The phosphatidylethanolamine derivative diDCP-LA-PE mimics intracellular insulin signaling.
The phosphatidylethanolamine derivative diDCP-LA-PE mimics intracellular insulin signaling.
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DOI：
10.1038/srep27267
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发表时间：
2016-06-02
影响因子：
4.6
通讯作者：
Tanaka A
中科院分区：
文献类型：
--
作者：
Nishizaki T;Gotoh A;Shimizu T;Tanaka A
胰岛素通过胰岛素受体(IR)/IR底物1 (IRS-1)/磷脂酰肌醇3激酶(PI3K)/3-磷酸肌醇依赖蛋白激酶1 (PDK1)/Akt轴将葡萄糖转运体GLUT4向细胞表面转运，促进葡萄糖进入细胞。新合成的磷脂酰乙醇胺衍生物1,2- o-二-[8-{2-（2-戊基-环丙基甲基）-环丙基}-辛烷基]-sn-甘油-3-磷脂酰乙醇胺（diDCP-LA-PE）具有抑制蛋白酪氨酸磷酸酶1B （PTP1B）和直接激活非典型同工酶PKCζ和新型同工酶PKCε的潜力。PTP1B抑制通过阻止酪氨酸去磷酸化增强胰岛素信号级联下游IR/IRS-1。PKCζ和PKCε分别通过磷酸化Thr309和Ser474位点直接激活Akt2。diDCP-LA-PE增加了GLUT4的细胞表面定位，并刺激分化的3T3-L1脂肪细胞对葡萄糖的摄取，但仍具有下调IR或缺乏胰岛素的情况。此外，diDCP-LA-PE能有效降低1型糖尿病（DM）模型小鼠的血清葡萄糖水平。因此，diDCP-LA-PE可以在不注射胰岛素的情况下治疗1型糖尿病。
Insulin facilitates glucose uptake into cells by translocating the glucose transporter GLUT4 towards the cell surface through a pathway along an insulin receptor (IR)/IR substrate 1 (IRS-1)/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis. The newly synthesized phosphatidylethanolamine derivative 1,2-O-bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]-sn-glycero-3-phosphatidylethanolamine (diDCP-LA-PE) has the potential to inhibit protein tyrosine phosphatase 1B (PTP1B) and to directly activate PKCζ, an atypical isozyme, and PKCε, a novel isozyme. PTP1B inhibition enhanced insulin signaling cascades downstream IR/IRS-1 by preventing tyrosine dephosphorylation. PKCζ and PKCε directly activated Akt2 by phosphorylating at Thr309 and Ser474, respectively. diDCP-LA-PE increased cell surface localization of GLUT4 and stimulated glucose uptake into differentiated 3T3-L1 adipocytes, still with knocking-down IR or in the absence of insulin. Moreover, diDCP-LA-PE effectively reduced serum glucose levels in type 1 diabetes (DM) model mice. diDCP-LA-PE, thus, may enable type 1 DM therapy without insulin injection.