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.