In the present study, we confirmed the anti-diabetic activity of S-Equol in ZDF rats, a type 2 diabetic animal model, and clarified the regulatory mechanism of insulin secretion by S-Equol in relation to influence the Chrebp/Txnip signaling via modulating the activities of PP2A and PKA in high glucose cultured INS-1 cells. Here, PTPA is linked to type 2 diabetes mellitus.