartan (VAL), enhance insulin secretion and if so, their effects are additive when combined in LCZ. C57BL/6 mice fed high fat diet (HFD) received injections of vehicle (VEH) or low-dose streptozotocin (3 × 30 mg/kg; STZ), the latter to induce diabetes. Mice were continued for 8 weeks on HFD alone (CTL) or supplemented with LCZ (114 mg/kg/d), SAC (48 mg/kg/d) or VAL (54 mg/kg/d). All drugs significantly reduced body weight gain in both VEH and STZ groups, with LCZ being more effective than SAC (Table). SAC and VAL, but not LCZ, lowered fed and fasting plasma glucose and increased insulin release during an IV glucose tolerance test (IVGTT) in STZ mice only (Table). In VEH and STZ mice, insulin sensitivity was similar among the 4 treatment groups; however, SAC enhanced glucose disposal during IVGTT (Table). None of the treatments altered pancreatic ß- and α-cell mass or lipolysis (not shown). In sum, SAC and VAL exert beneficial anti-obesity, glycemic and insulinotropic effects when given alone in obese and/or diabetic mice. Additional studies are needed to understand why, when SAC and VAL are combined in LCZ, only anti-obesity effects are observed.

Disclosure
N. Esser: None. C.R. Schmidt: None. B. Barrow: None. L. Cronic: None. D.J. Hackney: None. S.M. Mongovin: None. R.L. Hull: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation.

Funding
Novartis Pharmaceuticals Corporation (LCZ696BUSNC09T)
1798-P: Chronic Administration of a Long-Acting Glucagon Analogue Results in Enhanced Insulin Secretory Activity in a Directly-Observed Murine Model
Authors: SUBA KINGA , PATEL YATEEN S. , ALONSO ALDARA MARTIN , SCOTT REBECCA , MINNION JAMES S. , LECLERC ISABELLE , OWEN BRYN , DISTASO WALTER , TAN TRICIA M. , MURPHY KEVIN , BLOOM STEPHEN , RUTTER GUY A. , SALEM VICTORIA 
Published: June 2020

Aims: GLP-1 (GLP-1R) and glucagon (GCGR) receptor co-agonists are in development to treat type 2 diabetes. The effect of chronic GCGR agonism on weight loss is well-documented, but its direct influence on islet function remains poorly understood. We investigated the effects of a long-acting glucagon analogue G778 on pancreatic islet calcium dynamics.
Methods: C57Bl/6 (n=9 per group) mice with diet-induced obesity (DIO) received daily subcutaneous injections of G778 100nmol/kg or saline (and calorie restricted to achieve weight matching) for 40 days. All mice had syngeneic islets with beta-cell specific expression of the calcium fluorophore GCaMP6f implanted in the anterior chamber of the eye, providing a direct, longitudinal readout of beta-cell function in vivo using confocal microscopy. Such islets were tested in vitro to measure the effects of G778 on whole islet calcium dynamics. Another experiment measured the effects of G778 administration on oxygen consumption in a CLAMS system.
Results: G778 produced a small but significant rise in energy expenditure (EE) in mice. At 40 days, there was non-significant difference in body weight loss between the saline and G778-treated groups (0.9g ±1.1 vs. 3.4g ±0.7 p=0.07), but a marked improvement in glucose tolerance in mice treated long term with the glucagon analogue (15 min glucose on a 2mg/kg IPGTT 15.9 mmol/L vs. 9.2 mmol/L p&lt;0.001). Islet readouts over the course of the experiment revealed that glucagon receptor agonism was able to restore calcium activity of islets in DIO mice in vivo. In vitro findings confirmed that G778 promoted calcium waves of longer duration and heightened connectivity above 7mM glucose (p=0.05).
Summary: Our data suggest that the glucagon element of a glucagon/GLP-1 analogue contributes to weight-loss partly through an elevation in EE but also has independent effects on insulin secretory function, promoting more robust and sustained beta-cell calcium responses.

Disclosure
K. Suba: None. Y.S. Patel: None. A. Martin Alonso: None. R. Scott: None. J.S. Minnion: None. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. Research Support; Spouse/Partner; Servier. B. Owen: None. W. Distaso: None. T.M. Tan: None. K. Murphy: None. S. Bloom: None. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd. V. Salem: None.

Funding
Diabetes UK (15/0005317)
1803-P: Antifibrotic Effect of a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist (HM15211) in BDL-Induced Liver Fibrosis Mice
Authors: KIM JUNG KUK , LEE JONG SUK , KWON HYUNJOO , LEE JONGSOO , KIM DAEJIN , BAE SUNGMIN , LEE SANG HYUN , CHOI IN YOUNG 
Published: June 2020

Fibrosis due to nonalcoholic steatohepatitis (NASH) remains a major cause of liver-related mortality. However, no medication has been approved despite accelerated drug development. Since multiple biological pathways are involved, strategy simultaneously targeting multiple pathways might be required to effectively treat fibrosis. To address this, we developed a novel long-acting GLP-1/GIP/Glucagon triple agonist, HM15211. Previously, HM15211 significantly improved fibrosis as well as steatosis and inflammation in MCD-diet mice. In addition to the diet-induced models, bile duct ligation (BDL) has also been extensively used as an animal model of fibrosis. Here, we further investigated the anti-fibrotic effects of HM15211 in BDL-induced fibrosis mice. Two days post BDL (single ligation), the mice were administered either with HM152111 or obeticholic acid (OCA) for 2 weeks, followed by histological analysis. HM15211 treatment showed greater reduction in hepatic hydroxyproline (HP) (450.5, 351.7 and 253.6 nmol/g liver for vehicle, OCA and HM15211) and fibrosis score (1.7, 1.8 and 1.0 for vehicle, OCA and HM15211) compared to OCA. Consistently, HM15211, but not OCA, treatment was associated with the reduction of serum surrogate markers of fibrosis including TGF-β (-61.4, 9.1% vs. vehicle for HM15211, OCA), TIMP-1 (-71.6, -13.9% vs. vehicle), and hyaluronic acid (-68.9, 25.0% vs. vehicle). To further clarify its benefits in fibrosis, BDL (double ligation) mice with an extended induction period (up to 2 weeks) was used. Notably, despite the progression to advanced liver fibrosis, HM15211 treatment still attenuated HP (571.5 and 334.3 nmol/g liver for vehicle and HM15211) and fibrosis score markedly. Considering the pathologic features of BDL mice (liver fibrosis without liver fat accumulation), these results demonstrate the direct anti-fibrotic effect of HM15211. Further studies are needed to assess the clinical relevance of these findings.

Disclosure
J. Kim: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. H. Kwon: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.
1805-P: Dietary Nitrate Prevents High-Fat Diet-Induced Glucose Intolerance and Liver-Specific Reactive Oxygen Species Emission
Authors: DESORMEAUX GENEVIEVE , PETRICK HEATHER L. , BRUNETTA HENVER , HOLLOWAY GRAHAM 
Published: June 2020

Introduction: The liver is particularly susceptible to the detrimental effects of a high fat diet (HFD), and rapidly develops insulin resistance. While the underlying mechanisms associated with hepatic insulin resistance are not fully understood, mitochondria play a crucial role in regulating lipid metabolism and redox balance. Recently, dietary nitrate was shown to attenuate HFD-induced glucose intolerance, however the mechanism(s) remains unknown. Therefore, in the present study we examined the possibility that dietary nitrate increased mitochondrial lipid-supported respiration and/or attenuated reactive oxygen species (ROS) emission.
Methods: Male C57Bl/6J mice (n = 22) were randomly assigned to consume a control diet (10% fat), HFD (60% fat), or HFD with 4mM sodium nitrate in drinking water for 8 weeks. Whole body glucose tolerance and energy expenditure (indirect calorimetry) were determined, and mitochondrial respiration and reactive oxygen species (ROS) emission were assessed in liver samples.
Results: Compared to control animals, the consumption of HFD increased whole body fat oxidation and body mass, and induced glucose intolerance. The consumption of dietary nitrate did not affect HFD-mediated changes in energy expenditure, rates of fat oxidation or body mass, but nevertheless attenuated the induction of glucose intolerance. Within the liver, HFD-feeding in the presence or absence of dietary nitrate, did not alter pyruvate or lipid (palmitoyl-CoA) supported respiration, or the sensitivity to malonyl-CoA-mediated inhibition of lipid-supported respiration. In contrast, while HFD increased the endogenous ROS production, nitrate prevented this response.
Conclusion: These data demonstrate that nitrate supplementation attenuated the HFD-mediated induction of whole-body glucose intolerance in association with a reduction in ROS emission within the liver. Future research needs to determine causality between these observations.

Disclosure
G. DesOrmeaux: None. H.L. Petrick: None. H. Brunetta: None. G. Holloway: None.

Funding
Natural Sciences and Engineering Research Council of Canada (400362)
1806-P: Vitamin D Deficiency Impairs mTORC2/Akt Signaling through Downregulating SIRT1 and Results in Increased Hepatic Gluconeogenesis
Authors: YUAN QI , YANG JINGLEI , SUN MENGYUE , TANG SHAN , DONG MEIJUAN , MAO LI 
Published: June 2020

1,25(OH)2D3 as an active form of vitamin D is involved in the development of many metabolic-related diseases including diabetes. While prospective epidemiological studies have shown that vitamin D deficiency is implicated in the regulation of glucose metabolism, the specific mechanism still remains unclear. Here, we generated 1α(OH)ase-null mice and discovered that these mice developed hepatic glucose overproduction and hepatic insulin resistance accompanied by decreased expression of Sirt1. ChIP and Luciferase assay confirmed that 1,25(OH)2D3 activating vitamin D receptor (VDR) directly interacts with one vitamin D response element located in Sirt1 promoter to up-regulate its transcription, triggering a cascade of phosphorylation of Akt at S473 and FOXO1 at S256 and resulting in decreased transcription of the gluconeogenic genes glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (PCK1), eventually hepatic glucose overproduction. We have identified a signaling pathway involving VDR, Sirt1, Rictor (a component of mTOR complex 2 [mTorc2]), Akt, and FoxO1 that regulates gluconeogenesis, and identified Sirt1 and FoxO1 as key modulators of increased gluconeogenesis induced by vitamin D deficiency. Our work demonstrates a novel mechanism of 1,25(OH)2D3 deficiency-induced hyperglycemia mediated through Sirt1 downregulation.

Disclosure
Q. Yuan: None. J. Yang: None. M. Sun: None. S. Tang: None. M. Dong: None. L. Mao: None.

Funding
National Natural Science Foundation of China (81400789)
1808-P: Hepatocyte Traf Family Members Link Inflammation to Liver Steatosis and Insulin Resistance
Authors: ZHANG ZHIGUO , LIN HAIYAN , ZHONG XIAO , RUI LIANGYOU 
Published: June 2020

Obesity is associated with chronic inflammation that exacerbates insulin resistance and metabolic disease. Inflammation drives the pathogenesis of nonalcoholic fatty liver disease (NAFLD), hepatic manifestations of obesity. Hepatic inflammatory microenvironments are believed to induce reprogramming of metabolic pathways; however, intracellular molecules coupling inflammation to metabolism remain poorly understood. Cytokines, damage-associated (DAMPs) and pathogen-associated molecular patterns (PAMPs) are known to activate Traf family members that in turn activate the NF-κB and other inflammatory pathways. We previously reported that hepatic Traf2 and Traf3 augment hepatic glucose production. Here, we demonstrate that hepatocyte Traf2, Traf3 and Traf6 act in concert to promote liver steatosis and insulin resistance. We ablated hepatocyte Traf2, Traf3, and Traf6 individually and in combination (Traf2,3,6Δhep) in adult Traf2flox/flox, Traf3flox/flox, Traf6flox/flox, and Traf2,3,6flox/flox mice, respectively, using AAV-TBG-Cre vectors. Metabolic abnormality was more severe in Traf2,3,6Δhep mice relative to Traf2Δhep, Traf3Δhep and Traf6Δhep mice. Remarkably, Traf2,3,6Δhep mice were resistant to high fat diet-induced liver steatosis, insulin resistance, and glucose intolerance. Hepatic PPARα, a master regulator of fatty acid β oxidation, was substantially elevated in Traf2,3,6Δhep mice. Conversely, in primary hepatocytes, overexpression of Traf3 markedly decreased PPARα stability and protein levels. Traf3 coimmunoprecipitated with PPARα and decreased PPARα transcriptional activity. In primary hepatocytes, ablation of Traf2, Traf3 and Traf6 significantly increased fatty acid β oxidation, and overexpression of Traf3 had the opposite effects. Together, our results unveil an unrecognized hepatocyte Traf/PPARα/fatty acid β oxidation pathway that couples inflammation to liver steatosis and insulin resistance in obesity.

Disclosure
Z. Zhang: None. H. Lin: None. X. Zhong: None. L. Rui: None.
181-OR: Effect of Sevelamer and a Synbiotic on Insulin Sensitivity in Obese Individuals
Authors: BAEUERLE ERIC , LIANG HANYU , GANAPATHY VINUTHA , FERNANDEZ ROMAN , SATHAVARODOM NATTAPOL , WANG CHEN-PIN , ESPINOZA SARA E. , MUSI NICOLAS 
Published: June 2020

The human gut and its microbial content (microbiome) may contribute to the pathogenesis of obesity, insulin resistance and type 2 diabetes. Possible mechanisms include altered bacterial profile, increased intestinal permeability, and elevated bacterial lipopolysaccharide (LPS) leading to low-grade systemic inflammation termed metabolic endotoxemia. We hypothesized that two interventions with putative LPS-lowering effects, sevelamer and a synbiotic (combination pre- and probiotic), would improve peripheral insulin sensitivity in obese subjects. Based upon pre-clinical studies, sevelamer is reported to sequester LPS in the GI tract, whereas a synbiotic of Bifidobacterium longum plus oligofructose can improve intestinal barrier integrity. We randomized 22, normal glucose tolerant (NGT), lean (15F/7M, BMI=23.0, age=45.4yr, A1c=5.3%) and 28 NGT, obese subjects (20F/8M, BMI=32.7, age=51.9yr, A1c=5.5%) to receive oral sevelamer, synbiotic or placebo daily for 28 days. Insulin sensitivity (euglycemic clamp), cholesterol, endotoxemia (LPS, LBP, CD14), and intestinal permeability (lactulose/mannitol ratio, zonulin) were assessed before and after intervention. Obese subjects had reduced baseline insulin sensitivity compared to lean subjects (M value, -28.6%, p=0.0001 based on 2-sample t-test). Generalized estimating equation analysis showed that sevelamer increased insulin sensitivity (M value, +25.6%, p=0.022) and lowered plasma LDL (-16.4%, p=0.016) in obese subjects compared to placebo-treated obese subjects. Synbiotic did not significantly alter insulin sensitivity or lipids compared to placebo in obese subjects. Lean subjects saw no change in insulin sensitivity with either treatment. Neither treatment significantly altered plasma LPS or intestinal permeability in lean or obese subjects.
In conclusion, sevelamer improves insulin sensitivity and LDL in obese subjects, and this effect is mostly independent of parameters of endotoxemia and intestinal permeability.

Disclosure
E. Baeuerle: None. H. Liang: None. V. Ganapathy: None. R. Fernandez: None. N. Sathavarodom: None. C. Wang: None. S.E. Espinoza: None. N. Musi: None.

Funding
American Diabetes Association (7-13-GSK-01 to N.M.); National Institutes of Health (T32GM113896)
1810-P: Triple Combination Therapy of GLP-1 Receptor Agonist Semaglutide with an FXR Agonist and AC Inhibitor Reverses Nonalcoholic Steatohepatitis (NASH) in Diet-Induced and Biopsy-Confirmed Mice
Authors: NORLIN JENNY , MIRANDA DIEGO A. , BATES JAMIE G. , ZOIS NORA E. , VEIDAL SANNE , FEIGH MICHAEL , TREVASKIS JAMES L. , LATTA MARKUS 
Published: June 2020

Semaglutide (SEMA), FXR agonists and ACC inhibitors are under active clinical investigation for the treatment of NASH. Here, we explored whether the effects of SEMA (0.12 mg/kg, s.c., q.d.) on NASH endpoints could be enhanced by addition of an FXR agonist (cilofexor, CILO; 30 mg/kg) and/or an acetyl-CoA carboxylase inhibitor (firsocostat analogue, ACCi; 5 mg/kg, both p.o., q.d.) in the AMLN diet-induced and biopsy-confirmed DIO-NASH mouse (n=15-16/group). After 12 weeks of treatment, SEMA and triple therapy reduced body weight 18%, being slightly enhanced in the double combination of SEMA+CILO (21%). Liver triglyceride concentration was reduced by SEMA (by 38% vs. vehicle, p&lt;0.001). Addition of CILO or ACCi or both to SEMA further reduced liver lipid by 64%, 73% and 81%, respectively (all p&lt;0.001 vs. SEMA). Histopathological pre-to-post NAFLD activity score (NAS) was reduced in 3/16 (19%) of vehicle controls and in all mice (100%) treated with SEMA or triple therapy. Further, the number of mice that exhibited a 3+ point improvement in NAS was improved with the triple combination (12/16; 75%) vs. SEMA alone (2/16, 13%). Likewise, the triple combination caused the greatest improvements in fibrosis stage pre-to-post (7/16, 44%, improved; 1/16 worsened), followed by the SEMA-treated group (6/16, 38% improved; 0/16 worsened) relative to vehicle (2/16, 13% improved; 7/16, 44% worsened). Collagen-1a and a-SMA immunoreactivity (% area) tended to be or were significantly improved with SEMA (4.2%; n.s., and 1.4%; p&lt;0.001) and triple therapy (3.9%; p&lt;0.045 and 0.9% p&lt;0.001) vs. vehicle (6.3% and 4.6%). SEMA significantly improved NAS and fibrosis endpoints. While addition of either single agent improved liver fat reduction, triple therapy improved pre-to-post NAS and fibrosis stage relative to SEMA alone in DIO-NASH mice. These data support development of combination approaches for NASH.

Disclosure
J. Norlin: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. D.A. Miranda: None. J.G. Bates: Employee; Self; Gilead Sciences, Inc. N.E. Zois: Employee; Self; Gubra. S. Veidal: None. M. Feigh: None. J.L. Trevaskis: Employee; Self; Gilead Sciences, Inc. M. Latta: Employee; Self; Novo Nordisk A/S.