Abstract
Skeletal muscle is a major insulin-target tissue and plays an important role in glucose homeostasis. Impaired insulin action in muscles leads to insulin resistance and type 2 diabetes mellitus. 5′ AMP-activated kinase (AMPK) is an energy sensor, its activation increases glucose uptake in skeletal muscle and AMPK activators have been viewed as a targeted approach in combating insulin resistance. We previously reported AMPK activation and increased muscle glucose uptake by rosemary extract (RE). In the present study, we examined the effects and the mechanism of action of rosmarinic acid (RA), a major RE constituent, in L6 rat muscle cells. RA (5.0 µM) increased glucose uptake (186 ± 4.17% of control, p < 0.001) to levels comparable to maximum insulin (204 ± 10.73% of control, p < 0.001) and metformin (202 ± 14.37% of control, p < 0.001). Akt phosphorylation was not affected by RA, while AMPK phosphorylation was increased. The RA-stimulated glucose uptake was inhibited by the AMPK inhibitor compound C and was not affected by wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K). The current study shows an effect of RA to increase muscle glucose uptake and AMPK phosphorylation. RA deserves further study as it shows potential to be used as an agent to regulate glucose homeostasis.
Highlights
Skeletal muscle is a primary target tissue of insulin and plays a critical role in the maintenance of glucose homeostasis [1]
We reported previously that glucose uptake was significantly increased in L6 muscle cells by
Previous studies have indicated that rosmarinic acid (RA) is one of the major constituents found in rosemary extract (RE) [30], and we examined the levels of RA present in the RE that was extracted in our lab and utilized previously [27]
Summary
Skeletal muscle is a primary target tissue of insulin and plays a critical role in the maintenance of glucose homeostasis [1]. After binding to its receptor, insulin increases the receptor tyrosine kinase activity which leads to GLUT4 glucose transporter translocation to the plasma membrane via activation of the lipid kinase phosphoinositide 3-kinase (PI3K) and the serine/threonine kinase Akt/PKB [2,3]. Impairment of the PI3K–Akt cascade leads to insulin resistance and type 2 diabetes mellitus (T2DM) [4,5,6], a disease expected to affect 412 million people globally by 2040 [7]. AMP-activated protein kinase (AMPK) is a serine/threonine kinase that has a potential to regulate blood glucose levels. AMPK is activated by increased AMP/ATP ratio and/or via activation of its upstream kinases, liver kinase B1 (LKB1) and calmodulin dependent protein kinases (CaMKKs) [8,9]. Muscle AMPK is activated through muscle contraction/exercise [8]
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