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

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• 作者：Matthew J. Armstrong¹ ; ^{mattyarm2010@googlemail.com" class="auth_mail" title="E-mail the corresponding author} ; Diana Hull¹ ; Kathy Guo¹ ; Darren Barton² ; Jonathan M. Hazlehurst³ ; Laura L. Gathercole³ ; Maryam Nasiri³ ; Jinglei Yu⁴ ; Stephen C. Gough⁵ ; Philip N. Newsome¹ ; ^&dagger ; ; Jeremy W. Tomlinson⁵ ; ^&dagger ; ; ^{jeremy.tomlinson@ocdem.ox.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Glucagon-like peptide 1 ; Non-alcoholic fatty liver ; Insulin sensitivity ; Adipose tissue ; Lipolysis
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：64
• 期：2
• 页码：399-408
• 全文大小：1181 K

文摘

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 1.8 mg 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. +0.04 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 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.