S-equol enantioselectively activates cAMP-protein kinase A signaling and reduces alloxan-induced cell death in INS-1 pancreatic β-cells.

S-Equol is enantioselectively produced from the isoflavone daidzein by gut microflora and is absorbed by the body. An increase of pancreatic β-cell death is directly associated with defects in insulin secretion and an increased risk of type 2 diabetes mellitus. In the present study, we demonstrate that only the S-enantiomer has suppressive effects against alloxan-induced oxidative stress in INS-1 pancreatic β-cells. S-Equol reduced alloxan-induced cell death in a dose-dependent manner, whereas R-equol had no effects. In contrast, no significant differences were observed between the enantiomers in estrogenic activity. The cytoprotective effects of S-equol were stronger than those of its precursor daidzein and were blocked by the protein synthesis inhibitor cycloheximide. The cytoprotection was diminished when cells were incubated with a protein kinase A (PKA) inhibitor (H89), but not an estrogen receptor inhibitor. S-Equol increased intracellular cAMP levels in an enantioselective manner. S-Equol, but not R-equol, induced phosphorylation of cAMP-response element-binding protein at Ser 133, and induced cAMP-response element-mediated transcription, both of which were diminished in the presence of H89. Taken together, these results show that S-equol enantioselectively increases the survival of INS-1 cells presumably through activating PKA signaling. Thus, S-equol might have applications as an anti-type 2 diabetic agent.