Differential Effects of Camel Milk on Insulin Receptor Signaling - Toward Understanding the Insulin-Like Properties of Camel Milk
Differential Effects of Camel Milk on Insulin Receptor Signaling - Toward Understanding the Insulin-Like Properties of Camel Milk
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DOI：
10.3389/fendo.2016.00004
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发表时间：
2016-01-27
影响因子：
5.2
通讯作者：
Ayoub, Mohammed Akli
中科院分区：
文献类型：
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作者：
Abdulrahman, Abdulrasheed O.;Ismael, Mohammad A.;Ayoub, Mohammed Akli
以前对阿拉伯骆驼（骆驼单峰）的研究表明，其牛奶在不同的人类疾病模型中报告了有益的效果，包括大量的降血糖活性。然而，这种影响所涉及的细胞和分子机制仍然完全未知。在这项研究中，我们假设骆驼奶可能在人胰岛素受体（hIR）及其相关的细胞内信号通路的水平上发挥作用。因此，我们研究了骆驼奶对激活人胚肾293（HEK 293）细胞瞬时表达的hIR的影响，使用生物发光共振能量转移（BRET）技术。BRET被用来评估，在活细胞和实时，hIR和胰岛素受体信号传导蛋白（IRS 1）和生长因子受体结合蛋白2（Grb 2）之间的物理相互作用。我们的数据表明，骆驼奶没有促进任何增加BRET信号之间的hIR和IRS 1或Grb 2在胰岛素刺激的情况下。然而，它显着增强最大的胰岛素促进BRET信号之间的hIR和Grb 2，而不是IRS 1。有趣的是，骆驼奶似乎对下游信号传导有不同的影响，因为它显著激活了ERK 1/2，并增强了胰岛素诱导的ERK 1/2而不是Akt激活。这些观察结果在一定程度上与BRET数据一致，因为已知ERK 1/2和Akt活化分别反映Grb 2和IRS 1通路的参与。骆驼奶的初步分级表明骆驼奶中活性成分的肽/蛋白质性质。总之，我们的研究首次证明了骆驼奶对胰岛素受体构象和激活的变构效应，并对其细胞内信号传导产生不同的影响。这些发现将有助于阐明骆驼奶的降血糖活性及其潜在的治疗应用。
Previous studies on the Arabian camel (Camelus dromedarius) showed beneficial effects of its milk reported in diverse models of human diseases, including a substantial hypoglycemic activity. However, the cellular and molecular mechanisms involved in such effects remain completely unknown. In this study, we hypothesized that camel milk may act at the level of human insulin receptor (hIR) and its related intracellular signaling pathways. Therefore, we examined the effect of camel milk on the activation of hIR transiently expressed in human embryonic kidney 293 (HEK293) cells using bioluminescence resonance energy transfer (BRET) technology. BRET was used to assess, in live cells and real-time, the physical interaction between hIR and insulin receptor signaling proteins (IRS1) and the growth factor receptor-bound protein 2 (Grb2). Our data showed that camel milk did not promote any increase in the BRET signal between hIR and IRS1 or Grb2 in the absence of insulin stimulation. However, it significantly potentiated the maximal insulin-promoted BRET signal between hIR and Grb2 but not IRS1. Interestingly, camel milk appears to differentially impact the downstream signaling since it significantly activated ERK1/2 and potentiated the insulin-induced ERK1/2 but not Akt activation. These observations are to some extent consistent with the BRET data since ERK1/2 and Akt activation are known to reflect the engagement of Grb2 and IRS1 pathways, respectively. The preliminary fractionation of camel milk suggests the peptide/protein nature of the active component in camel milk. Together, our study demonstrates for the first time an allosteric effect of camel milk on insulin receptor conformation and activation with differential effects on its intracellular signaling. These findings should help to shed more light on the hypoglycemic activity of camel milk with potential therapeutic applications.