Glucagon-Like Peptide 1 Decreases Lipotoxicity in Non-Alcoholic Steatophepatitis

Research output: Contribution to journalArticle

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.

DESIGN: 14 patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomized, 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. +0.04 kg/m2;p<0.001), HbA1c (-0.3 vs. +0.3%;p<0.01), cholesterol-LDL (-0.7 vs. +0.05 mmol/L;p<0.01), ALT (-54 vs -4.0 IU/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. +54.8 pmol/L insulin required to ½ maximally suppress serum NEFA; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic DNL 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.

Details

Original languageEnglish
Pages (from-to)399–408
JournalJournal of Hepatology
Volume64
Issue number2
Early online date21 Sep 2015
Publication statusPublished - Feb 2016

Keywords

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