Cell Metab:颠覆认知!脂肪组织竟是糖尿病罪魁祸首!

2018-10-17 奇点糕 奇点网

研究人员将目光放到了每个人都有的组织—脂肪上。他们发现,只要去除糖尿病小鼠全身脂肪组织中的PKCε,小鼠就不会出现葡萄糖耐受不良,换言之,就是胰岛素抵抗消除!

国际糖尿病联盟(IDF)最新数据显示,2017年全球约4.25亿成人患糖尿病,平均每11个人中就有1位患病。有人说肥胖跟糖尿病就象是孪生兄弟一样,研究界普遍认为肥胖是糖尿病的重要诱因之一,但二者关系仅限于此吗?近期,澳大利亚研究人员的一项研究彻底颠覆了糖尿病病因的固有思维!他们指出,肥胖正是糖尿病的罪魁祸首!也就是说,我们过往认知中的“元凶”—肝脏并没有那么穷凶极恶,脂肪组织才真正罪无可赦!

想抓出元凶,得先知道糖尿病是怎么发生的。高血糖状况下,多元醇代谢亢进,葡萄糖的自身氧化、氧化磷酸化等引起活性氧自由基过量产生,损伤细胞的结构和功能,进而引发糖尿病的血管机能障碍。活性氧自由基通过活化c-Jun激酶、NF-kB、蛋白激酶ε(PKCε)等,使胰岛素底物蛋白磷酸化,加速胰岛素受体底物(IRS)的降解,引起胰岛素抵抗。

另外,多元醇代谢的亢进可引起PKCε活化,导致糖化终末产物增加,引起蛋白质机能改变,细胞内运输障碍,细胞凋亡等,最终引发糖尿病神经功能障碍。简而言之,糖尿病的发生,有几个关键节点:1.血管机能障碍;2.胰岛素抵抗;3.神经功能障碍,而这几个节点,全都跟一个重要激酶—PKCε有关。


去除PKCε可抑制饮食诱导的葡萄糖不耐受

PKCε可是导致胰岛素抵抗的主要分子元凶之一。二酰甘油(DAG)主要存在于肝细胞中,高血糖状态下其代谢亢进,可异常激活PKCε,而激活的PKCε会促进肝糖原的分解,抑制糖原合成,没错,PKCε的功能和胰岛素完完全全相反!

而且,有研究指出激活的PKCε会导致胰岛素受体关键酶(IRTK)失活,降低肝脏对胰岛素的敏感性!另一方面,异常激活的PKCε可迅速拮抗胰岛素的作用,从而维持高血糖状态,进一步导致糖化终末产物增加。

甚至有研究指出,即使是糖尿病患者,只要器官中不存在PKCε,该器官就不会出现糖尿病症状!换句话说,异常激活的PKCε是引起糖尿病的分子水平上真正的大boss,而这些PKCε主要活动的组织器官,自然就是糖尿病的罪魁祸首。

PKCε的激活因子DAG存在肝脏,PKCε也主要作用于肝脏细胞,因此长期以来,科学家们普遍认为异常激活的PKCε的主要活动器官就是肝脏了。那么,按照这个逻辑,去除糖尿病肝脏中的PKCε,应该就可以最大限度阻断患者的胰岛素抵抗了吧?

研究结果大大出乎预料。当研究人员去除糖尿病小鼠肝脏中的PKCε并阻断其产生时,糖尿病小鼠除肝脏外依旧产生高强度的胰岛素抵抗,也就是说,肝脏并非异常激活的PKCε的主要活动场所。那么,这些PKCε跑哪去了?


去除脂肪组织中PKCε对小鼠葡萄糖耐受量的影响


去除脂肪组织中PKCε可消除小鼠胰岛素抵抗

研究人员将目光放到了每个人都有的组织—脂肪上。他们发现,只要去除糖尿病小鼠全身脂肪组织中的PKCε,小鼠就不会出现葡萄糖耐受不良,换言之,就是胰岛素抵抗消除!

PKCε可在多种组织中表达,而脂肪组织中的PKCε不仅可以改变脂肪的性质、影响脂肪细胞的整体健康状况,还可以发送信号控制其他器官的葡萄糖代谢,这些才是真正异常激活的PKCε。

肥胖意味着大量脂肪细胞的堆积,自然也意味着PKCε异常激活途径愈加活跃。因此,减肥是糖尿病患者的必修课。当然,这项实验目前只在临床前阶段,仍需要更多数据说明,研究人员也致力于找出克制异常激活的PKCε的药物和疗法。

而于我们而言,降低脂肪含量是现阶段治疗、预防糖尿病的绝佳路径之一,也是我们个人力所能及的最佳选择。所以,赶紧减肥吧!

原始出处:Amanda E. Brandon, Bing M. Liao, Barbara Diakanastasis, et al. Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance. Cell Metab. October 11, 2018

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    2019-05-22 guojianrong
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    2019-01-09 hb2008ye
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    2019-06-23 维他命
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    2018-12-31 kafei

    学习了谢谢

    0

  5. 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  6. 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    2018-10-19 1237cdb8m17暂无昵称

    学习了

    0

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    2018-10-17 小柴胡疏肝

    我记得上次听上交教授的讲座就是这个课题

    0

  9. 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    2018-10-17 1239bfd7m98暂无昵称

    受益匪浅

    0

  10. 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    2018-10-17 fenfei_100

    学习了

    0

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J Hepatol:较低的皮下脂肪组织指数与女性肝硬化患者死亡率风险较高相关

较低的SATI与女性肝硬化患者死亡率较高有关。皮下脂肪组织具有良好的代谢特征——低脂的脂肪组织可能反映了这个主要能量库的耗竭,导致了不良的临床结果。

Molecular Metabolism:脂肪组织内血管的全组织三维分布及交感神经调控血管可塑性的重要功能

近日,清华大学医学院、免疫所曾文文课题组于《Molecular Metabolism》杂志发表研究论文,报导脂肪组织内血管的全组织三维分布状态以及生理和病理条件下的变化趋势,并进一步揭示交感神经调控血管再生和可塑性特征的重要功能。