Korsheninnikova E, Voshol P J, Baan B, van der Zon G C M, Havekes L M, Romijn J A, Maassen J A, Ouwens D M
Departments of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands.
Arch Physiol Biochem. 2007 Oct-Dec;113(4-5):173-85. doi: 10.1080/13813450701669084.
Insulin is an important regulator of hepatic carbohydrate, lipid, and protein metabolism, and the regulation of these processes by insulin is disturbed under conditions of insulin resistance and type 2 diabetes. Despite these alterations, the impact of insulin resistance on insulin signalling in the liver is not well defined. Variations in time and dose of insulin stimulation as well as plasma glucose levels may underlie this. The present study aimed at determining the dynamics of activation of hepatic insulin signalling in vivo at insulin concentrations resembling those achieved after a meal, and addressing the effects of high-fat feeding. An unexpected finding of this study was the biphasic activation pattern of the IRS-PI3K-PKB/Akt pathway. Our findings indicate that the first burst of activation contributes to regulation of glucose metabolism. The physiological function of the second peak is still unknown, but may involve regulation of protein synthesis. Finally, high-fat feeding caused hepatic insulin resistance, as illustrated by a reduced suppression of hepatic glucose production. A sustained increased phosphorylation of the serine/threonine kinases p70S6kinase and Jun N-terminal kinase in the absence of insulin may underlie the abrogated phosphorylation of the IRS proteins and their downstream targets.
胰岛素是肝脏碳水化合物、脂质和蛋白质代谢的重要调节因子，在胰岛素抵抗和2型糖尿病的情况下，胰岛素对这些过程的调节会受到干扰。尽管存在这些改变，但胰岛素抵抗对肝脏胰岛素信号传导的影响仍未明确。胰岛素刺激的时间和剂量以及血浆葡萄糖水平的变化可能是其原因。本研究旨在确定在类似于餐后达到的胰岛素浓度下，体内肝脏胰岛素信号激活的动力学，并探讨高脂喂养的影响。本研究的一个意外发现是IRS-PI3K-PKB/Akt途径的双相激活模式。我们的研究结果表明，第一次激活爆发有助于葡萄糖代谢的调节。第二个峰值的生理功能仍然未知，但可能涉及蛋白质合成的调节。最后，高脂喂养导致肝脏胰岛素抵抗，这表现为肝脏葡萄糖生成的抑制作用减弱。在没有胰岛素的情况下，丝氨酸/苏氨酸激酶p70S6激酶和Jun N末端激酶的持续磷酸化增加可能是IRS蛋白及其下游靶点磷酸化被废除的基础。
