Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity.
Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity.
复制标题
胰岛素受体底物的差异肝分布会导致糖尿病和肥胖症的选择性胰岛素耐药性。
DOI：
10.1038/ncomms12977
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发表时间：
2016-10-06
影响因子：
16.6
通讯作者：
Kadowaki, Takashi
中科院分区：
文献类型：
--
作者：
Kubota, Naoto;Kubota, Tetsuya;Kajiwara, Eiji;Iwamura, Tomokatsu;Kumagai, Hiroki;Watanabe, Taku;Inoue, Mariko;Takamoto, Iseki;Sasako, Takayoshi;Kumagai, Katsuyoshi;Kohjima, Motoyuki;Nakamuta, Makoto;Moroi, Masao;Sugi, Kaoru;Noda, Tetsuo;Terauchi, Yasuo;Ueki, Kohjiro;Kadowaki, Takashi
肝脏胰岛素信号传导涉及胰岛素受体底物（Irs）1/2，通常与抑制肝脏异生和激活脂肪生成有关。在糖尿病和肥胖症中，胰岛素不再抑制肝细胞生成，同时继续激活脂肪生成，这种状态被称为“选择性胰岛素抵抗”。在这里，我们表明，“选择性胰岛素抵抗”是由Irs 1和Irs 2在肝脏不同区域的差异表达引起的。我们证明，肝Irs 2基因敲除小鼠发展的“选择性胰岛素抵抗”，而小鼠缺乏Irs 1，或Irs 1和Irs 2，发展的“总胰岛素抵抗”。在肥胖糖尿病小鼠中，Irs 1/2介导的胰岛素信号传导在门静脉周围区受损，这是脂肪生成的主要部位，但在静脉周围区增强，这是脂肪生成的主要部位。虽然高胰岛素血症降低了Irs 2在门静脉周围和静脉周围区的表达，但Irs 1主要在静脉周围区的表达基本上不受影响。这些数据表明，“选择性胰岛素抵抗”是由肝脏Irs 1和Irs 2表达的差异分布和改变引起的。 2型糖尿病和肥胖症与肝脏脂肪生成和脂肪生成增加有关，称为选择性胰岛素抵抗。Kubota等人在本文中解释了肝脏中的选择性胰岛素抵抗与Irs 1和Irs 2的带状分布和选择性胰岛素介导的调节。
Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as ‘selective insulin resistance'. Here, we show that ‘selective insulin resistance' is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop ‘selective insulin resistance', whereas mice lacking in Irs1, or both Irs1 and Irs2, develop ‘total insulin resistance'. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that ‘selective insulin resistance' is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression. Type 2 diabetes and obesity are associated with increased hepatic gluconeogenesis and lipogenesis, known as selective insulin resistance. Here Kubota et al. explain selective insulin resistance in the liver with the zonal distribution and selective insulin-mediated regulation of Irs1 and Irs2.
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影响因子：
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作者：
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通讯作者：
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DOI：
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