Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
J Mol Endocrinol. 2010 Nov;45(5):329-40. doi: 10.1677/JME-10-0102. Epub 2010 Aug 26.
This study was undertaken to elucidate the effects of dietary protein deprivation on glucose metabolism and hepatic insulin signaling in rats. The results of glucose and pyruvate tolerance tests in rats fed with a 12% casein diet (12C) and a protein-free diet (PF) indicated that protein deprivation enhanced clearance of blood glucose and suppressed gluconeogenesis. Correspondingly, the mRNA level of hepatic phosphoenolpyruvate carboxykinase, a key gluconeogenic enzyme, was suppressed by dietary protein deprivation. In PF-fed rats, total tyrosine phosphorylation of insulin receptor (IR) in the liver induced by insulin injection was enhanced compared with 12C pair-fed rats due to an increase in IR protein level. In addition, protein deprivation caused an increase in protein levels of IR substrate 1 (IRS1) and IRS2, leading to the marked enhancement of insulin-induced tyrosine phosphorylation of IRS2 and its binding to the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K). Based on these results, we conclude that protein deprivation suppresses gluconeogenesis by a mechanism primarily mediated by the enhancement of the insulin signals through the IR/IRS/PI3K/mammalian target of rapamycin complex 1 pathway in the liver. Taken together with our previous report, these findings suggest that tissue-specific potentiation of insulin action in the liver and the skeletal muscle plays important roles in maintaining glucose homeostasis even when energy usage is reduced by dietary protein deprivation.
本研究旨在阐明膳食蛋白质缺乏对大鼠葡萄糖代谢和肝胰岛素信号的影响。给予 12%酪蛋白饮食（12C）和无蛋白饮食（PF）的大鼠进行葡萄糖和丙酮酸耐量试验的结果表明，蛋白质缺乏增强了血糖清除能力并抑制了糖异生。相应地，肝磷酸烯醇丙酮酸羧激酶（一种关键的糖异生酶）的 mRNA 水平因膳食蛋白质缺乏而受到抑制。在 PF 喂养的大鼠中，由于胰岛素受体（IR）蛋白水平增加，胰岛素注射诱导的肝 IR 总酪氨酸磷酸化增强，与 12C 配对喂养的大鼠相比。此外，蛋白质缺乏导致胰岛素受体底物 1（IRS1）和 IRS2 的蛋白水平增加，导致 IRS2 的胰岛素诱导的酪氨酸磷酸化及其与磷脂酰肌醇 3-激酶（PI3K）的 p85 调节亚基的结合显著增强。基于这些结果，我们得出结论，蛋白质缺乏通过增强肝中胰岛素信号的机制主要通过增强胰岛素信号来抑制糖异生IR/IRS/PI3K/雷帕霉素靶蛋白复合物 1 途径。结合我们之前的报告，这些发现表明，即使通过饮食蛋白质缺乏减少能量利用，肝和骨骼肌中胰岛素作用的组织特异性增强在维持葡萄糖稳态方面也起着重要作用。
