Safranal, a novel protein tyrosine phosphatase 1 B inhibitor, activates insulin signaling in C 2 C 12 myotubes and improves glucose tolerance in diabetic KK ‐ A y mice

Scope Protein tyrosine phosphatase 1B ( PTP 1 B ) negatively regulates insulin signaling by tyrosine dephosphorylation of insulin receptor, and its increased activity and expression is implicated in the pathogenesis of insulin resistance. Hence, PTP 1 B inhibition is anticipated to improve insulin resistance in type 2 diabetic subjects. The aim of this study was to find a novel PTP 1 B inhibitor from medicinal food and to evaluate its antidiabetic effects. Methods and results We found that saffron ( C rocus sativus L .), which is used both as a spice and as a traditional medicine, potently inhibits PTP 1 B activity. Analyses of saffron extracts demonstrated that safranal, the saffron's aroma compound, is a principal PTP 1 B inhibitor, and induces a ligand‐independent activation of insulin signaling in cultured myotubes. Our data implied that the molecular mechanism underlying the inactivation of PTP 1 B could be attributed to the covalent modification of the catalytic cysteinyl thiol by safranal through a Michael addition. Furthermore, safranal significantly enhanced glucose uptake through the translocation of glucose transporter 4. We also demonstrated that 2‐wk oral administration of 20 mg/kg/day safranal improved impaired glucose tolerance in type 2 diabetic KK ‐ A y mice. Conclusion Our results strongly suggest the usefulness of safranal in antidiabetic treatment for type 2 diabetic subjects.