Mice were treated with both
nicotinamide and
streptozotocin (NA/STZ) to reduce
insulin secretory capacity, and then fed a high fat diet containing
trans fatty acids (HFDT) for 8 weeks. The NA/STZ HFDT-fed mice were divided into two groups, either treated with
luseogliflozin or untreated, during this period. The
glucose elevations in the NA/STZ-treated and HFDT-fed mice were significantly improved by
luseogliflozin administration. While HFDT feeding induced NASH development as shown by liver
weight gain with
lipid accumulation and increased serum
alanine aminotransferase, these changes were all attenuated in the group treated with
luseogliflozin. In addition, fibrotic change and increases in
collagen deposition with upregulations of collagen1 and smooth muscle actin and inflammatory
cytokine expressions observed in the HFDT-fed mouse livers were also normalized by
luseogliflozin administration.
CONCLUSIONS: Taken together, these results obtained in mice demonstrate the favorable effects of administering
SGLT2 inhibitors, for the treatment of NASH associated with
diabetes mellitus. We anticipate that these agents would be applicable to humans.