Abstract
Astaxanthin (AST) is a carotenoid with therapeutic values on hyperglycemia and diabetic complications. The mechanisms of action of AST remain incompletely understood. p70 S6 kinase 1 (S6K1) is a serine/threonine kinase that phosphorylates insulin receptor substrate 1 (IRS-1)S1101 and desensitizes the insulin receptor (IR). Our present study aims to determine if AST improves glucose metabolisms by targeting S6K1. Western blot analysis revealed that AST inhibited the phosphorylation of two S6K1 substrates, S6S235/236 and IRS-1S1101, but enhanced the phosphorylation of AKTT308, AKTS473, and S6K1T389 by feedback activation of the phosphatidylinositol-3 (PI-3) kinase in 3T3-L1 adipocytes and L6 myotubes. In vitro kinase assays revealed that AST inhibited S6K1 activity with an IC50 value of approximately 13.8 μM. AST increased insulin-induced IR tyrosine phosphorylation and IRS-1 binding to the p85 subunit of PI-3 kinase. Confocal microscopy revealed that AST increased the translocation of the glucose transporter 4 (GLUT4) to the plasma membrane in L6 cells. Glucose uptake assays using a fluorescent dye, 2-NBDG (2-N-(Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose), revealed that AST increased glucose uptake in 3T3-L1 adipocytes and L6 myotubes under insulin resistance conditions. Our study identifies S6K1 as a previously unrecognized molecular target of AST and provides novel insights into the mechanisms of action of AST on IR sensitization.
Highlights
Diabetes mellitus is a highly prevalent chronic disease characterized by high blood glucose levels and many devastating complications [1,2]
The PI-3 kinase pathway is activated by the IR and plays an important role in glucose metabolism [9]
We first evaluated the effect of AST on the PI-3 kinase pathway in 3T3-L1 adipocytes and L6 myotubes, two cell types that have been widely used to study insulin resistance
Summary
Diabetes mellitus is a highly prevalent chronic disease characterized by high blood glucose levels and many devastating complications [1,2]. PI-3 kinase as evidenced by weak binding of the PI-3 kinase to IRS-1 and weak AKT phosphorylation upon insulin stimulation [9,10] Several natural products such as gingerenone A and evodiamine, which inhibit S6K1 activity, can increase glucose uptake or improve glucose tolerance [15,16]. AST induces AKT phosphorylation and enhances GLUT4 translocation to the plasma membrane and glucose uptake in L6 myotubes [26,30]. Our present study provides evidence that AST functions as an S6K1 inhibitor to induce feedback activation of the PI-3 kinase pathway, subsequently activating AKT to increase GLUT4 translocation to the cell membrane and enhance glucose uptake in 3T3-L1 adipocytes and L6 myotubes. Our study identifies a new molecular target of AST and provides novel insights into how AST sensitizes the IR and improves glucose metabolism
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