Department of Biological Chemistry, Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai 599-8531, Japan.
Biochem Biophys Res Commun. 2012 Nov 16;428(2):315-20. doi: 10.1016/j.bbrc.2012.10.055. Epub 2012 Oct 22.
Insulin resistance is a pathological hallmark of type 2 diabetes mellitus and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling by tyrosine dephosphorylation of insulin receptor, and increased activity and expression of PTP1B is implicated in the pathogenesis of insulin resistance. Therefore, inhibition of PTP1B is anticipated to improve insulin resistance in type 2 diabetic subjects. Pyrroloquinoline quinone (PQQ), a redox cofactor for bacterial dehydrogenases, inhibits PTP1B to oxidatively modify the catalytic cysteine through its redox cycling activity. Here, we report that PQQ induces the ligand-independent activation of insulin signaling by inhibiting cellular PTP1B and enhances glucose uptake through the translocation of glucose transporter 4 in mouse C2C12 myotubes. Furthermore, we demonstrated that oral administration of PQQ improved impaired glucose tolerance in type 2 diabetic KK-A(y) mice. Our results strongly suggest that PQQ can be useful in anti-diabetic treatment for type 2 diabetic subjects.
胰岛素抵抗是 2 型糖尿病的病理标志，其特征是胰岛素信号转导缺陷。蛋白酪氨酸磷酸酶 1B（PTP1B）通过胰岛素受体的酪氨酸去磷酸化负调节胰岛素信号转导，而 PTP1B 的活性和表达增加与胰岛素抵抗的发病机制有关。因此，抑制 PTP1B 有望改善 2 型糖尿病患者的胰岛素抵抗。吡咯喹啉醌（PQQ）是细菌脱氢酶的氧化还原辅助因子，通过其氧化还原循环活性抑制 PTP1B，使催化半胱氨酸发生氧化修饰，从而抑制 PTP1B。在这里，我们报告 PQQ 通过抑制细胞 PTP1B 诱导胰岛素信号的配体非依赖性激活，并通过葡萄糖转运蛋白 4 的易位增强葡萄糖摄取，从而在小鼠 C2C12 肌管中增强胰岛素信号。此外，我们证明了 PQQ 的口服给药可改善 2 型糖尿病 KK-A（y）小鼠的葡萄糖耐量受损。我们的研究结果强烈表明，PQQ 可用于 2 型糖尿病患者的抗糖尿病治疗。
