Type 2 diabetes presence is a major pathogenic factor in human NASH progression. The aim of this study was to determine whether sitagliptin may protect against NASH progression in a published murine diabetes model induced by high fat feeding and streptozotocin.

Methods: C57BL/6 male mice(n=58) were fed either a high fat diet (HFD:45%kCal fat) or standard chow (Chow:12%kCal fat). At 15weeks some animals were injected with low dose streptozotocin (65mg/kg) to induce type 2 diabetes. From diabetes induction some mice from each group were treated with oral sitagliptin (3g/kg of food) for 10weeks. At termination livers were i) fixed for histology, or ii) snap frozen for qRT-PCR. Morphological change was assessed by H&E and PSR. Hepatocyte primary culture was undertaken for mechanistic examine in vitro.

Results: Sitagliptin prevented collagen-I/-IV/-VI and pro-fibrotic connective tissue growth factor(CCN-2) mRNA increases and liver fibrosis at PSR stain in DM+HFD group. Anti-fibrotic CCN-3 was increased by Sitagliptin. Hepatocyte primary culture data showed anti-fibrotic effects of sitagliptin on these end-points across 6 to 48 hours (not shown).

Conclusions: These results indicate that sitagliptin has desirable effects in protecting against NASH in a murine diabetes model. Whether similar effects occur in human type 2 diabetes remains to be determined.