Abstract
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.
Key words
cardamonin - mTOR - insulin resistance - VSMCs - glucose metabolism - IRS-1 - S6K1
