Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 211198, PR China.
J Nutr Biochem. 2013 Jan;24(1):222-30. doi: 10.1016/j.jnutbio.2012.05.008. Epub 2012 Aug 15.
Genistein is an isoflavone phytoestrogen with biological activities in management of metabolic disorders. This study aims to evaluate the regulation of insulin action by genistein in the endothelium. Genistein inhibited insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and attenuated downstream Akt and endothelial nitric oxide synthase (eNOS) phosphorylation, leading to a decreased nitric oxide (NO) production in endothelial cells. These results demonstrated its negative regulation of insulin action in the endothelium. Palmitate (PA) stimulation evoked inflammation and induced insulin resistance in endothelial cells. Genistein inhibited IKKβ and nuclear factor-кB (NF-кB) activation with down-regulation of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production and expression. Genistein inhibited inflammation-stimulated IRS-1 serine phosphorylation and restored insulin-mediated tyrosine phosphorylation. Genistein restored insulin-mediated Akt and eNOS phosphorylation, and then led to an increased NO production from endothelial cells, well demonstrating its positive regulation of insulin action under insulin-resistant conditions. Meanwhile, genistein effectively inhibited inflammation-enhanced mitogenic actions of insulin by down-regulation of endothelin-1 and vascular cell adhesion protein-1 overexpression. PA stimulation impaired insulin-mediated vessel dilation in rat aorta, while genistein effectively restored the lost vasodilation in a concentration-dependent manner (0.1, 1 and 10 μM). These results suggested that genistein inhibited inflammation and ameliorated endothelial dysfunction implicated in insulin resistance. Better understanding of genistein action in regulation of insulin sensitivity in the endothelium could be beneficial for its possible applications in controlling endothelial dysfunction associated with diabetes and insulin resistance.
染料木黄酮是一种具有生物活性的异黄酮植物雌激素，可用于代谢紊乱的治疗。本研究旨在评估染料木黄酮对内皮细胞胰岛素作用的调节。染料木黄酮抑制胰岛素刺激的胰岛素受体底物-1（IRS-1）酪氨酸磷酸化，并减弱下游 Akt 和内皮型一氧化氮合酶（eNOS）磷酸化，导致内皮细胞一氧化氮（NO）产生减少。这些结果表明其对内皮细胞胰岛素作用的负调节。棕榈酸（PA）刺激可引发内皮细胞炎症和胰岛素抵抗。染料木黄酮抑制 IKKβ 和核因子-кB（NF-кB）的激活，下调肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的产生和表达。染料木黄酮抑制炎症刺激的 IRS-1丝氨酸磷酸化，并恢复胰岛素介导的酪氨酸磷酸化。染料木黄酮恢复了胰岛素介导的 Akt 和 eNOS 磷酸化，随后导致内皮细胞中 NO 产生增加，充分证明了其在胰岛素抵抗条件下对胰岛素作用的正向调节。同时，染料木黄酮通过下调内皮素-1 和血管细胞黏附蛋白-1的过表达，有效抑制了炎症增强的胰岛素有丝分裂作用。PA 刺激可损害大鼠主动脉中胰岛素介导的血管扩张，而染料木黄酮可有效浓度依赖性地恢复失去的血管扩张（0.1、1 和 10 μM）。这些结果表明，染料木黄酮可抑制炎症并改善与胰岛素抵抗相关的内皮功能障碍。更好地了解染料木黄酮在调节内皮细胞胰岛素敏感性方面的作用，可能有助于控制与糖尿病和胰岛素抵抗相关的内皮功能障碍。
