Abstract: Objective The aim of this experiment was to explore the mechanism by which saxagliptin on adenosine 5-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)-transcription factor EB (TFEB) autophagy signaling pathway in rats with high-fat diet feed non-alcoholic fatty liver disease (NAFLD) and concomitant type 2 diabetes mellitus (T2DM). Methods 42 SD rats were randomly divided into control, model and saxagliptin-intervened group, with 14 rats in each group. The NAFLD and T2DM models in rats was established by high-fat diet feeding and intraperitoneal injection of streptozotocin. After two rats sacrificed in each groups for successful modeling proven, the left 12 rats in saxagliptin-intervened group were given saxagliptin gavage for 8 weeks, and the rats in other two groups were treated with the same amount of normal saline for gavage for 8 weeks. The body mass and liver mass were obtained and the liver index was calculated. Serum fasting insulin (INS) level was assayed by radioimmunoassay, fasting plasma glucose (FPG) levels were detected, and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The hepatic expressions of p-AMPK, mTOR, TFEB and autophagy marker, LC3B-II, were detected by Western blotting. Results The body mass, liver mass and liver index were (341.53±5.15) g, (11.06±0.49) g and (3.32±0.25) % in saxagliptin-intervened group, significantly lower than [(353.27±8.74) g, (12.77±0.84) g and (3.67±0.18)%, P<0.05] in the model group; the FPG, INS and HOMA-IR were (9.45±0.71) mmol/L, (7.92±0.34) mIU/L and (3.44±0.36), significantly lower than [(13.97±0.92) mmol/L, (14.57±0.84) mIU/L and (9.03±0.91), P<0.05] in the model group; serum TC, TG, ALT and AST levels were (3.79±0.17) mmol/L, (0.81±0.13) mmol/L, (68.76±4.11) IU/L and (54.49±5.21) IU/L, significantly lower than [(4.05±0.20) mmol/L, (2.04±0.15) mmol/L, (119.73±3.94) IU/L and (83.27±7.68) IU/L, P<0.05] in the model group; the hepatic expressions of p-AMPK, TFEB and LC3B-II were (1.13±0.11), (1.23±0.13) and (1.17±0.12), significantly stronger higher than (0.62±0.07), (0.48±0.05) and (0.37±0.04), while the expression of mTOR was (0.89±0.08), significantly weaker than [(1.53±0.16), P<0.05] in the model group. Conclusion Saxagliptin could significantly reduce blood glucose and blood lipids levels and ameliorate liver steatosis in rats with NAFLD and T2DM, which might be achieved by regulation of AMPK/mTOR-TFEB autophagy signaling pathway.

Key words: Non-alcoholic fatty liver disease, Type 2 diabetes mellitus, Saxagliptin, Autophagy, Adenosine 5-monophosphate-activated protein kinase /mammalian target of rapamycin -transcription factor EB autophagy signaling pathway