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Shikonin Increases Glucose Uptake in Skeletal Muscle Cells and Improves Plasma Glucose Levels in Diabetic Goto-Kakizaki Rats
Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, e22510- p.Article in journal (Refereed) Published
Abstract [en]

Background: There 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 Findings: Shikonin 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/Significance: Shikonin 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.

Place, publisher, year, edition, pages
2011. Vol. 6, no 7, e22510- p.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:su:diva-66594DOI: 10.1371/journal.pone.0022510ISI: 000293175100029OAI: oai:DiVA.org:su-66594DiVA: diva2:468497
Note
authorCount :9Available from: 2011-12-21 Created: 2011-12-20 Last updated: 2017-12-08Bibliographically approved
In thesis
1. β-adrenergic signalling and novel effects in skeletal muscle
Open this publication in new window or tab >>β-adrenergic signalling and novel effects in skeletal muscle
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Skeletal muscles have, due to their large mass, a big impact on the whole body metabolism. There are many signals that can regulate the functions of skeletal muscles and one such signal is activation of α- and β-adrenoceptors (α- and β-ARs) by epinephrine and norepinephrine. This activation leads to several effects which are examined in this thesis.

 

Stimulation of β-AR on muscle cells induces glucose uptake, an event that both provides the muscle with energy and lowers the blood glucose levels. We discovered two key components in the β-ARs signal to glucose uptake: the transporter protein GLUT4 and the kinase mTOR, a molecule involved in several metabolic processes but not previously known to be activated by β-ARs.

 

The classical second messenger downstream of β-ARs, cAMP, was surprisingly found to be only partly involved in the β-adrenergic glucose uptake. We also found that a molecule called GRK2 is very important for this glucose uptake.

 

A novel effect of β-AR stimulation presented in this thesis is the inhibition of myosin II-dependent contractility in skeletal muscle cells. The intracellular pathway regulating this event was different from that regulating glucose uptake and involved both classical and novel molecules in the β-AR pathway.

 

Another stimulus that we found to activate insulin-independent glucose uptake in skeletal muscle cells was the natural compound Shikonin. Shikonin increased glucose uptake in skeletal muscle cells via a calcium- and GLUT4-dependent mechanism and improved glucose homeostasis in diabetic rats.

 

Taken together, we have identified new key molecules in the adrenergic signaling pathway as well as novel downstream effects. We conclude that glucose uptake in muscles can be activated by β-adrenergic stimulation or by Shikonin and that both treatments improves glucose homeostasis in diabetic animals. This knowledge can hopefully be used in the search for new drugs to combat type II diabetes.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. 61 p.
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-87205 (URN)978-91-7447-624-8 (ISBN)
Public defence
2013-03-08, hörsalen, Frescati backe, Svante Arrhenius väg 21 A, Stokcholm, 10:00 (English)
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Supervisors
Note

At the time of doctoral defence the following papers were unpublished and had a status as follows. Paper 1: Manuscript; Paper 3: Manuscript

Available from: 2013-02-14 Created: 2013-01-29 Last updated: 2013-02-05Bibliographically approved

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