Li Yin, Jiang Changtao, Xu Guoheng, Wang Nanping, Zhu Yi, Tang Chaoshu, Wang Xian
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
Diabetes. 2008 Apr;57(4):817-27. doi: 10.2337/db07-0617. Epub 2008 Jan 11.
Homocysteine (Hcy) is epidemiologically related to insulin resistance, which has been speculated to be a low-grade systemic inflammatory condition. Resistin acts as a critical mediator of insulin resistance associated with inflammatory conditions. We aimed to determine whether Hcy can induce insulin resistance by directly regulating the expression and secretion of resistin from adipose tissue.
The effect of Hcy on the expression and secretion of resistin and insulin resistance was investigated using primary rat adipocytes and mice with hyperhomocysteinemia (HHcy).
Hcy impaired glucose transport and, particularly, the insulin signaling pathway as shown by decreased insulin-stimulated tyrosine phosphorylation of insulin receptor and insulin receptor substrate (IRS)-1, increased serine phosphorylation of IRS-1, and inhibited Akt phosphorylation both in vitro and in vivo, and these impairments were accompanied by an increase in resistin expression. Compared with normal mice, HHcy mice with a clinically relevant level of plasma Hcy (19 micromol/l) showed significantly increased resistin production from adipose tissue (33.38 +/- 3.08 vs. 19.27 +/- 1.71 ng/ml, P < 0.01). Hcy (300-1000 micromol/l) also increased mRNA expression of resistin in primary rat adipocytes in a time- and concentration-dependent manner, with maximal induction at 24 h of approximately fourfold with 1,000 micromol/l. In addition, Hcy-induced resistin expression attenuated by treatment with reactive oxygen species (ROS) scavengers, protein kinase C (PKC), and nuclear factor (NF)-kappaB inhibitors implies a role in the process for ROS, PKC, and NF-kappaB.
HHcy may promote insulin resistance through the induction of resistin expression and secretion from adipocytes via the activation of the ROS-PKC-NF-kappaB pathway.
同型半胱氨酸（Hcy）在流行病学上与胰岛素抵抗相关，胰岛素抵抗被推测为一种低度全身性炎症状态。抵抗素是与炎症状态相关的胰岛素抵抗的关键介质。我们旨在确定Hcy是否可通过直接调节脂肪组织中抵抗素的表达和分泌来诱导胰岛素抵抗。
使用原代大鼠脂肪细胞和高同型半胱氨酸血症（HHcy）小鼠，研究Hcy对抵抗素表达、分泌及胰岛素抵抗的影响。
Hcy损害葡萄糖转运，尤其是胰岛素信号通路，体外和体内实验均显示胰岛素刺激的胰岛素受体及胰岛素受体底物（IRS）-1酪氨酸磷酸化降低、IRS-1丝氨酸磷酸化增加以及Akt磷酸化受抑制，这些损害伴随着抵抗素表达增加。与正常小鼠相比，血浆Hcy处于临床相关水平（19微摩尔/升）的HHcy小鼠脂肪组织中抵抗素产生显著增加（33.38±3.08对19.27±1.71纳克/毫升，P<0.01）。Hcy（300 - 1000微摩尔/升）还以时间和浓度依赖方式增加原代大鼠脂肪细胞中抵抗素的mRNA表达，1000微摩尔/升时在24小时诱导作用最大，约为四倍。此外，用活性氧（ROS）清除剂、蛋白激酶C（PKC）和核因子（NF）-κB抑制剂处理可减弱Hcy诱导的抵抗素表达，这表明ROS、PKC和NF-κB在此过程中起作用。
HHcy可能通过激活ROS-PKC-NF-κB途径诱导脂肪细胞抵抗素表达和分泌，从而促进胰岛素抵抗。
