Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic disease, is an important complication of diabetes mellitus (DM). Inflammation plays a crucial role in the development and progression of NAFLD. Moreover, the pathological formation of NAFLD is closely related to accumulation and polarization of hepatic macrophages. Saxagliptin, a newly antidiabetic agent, can suppress hepatic inflammation reportedly. However, underlying mechanisms remain poorly explored. In this study, we showed saxagliptin alleviated lipid accumulation and attenuated liver inflammation with down regulation of inflammation factors in diabetic rats. Moreover, saxagliptin could reduce the phenotype of M1 macrophage iNOS and increase the phenotype of M2 macrophage CD206. We also found saxagliptin increased CaMKK beta/AMPK activation. In vitro, human THP-1 monocytes were differentiated into M1/M2 macrophages by LPS/IL-4. We clarified saxagliptin's anti-inflammatory effect by reducing NF-kappa B, TNF-alpha expression and promoting M2 macrophage polarization. Furthermore, we demonstrated CaMKK beta-dependent AMPK activation was involved in macrophage polarization. In conclude, our results detected saxagliptin could attenuated inflammation through regulation of M1/M2 macrophage polarization and might be via CaMKK beta/AMPK pathway. (C) 2018 Published by Elsevier Inc.