Glucagon-like peptide-1 in nonalcoholic steatohepatitis

Armstrong, Matthew James (2014). Glucagon-like peptide-1 in nonalcoholic steatohepatitis. University of Birmingham. Ph.D.

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Abstract

Nonalcoholic fatty liver disease (NAFLD), and in particular its inflammatory component steatohepatitis (NASH), are associated with significant risk of liver/cardiovascular morbidity and death. My findings highlight that NAFLD is now the commonest cause of liver disease in primary care, yet significant numbers with advanced fibrosis remain undetected. Application of simple non-invasive scoring systems could aid with identifying those in greatest need of intervention. By adopting an integrative physiological approach with functional measures of lipid and carbohydrate flux, I demonstrated that patients with NASH (vs. healthy controls) have marked adipose tissue dysfunction (especially in abdominal subcutaneous adipose tissue), alongside increased hepatic and muscle insulin resistance (IR). Targeting adipose-derived lipotoxicity should be the mainstay of therapy in NASH. Glucagon-like peptide-1 (GLP-1) based therapy (liraglutide) appears to be safe and well tolerated in patients at risk of underlying NAFLD. My prospective randomised-controlled study highlighted that liraglutide reduces metabolic dysfunction, hepatic lipogenesis, hepatic/adipose IR and inflammation in patients with NASH. My in vitro studies in human hepatocytes indicate that the anti-steatotic effects are not solely reliant on improvements in weight and/or glycaemic control. Taken together, my findings highlight that GLP-1 based therapies have all the metabolic and clinical attributes to make them a promising therapeutic option in patients with NASH. However, the safety and histological efficacy of such awaits the completion of my 48-week Phase II ‘LEAN’ trial, which is integral as to whether larger clinical trials are warranted.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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