Abstract
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. 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. 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). 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.
Highlights
Non-alcoholic steatohepatitis (NASH) incurs a significantly increased risk of both liver- and cardiovascular disease (CVD)related morbidity and mortality [1], yet, there remains a lack of safe and efficacious pharmacological treatments [2].Insulin resistance (IR) in both liver and adipose tissue is believed to be a key driver in the pathogenesis of NASH [3]
Detailed metabolic studies, using ‘gold-standard’ euglycaemic clamps and/or stable isotope tracers, have demonstrated that patients with NASH have severe adipose IR, alongside increased hepatic IR [4,5] and de novo lipogenesis (DNL) [6,7]. Even though collectively these contribute to excess lipid accumulation in the liver, it is widely believed that the overspill of non-esterified fatty acids (NEFA) and release of triglyceride-derived toxic metabolites from adipose tissue lipolysis, form the primary lipotoxic insult in the pathogenesis of NASH and its extrahepatic complications including increased CVD-morbidity and mortality [1,8]
Our experimental medicine study dissects the mechanism of action of the Glucagon-like peptide-1 (GLP-1) analogue, liraglutide, in patients with NASH
Summary
Non-alcoholic steatohepatitis (NASH) incurs a significantly increased risk of both liver- and cardiovascular disease (CVD)related morbidity and mortality [1], yet, there remains a lack of safe and efficacious pharmacological treatments [2].Insulin resistance (IR) in both liver and adipose tissue is believed to be a key driver in the pathogenesis of NASH [3]. Detailed metabolic studies, using ‘gold-standard’ euglycaemic clamps and/or stable isotope tracers, have demonstrated that patients with NASH have severe adipose IR, alongside increased hepatic IR [4,5] and de novo lipogenesis (DNL) [6,7]. Even though collectively these contribute to excess lipid accumulation in the liver, it is widely believed that the overspill of non-esterified fatty acids (NEFA) and release of triglyceride-derived toxic metabolites from adipose tissue lipolysis, form the primary lipotoxic insult in the pathogenesis of NASH and its extrahepatic complications including increased CVD-morbidity and mortality [1,8]. Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally
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