Format

Send to

Choose Destination
J Hepatol. 2016 Feb;64(2):399-408. doi: 10.1016/j.jhep.2015.08.038. Epub 2015 Sep 21.

Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.

Author information

1
NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK. Electronic address: mattyarm2010@googlemail.com.
2
NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK.
3
CRUK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
4
Centre for Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham, UK.
5
School of Sport, Exercise & Rehabilitation Sciences, University of Birmingham, Birmingham, UK.
6
Oxford Centre for Diabetes, Endocrinology and Metabolism, and NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK.
7
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.

Abstract

BACKGROUND & AIMS:

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.

KEYWORDS:

Adipose tissue; Glucagon-like peptide 1; Insulin sensitivity; Lipolysis; Non-alcoholic fatty liver

PMID:
26394161
PMCID:
PMC4713865
DOI:
10.1016/j.jhep.2015.08.038
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center