Synthetic Inositol Phosphoglycans Related to GPI Lack Insulin-Mimetic Activity
Synthetic Inositol Phosphoglycans Related to GPI Lack Insulin-Mimetic Activity
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DOI：
10.1021/cb1002152
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发表时间：
2010-11-01
影响因子：
4
通讯作者：
Seeberger, Peter H.
中科院分区：
文献类型：
--
作者：
Hecht, Marie-Lyn;Tsai, Yu-Hsuan;Seeberger, Peter H.
胰岛素信号转导已被认为，至少部分地受到低分子量的胰岛素模拟物质的影响。这些肌醇β-葡聚糖（IPG）在生长激素/细胞因子刺激后产生，并控制多种胰岛素效应酶的活性。IPG对拟胰岛素作用的最低结构要求一直存在争议。提出了两种类型的IPG，IPG-A型类似于糖基磷脂酰肌醇（GPI）锚的核心聚糖。事实上，低真核生物来源的纯化GPI锚已被证明影响葡萄糖稳态。为了阐明活性IPG，测试了基于先前活性报告设计的合成IPG的集合的胰岛素模拟活性。采用啮齿动物脂肪组织中的体外和离体测定以及小鼠中的体内分析来测试合成IPG。通过PKB/Akt磷酸化和葡萄糖转运和脂肪生成的定量测定，我们测试的IPG均未模拟胰岛素作用。此外，IPG在体内胰岛素耐受试验中均无任何影响。与之前的声明形成鲜明对比，我们得出结论，测试的化合物都不是胰岛素模拟物。
Insulin signaling has been suggested, at least in part, to be affected by an insulin-mimetic species of low molecular weight. These inositol phos-phoglycans (IPGs) are generated upon growth hormone/cytokine stimulation and control the activity of a multitude of insulin effector enzymes. The minimal structural requirements of IPGs for insulin-mimetic action have been debated. Two types of IPGs were suggested, and the IPG-A type resembles the core glycan of glycosylphosphatidylinositol (GPI)-anchors. In fact, purified GPI-anchors of lower eukaryotic origin have been shown to influence glucose homeostasis. To elucidate active IPGs, a collection of synthetic IPGs designed on the basis of previous reports of activity were tested for their insulin-mimetic activity. In vitro and ex vivo assays In rodent adipose tissue as well as In vivo analyses In mice were employed to test the synthetic IPGs. None of the IPGs we tested mimic insulin actions as determined by PKB/Akt phosphorylation and quantification of glucose transport and Iipogenesis. Furthermore, none of the IPGs had any effect in In vivo Insulin tolerance assays. In stark contrast to previous claims, we conclude that neither of the compounds tested is insulin-mimetic.