Safranal, a novel protein tyrosine phosphatase 1B inhibitor, activates insulin signaling in C2C12 myotubes and improves glucose tolerance in diabetic KK-Ay mice
Safranal, a novel protein tyrosine phosphatase 1B inhibitor, activates insulin signaling in C2C12 myotubes and improves glucose tolerance in diabetic KK-Ay mice
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DOI：
10.1002/mnfr.201300675
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发表时间：
2014-06-01
影响因子：
5.2
通讯作者：
Akagawa, Mitsugu
中科院分区：
文献类型：
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作者：
Maeda, Ayumi;Kai, Kenji;Akagawa, Mitsugu
适用范围：蛋白酪氨酸磷酸酶1B（Protein tyrosine phosphatase 1B，PTP 1B）通过对胰岛素受体的酪氨酸去磷酸化而负性调节胰岛素信号转导，其活性和表达的增加与胰岛素抵抗的发病机制有关。因此，预期PTP 1B抑制可改善2型糖尿病受试者的胰岛素抵抗。本研究的目的是从药用食品中寻找一种新的PTP 1B抑制剂，并评价其抗糖尿病作用。其既用作香料又用作传统药物，有效地抑制PTP 1B活性。对藏红花提取物的分析表明，藏红花的芳香化合物番红花醛是主要的PTP 1B抑制剂，并诱导培养的肌管中胰岛素信号的配体非依赖性激活。我们的数据表明，PTP 1B的失活的分子机制可以归因于通过迈克尔加成番红花醛的催化半胱氨酰硫醇的共价修饰。此外，番红花醛通过葡萄糖转运蛋白4的转位显著增强葡萄糖摄取。我们还表明，2周口服20 mg/kg/天的番红花醛改善2型糖尿病KK-A（y）mice.Conclusion：我们的研究结果强烈表明，番红花醛在抗糖尿病治疗2型糖尿病受试者的有用性。
Scope: Protein tyrosine phosphatase 1B (PTP1B) 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, PTP1B inhibition is anticipated to improve insulin resistance in type 2 diabetic subjects. The aim of this study was to find a novel PTP1B inhibitor from medicinal food and to evaluate its antidiabetic effects.Methods and results: We found that saffron (Crocus sativus L.), which is used both as a spice and as a traditional medicine, potently inhibits PTP1B activity. Analyses of saffron extracts demonstrated that safranal, the saffron's aroma compound, is a principal PTP1B inhibitor, and induces a ligand-independent activation of insulin signaling in cultured myotubes. Our data implied that the molecular mechanism underlying the inactivation of PTP1B 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.