Date of Award
Doctor of Philosophy (PhD)
Biotechnology Science and Engineering
Luis R. Cruz-Vera
Fatty liver, Insulin resistance, Diabetes--Animal models
The pathophysiological causes of nonalcoholic steatohepatitis (NASH) development are not fully understood but are often associated with hyperinsulinemia, insulin resistance and ectopic lipid accumulation. A subpopulation of type 1 diabetes patients develops the pathophysiological parameters to be termed “double diabetes,” which is associated with NASH. The objective of this work was to identify metabolic features of double diabetes and assess if LEW.1WR1 rats develop NASH. I assessed pathophysiologically relevant protein changes using proteomics and western blotting. I found that 17-week-old LEW.1WR1 rats showed protein changes related to non-alcoholic fatty liver disease, a precursor to NASH. We tested a second population of LEW.1WR1 rats’ peripheral insulin sensitivity via insulin tolerance tests and HOMA-IR at different time points. My results showed that these rats present significant continuous reduction of insulin sensitivity over the course of the study. Hyperinsulinemia was confirmed with blood insulin and C-peptide levels at 23 weeks. 23-week-old LEW.1WR1 rats showed increased body mass, epididymal fat, and liver mass, suggesting obesity driven metabolic dysfunction. 23-week-old LEW.1WR1 rats also develop NASH as assessed in the liver. I observed steatosis, liver injury ballooning, inflammation, Mallory Denk body formation with hematoxylin and eosin (H&E) and fibrosis in staining of liver sections. These data emphasize that hyperinsulinemic LEW.1WR1 rats develop insulin resistance, which eventually leads to development of NASH.
Wimalarathne, Madushika M., "Hyperinsulinemic LEW.1WR1 rats develop insulin resistance and nonalcoholic steatohepatitis" (2023). Dissertations. 270.
Available for download on Friday, September 08, 2023