Although phlorizin has been used in the treatment of diabetes mellitus for over 100 years, the underlying molecular mechanisms have not been fully elucidated. This study investigated the effect of phlorizin on body weight, blood glucose, blood triglycerides (TG), blood total cholesterol (TC), as well as overall changes in protein expression in db/db diabetic mouse liver. Phlorizin significantly decreased body weight gain and the levels of glucose, TC and TG in blood. Isobaric tag for relative and absolute quantitation (iTRAQ) quantitative proteomics profiling revealed that phlorizin interfered with the processes of carbohydrate metabolism, fatty acid biosynthesis and β-oxidation, cholesterol biosynthesis, and free radical scavenging by affecting the expression of key proteins in these processes. Ingenuity Pathway Analysis successfully established several pathway networks, in which many differentially expressed proteins were involved. The differential expression of several proteins was validated by western blotting. Our study offers important information on the mechanism of phlorizin treatment in diabetes mellitus, particularly in the liver.

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