Department of Pharmacy, Fujian Provincial Maternal and Child Health Hospital, Fuzhou, Fujian, China.
Planta Med. 2013 Apr;79(6):452-8. doi: 10.1055/s-0032-1328325. Epub 2013 Mar 19.
The mammalian target of rapamycin is crucial in the regulation of cell growth and metabolism. Recent studies suggest that the mammalian target of rapamycin and its downstream 70-kDa ribosomal S6 kinase 1 negatively modulate the insulin-signaling pathway, which is considered the main cause of insulin resistance. The aim of this study is to investigate the effects of cardamonin, a potential inhibitor of the mammalian target of the rapamycin, on insulin-resistant vascular smooth muscle cells and the molecular mechanisms involved. Vascular smooth muscle cells were cultured with high glucose and high insulin to induce insulin resistance. The mammalian target of rapamycin was overstimulated in cells that were incubated with high glucose and high insulin, as reflected by the excessive activation of S6 kinase 1. Insulin-resistant vascular smooth muscle cells displayed hyperphosphorylation of insulin receptor substrate-1 at Ser residues 636/639, which decreased the activity of insulin receptor substrate-1. Also, the activation of protein kinase B and phosphorylation of glycogen synthesis kinase-3β were inhibited. Cardamonin increased the 2-deoxyglucose uptake and glycogen concentration, which was reduced by insulin resistance. As with rapamycin, cardamonin inhibited the activity of the mammalian target of rapamycin and S6 kinase 1, decreased the Ser 636/639 phosphorylation of insulin receptor substrate-1 and increased the activation of protein kinase B. Both of them increased the Ser9 phosphorylation of glycogen synthesis kinase-3β and decreased the expression of glycogen synthesis kinase-3β. However, neither cardamonin nor rapamycin increased the expression of glucose transport 4 which decreased in insulin-resistant vascular smooth muscle cells. This study suggests that cardamonin inhibited the activity of the mammalian target of rapamycin and eliminated the negative feedback of the mammalian target of rapamycin and S6 kinase 1 on the insulin-signaling pathway.
哺乳动物雷帕霉素靶蛋白在细胞生长和代谢的调节中起着关键作用。最近的研究表明，哺乳动物雷帕霉素靶蛋白及其下游 70kDa 核糖体 S6 激酶 1 负调控胰岛素信号通路，这被认为是胰岛素抵抗的主要原因。本研究旨在探讨卡纳明作为哺乳动物雷帕霉素潜在抑制剂对胰岛素抵抗血管平滑肌细胞的作用及其相关分子机制。将血管平滑肌细胞在高糖和高胰岛素条件下培养以诱导胰岛素抵抗。高糖和高胰岛素孵育的细胞中，哺乳动物雷帕霉素过度刺激，反映在 S6 激酶 1 的过度激活。胰岛素抵抗的血管平滑肌细胞中胰岛素受体底物-1 的丝氨酸残基 636/639 过度磷酸化，降低了胰岛素受体底物-1 的活性。此外，蛋白激酶 B 的激活和糖原合成激酶-3β的磷酸化受到抑制。卡纳明增加了 2-脱氧葡萄糖的摄取和糖原浓度，而胰岛素抵抗会降低这些浓度。与雷帕霉素一样，卡纳明抑制哺乳动物雷帕霉素靶蛋白和 S6 激酶 1 的活性，降低胰岛素受体底物-1 的丝氨酸 636/639 磷酸化，增加蛋白激酶 B 的激活。两者均增加糖原合成激酶-3β的丝氨酸 9 磷酸化，降低糖原合成激酶-3β的表达。然而，卡纳明和雷帕霉素都没有增加葡萄糖转运蛋白 4 的表达，而葡萄糖转运蛋白 4 在胰岛素抵抗的血管平滑肌细胞中减少。本研究表明，卡纳明抑制哺乳动物雷帕霉素靶蛋白的活性，消除了哺乳动物雷帕霉素靶蛋白和 S6 激酶 1 对胰岛素信号通路的负反馈作用。
