Effect of liraglutide on adipose insulin resistance and hepatic de-novo lipogenesis in non-alcoholic steatohepatitis: substudy of a phase 2, randomised placebo-controlled trial

Abstract

BackgroundAdipose tissue insulin resistance and lipotoxicity are key pathognomonic features in non-alcoholic steatohepatitis (NASH). Liraglutide is a once daily, glucagon-like peptide 1 (GLP-1) analogue that significantly improves glycaemic control, weight, and hepatic steatosis. The aim of this phase 2 study was to determine the effect of liraglutide on insulin sensitivity (hepatic, muscle, adipose), hepatic lipogenesis, and markers of adipose inflammation. Methods14 patients with biopsy-proven NASH were randomly assigned to either 1·8 mg liraglutide or placebo (once a day subcutaneously) for 12 weeks as part of the metabolic substudy of the double-blind, randomised placebo-controlled LEAN trial. At baseline and 12 weeks, patients underwent paired two-step hyperinsulinaemic euglycaemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis. Serum adipocytokines were measured with Fluorokine MAP multiplex kits (R&D Systems, UK). In-vitro isotope experiments were performed with Huh-7 and primary human hepatocytes. The LEAN trial is registered with ClinicalTrials.gov, number NCT01237119. FindingsLiraglutide significantly decreased weight, waist circumference, HbA1c, fasting glucose, LDL, and liver enzymes compared with placebo. Liraglutide significantly increased the suppression of hepatic glucose production with low-dose insulin. Liraglutide significantly decreased circulating non-esterified fatty acid (NEFA) in the fasting, low-dose, and high-dose insulin states. Liraglutide significantly reduced the insulin concentration required to half-maximally suppress circulating NEFA and significantly decreased adipose tissue lipolysis, as shown by a reduction in interstitial fluid glycerol concentrations. Furthermore, liraglutide significantly improved serum markers of adipose inflammation—namely, leptin, adiponectin, and chemokine ligand 2. In addition, liraglutide significantly decreased de-novo lipogenesis in vivo, as measured by incorporation of deuterated 2H20 into palmitate, compared with placebo. In support of our clinical observations, in-vitro experiments using both the Huh-7 cell line and primary cultures of human hepatocytes showed decreased de-novo lipogenesis, measured by incorporation of 14C-acetate into cellular lipid after treatment with GLP-1 (exendin-4). InterpretationLiraglutide significantly reduces metabolic dysfunction, hepatic lipogenesis, hepatic and adipose insulin resistance, and adipose inflammation in patients with NASH. GLP-1 analogue therapy might be a novel treatment for patients with this condition. FundingWellcome Trust, National Institute of Health Research, Novo Nordisk.