Abstract
BackgroundThere is considerable interest in identifying compounds that can improve glucose homeostasis. Skeletal muscle, due to its large mass, is the principal organ for glucose disposal in the body and we have investigated here if shikonin, a naphthoquinone derived from the Chinese plant Lithospermum erythrorhizon, increases glucose uptake in skeletal muscle cells.Methodology/Principal FindingsShikonin increases glucose uptake in L6 skeletal muscle myotubes, but does not phosphorylate Akt, indicating that in skeletal muscle cells its effect is medaited via a pathway distinct from that used for insulin-stimulated uptake. Furthermore we find no evidence for the involvement of AMP-activated protein kinase in shikonin induced glucose uptake. Shikonin increases the intracellular levels of calcium in these cells and this increase is necessary for shikonin-mediated glucose uptake. Furthermore, we found that shikonin stimulated the translocation of GLUT4 from intracellular vesicles to the cell surface in L6 myoblasts. The beneficial effect of shikonin on glucose uptake was investigated in vivo by measuring plasma glucose levels and insulin sensitivity in spontaneously diabetic Goto-Kakizaki rats. Treatment with shikonin (10 mg/kg intraperitoneally) once daily for 4 days significantly decreased plasma glucose levels. In an insulin sensitivity test (s.c. injection of 0.5 U/kg insulin), plasma glucose levels were significantly lower in the shikonin-treated rats. In conclusion, shikonin increases glucose uptake in muscle cells via an insulin-independent pathway dependent on calcium.Conclusions/SignificanceShikonin increases glucose uptake in skeletal muscle cells via an insulin-independent pathway dependent on calcium. The beneficial effects of shikonin on glucose metabolism, both in vitro and in vivo, show that the compound possesses properties that make it of considerable interest for developing novel treatment of type 2 diabetes.
Highlights
Due to the increasing number of people with type 2 diabetes mellitus, there is considerable interest in identifying compounds that can improve glucose tolerance
Longer term treatment of cells with either shikonin (1 mM) or insulin (1 mM) for 20 h showed no significant increase in glucose uptake at this time point (there was a tendency of shikonin and insulin to increase glucose uptake but this was not significantly different from control, indicating that the shikonin effect is within hours and not long-term (Fig. 1C))
In this study we have investigated the effect of shikonin on glucose uptake in L6 myotubes and examined its in vivo effect on plasma glucose levels in diabetic GK-rats
Summary
Due to the increasing number of people with type 2 diabetes mellitus (an estimated 285 million people, corresponding to 6.4% of the world’s adult population in 2010), there is considerable interest in identifying compounds that can improve glucose tolerance. The mechanisms whereby shikonin increases glucose uptake into adipocytes are not fully understood. Insulin increases glucose uptake in adipocytes and skeletal muscle cells by increasing the translocation of intracellular vesicles containing GLUT4 to the cell surface by a mechanism dependent upon activation of phosphatidylinositol 3-kinase (PI3K) and Akt [4]. Previous studies have shown that shikonin increases glucose uptake in adipocytes independently of the insulin receptor, IRS proteins and PI3K but through an unidentified tyrosine kinase mediated mechanism requiring Akt phosphorylation [2]. Due to its large mass, is the principal organ for glucose disposal in the body and we have investigated here if shikonin, a naphthoquinone derived from the Chinese plant Lithospermum erythrorhizon, increases glucose uptake in skeletal muscle cells
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