Type 2 diabetes mellitus-related non-alcoholic steatohepatitis in the Zucker Diabetic Sprague Dawley rat

Abstract

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease that is highly prevalent in Type 2 diabetes mellitus (T2DM). NASH progresses into cirrhosis and hepatocellular carcinoma and is known to worsen the prognosis and mortality in T2DM. Our understanding of the mechanisms underlying NASH development in T2DM is hindered by the absence of a good animal model that can physiologically develop T2DM and NASH. This study investigated the potential of the Zucker Diabetic Sprague Dawley (ZDSD) rat as a suitable model for studying T2DM-related NASH. Eight, twenty-week old ZDSD rats which became diabetic at week sixteen, were compared with six age-matched, non-diabetic Sprague Dawley (SD) rats. We measured body mass gain, fasting glucose, fasting triglycerides and glucose handling pre and post diabetic onset. We also measured circulating levels of the liver function enzymes; alanine transaminase and alkaline phosphatase, and other surrogate markers of kidney and pancreatic function. Liver samples were also scored for histopathological markers of NASH. ZDSD rats developed frank T2DM and exhibited impaired glucose handling, chronic hyperglycaemia, deranged lipid metabolism and impaired kidney function compared to SD rats. Histopathological analyses of the diabetic ZDSD rat liver showed the presence of steatosis, inflammation, hypertrophy and fibrosis. The co-occurrence of both T2DM and advanced NASH in the ZDSD rat compared to SD rats validates our hypothesis of its potential as a model for studying the pathogenesis of these two closely related diseases.