title: Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.
abstract: OBJECTIVE
  Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH.
  
  
  METHODS
  Fourteen patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomised, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes.
  
  
  RESULTS
  Liraglutide reduced BMI (-1.9 vs. +0.04kg/m(2); p<0.001), HbA1c (-0.3 vs. +0.3%; p<0.01), cholesterol-LDL (-0.7 vs. +0.05mmol/L; p<0.01), ALT (-54 vs. -4.0IU/L; p<0.01) and serum leptin, adiponectin, and CCL-2 (all p<0.05). Liraglutide increased hepatic insulin sensitivity (-9.36 vs. -2.54% suppression of hepatic endogenous glucose production with low-dose insulin; p<0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (-24.9 vs. +54.8pmol/L insulin required to ½ maximally suppress serum non-esterified fatty acids; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic de novo lipogenesis in vivo (-1.26 vs. +1.30%; p<0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01).
  
  
  CONCLUSIONS
  Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.
authors.affiliation: NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK. Electronic address: mattyarm2010@googlemail.com.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Armstrong
authors.affiliation: NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Hull
authors.affiliation: NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK.
authors.forename: Kathy
authors.initials: K
authors.lastname: Guo
authors.affiliation: CRUK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Barton
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Hazlehurst
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Gathercole
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Maryam
authors.initials: M
authors.lastname: Nasiri
authors.affiliation: School of Sport, Exercise & Rehabilitation Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Jinglei
authors.initials: J
authors.lastname: Yu
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, and NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Gough
authors.affiliation: NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Newsome
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, and NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK. Electronic address: jeremy.tomlinson@ocdem.ox.ac.uk.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
mesh_terms: D000328:Adult; D000368:Aged; D015992:Body Mass Index; D004311:Double-Blind Method; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives*; D015309:Glucose Clamp Technique / Q000379:methods; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D000069450:Liraglutide / Q000008:administration & dosage / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000069450:Liraglutide
keywords: Adipose tissue; Glucagon-like peptide 1; Insulin sensitivity; Lipolysis; Non-alcoholic fatty liver