支链氨基酸缺乏提高胰岛素敏感性的机制研究
文献类型:学位论文
作者 | 肖斐 |
学位类别 | 博士 |
答辩日期 | 2012-05-11 |
授予单位 | 中国科学院上海生命科学研究院营养科学研究所 |
授予地点 | 中国科学院上海生命科学研究院 |
导师 | 郭非凡 |
关键词 | 支链氨基酸 胰岛素敏感性 糖代谢 GCN2 mTOR AMPK |
其他题名 | Mechanism for Improved Insulin Sensitivity by Branched-chain Amino Acids |
学位专业 | 生物化学与分子生物学 |
中文摘要 | II型糖尿病是最常见的慢性疾病之一。各种原因所导致的胰岛素抵抗是II型糖尿病的重要发病机制。目前缓解胰岛素抵抗的方法有多种,包括药物治疗和改善生活方式。最近,许多科研工作者提出改变膳食中营养元素来缓解胰岛素抵抗,其中就包括改变支链氨基酸(Branched-chain Amino Acids, BCAAs)含量。 支链氨基酸不仅是机体蛋白质合成的原料,而且是重要的信号调节分子。我们前期的研究发现,短期亮氨酸(leucine)缺乏能够诱导小鼠在低水平胰岛素条件下维持正常血糖水平,提示小鼠整体胰岛素敏感性增强,但具体机制尚不清楚。本课题研究发现,无论在正常还是胰岛素抵抗情况下,亮氨酸缺乏均能够增强细胞的胰岛素信号通路以及小鼠全身的胰岛素敏感性。亮氨酸缺乏主要是通过下调General Control Nonderepressible (GCN)2 / mammalian Target of Rapamycin (mTOR) / ribosomal protein S6 kinase 1 (S6K1)和上调AMP-activated protein kinase(AMPK)信号通路来提高胰岛素敏感性的。 此外,我们发现另两种支链氨基酸缬氨酸(valine)和异亮氨酸(isoleucine)缺乏同样能够提高胰岛素敏感性。这两种氨基酸缺乏能够下调mTOR / S6K1和上调AMPK信号通路。这三种支链氨基酸缺乏一天即可提高小鼠全身胰岛素敏感性。然而,这三种支链氨基酸缺乏对于血糖的调节并不一致:亮氨酸缺乏不影响餐后血糖,但缬氨酸和异亮氨酸缺乏会降低餐后血糖。这可能是由于这三种氨基酸对于糖异生中的重要基因葡萄糖-6-磷酸脱氢酶(glucose-6-phosphatase, g6pase)的调节不同。 综上所述,本课题阐明了支链氨基酸缺乏提高胰岛素敏感性的重要机制。一般认为调节糖代谢和氨基酸稳态的信号通路是不同的。GCN2已知的功能是氨基酸缺乏感受器,在氨基酸缺乏时抑制蛋白合成。该项研究揭示了GCN2在调节胰岛素敏感性方面的新功能。此外通过本课题的研究,可以探索亮氨酸等营养分子对于胰岛素敏感性调节的理论基础和实验依据。 |
索取号 | D2012-059 |
英文摘要 | We have previously shown that serum insulin levels decrease three-fold whereas blood glucose levels remain normal in mice fed a leucine-deficient diet [1],suggesting increased insulin sensitivity. The goal of the present study is to investigate this possibility and elucidate the underlying cellular mechanisms. Here we showed that leucine deprivation improves hepatic insulin sensitivity by sequentially activating General Control Nonderepressible (GCN)2 and decreasing mammalian Target of Rapamycin (mTOR)/ ribosomal protein S6 kinase 1 (S6K1) signaling. In addition, we found that activation of AMP-activated protein kinase (AMPK) also contributes to leuicne deprivation-increased hepatic insulin sensitivity. Finally, we showed that leucine deprivation improves insulin sensitivity under insulin-resistant conditions. This study describes mechanisms underlying increased hepatic insulin sensitivity under leucine deprivation. Furthermore, we demonstrate a novel function for GCN2 in the regulation of insulin sensitivity. Besides, we investigate whether the above effects is leucine specific or can be generalized to the deficiency of other branched-chain amino acids (BCAAs) including valine and isoleucine. In the present study, we showed that valine or isoleucine deprivation for 7 days produces similar effects as leucine on insulin sensitivity regulated in a similar manner. Different from leucine, valine or isoleucine deprivation for 7 days significantly decreases fed blood glucose levels, possibly by decreasing expression of a key gluconeogenesis gene glucose-6-phosphatase. Finally, we showed that insulin sensitivity is rapidly improved in mice following maintenance on a diet deficient for any individual BCAAs for 1 day. Our results showed that the effect of leucine deprivation represents a general effect of BCAAs on regulation of insulin sensitivity, but not glucose levels, suggesting that each individual BCAA has unique feature in metabolic regulation.These observations also provide a rationale for short-term dietary deprivation or restriction of BCAAs for the treatment of insulin resistance and associated metabolic diseases. |
语种 | 中文 |
公开日期 | 2016-02-26 |
源URL | [http://202.127.25.144/handle/331004/391] |
专题 | 中国科学院上海生命科学研究院营养科学研究所_代谢的遗传与营养调控研究组 |
推荐引用方式 GB/T 7714 | 肖斐. 支链氨基酸缺乏提高胰岛素敏感性的机制研究[D]. 中国科学院上海生命科学研究院. 中国科学院上海生命科学研究院营养科学研究所. 2012. |
入库方式: OAI收割
来源:上海营养与健康研究所
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