Abstract
Skeletal muscle is highly important in glucose homeostasis since it is quantitatively a major insulin‐target tissue. Insulin action in muscle cells activates the phosphatidylinositol‐3 kinase (PI3K)/Akt signaling pathway causing the translocation of intracellularly stored GLUT4 glucose transporters to the plasma membrane leading to increased glucose uptake. Impaired insulin action in muscle leads to insulin resistance and type 2 diabetes mellitus (T2DM).AMP‐activated kinase (AMPK) is a cellular energy sensor and its activation increases glucose uptake by skeletal muscle cells. Finding AMPK activators is viewed as an effective approach to combat insulin resistance and T2DM. Rosemary extract (RE) has been shown to increase muscle glucose uptake and AMPK activity but the components responsible for these effects have not been identified yet. In the current study, we investigated the effect of carnosol, a polyphenol found in high concentrations in RE. L6 rat muscle cells were used to measure uptake of [3H]‐2‐deoxy‐D‐glucose and the signaling molecules involved were investigated by immunoblotting. Carnosol stimulated glucose uptake in L6 myotubes in a dose‐ and time‐dependent manner. A response comparable to maximum insulin stimulation (196±9.2 % of control) was seen with 50μM of carnosol (2h) (182±7.8 % of control). Carnosol did not affect Akt phosphorylation while it significantly increased AMPK phosphorylation. Furthermore, the increase in glucose uptake in the presence of carnosol was significantly reduced by the AMPK inhibitor compound C (CC) while it was not affected by the PI3K inhibitor wortmannin. Carnosol increased plasma membrane GLUT4 glucose transporter levels in GLUT4myc overexpressing L6 cells and this response was abolished by the AMPK inhibitor CC. Our study is the first to show a significant increase in muscle glucose uptake by carnosol via a mechanism that involves AMPK.Support or Funding InformationSupported by a Natural Sciences and Engineering Research Council of Canada (NSERC) grant to ET.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Highlights
Skeletal muscle tissue is a primary insulin target that accounts for approximately 80% of insulin-mediated glucose uptake in the postprandial state and plays a major role in glucose homeostasis [1,2]
L6 myotubes to different concentrations of carnosol (1, 5, 10, 25, 50, 75 μM) for 4 h resulted in a dose-dependent increase in glgulcuocsoeseuupptatkakee. .AA ssiiggnniifificcaanntt iinnccrreeaassee wwaass sseeeennwwiitthh1100μμMMoof fcacranronsooslo(l1(6156.51.1± 9±.19%.1o%f coofnctoronlt)roanl)d anmdamximaxuimmurmesrpeosnpsoensweaws asseseenenwwithith5050μμMM((330033 ±±1144.5.5%% ooff ccoonnttrrooll)) ((FFiigguurree 11BB))..ImImppoortratanntltyly,thtehe rersepsopnosneseofotfhtehececlelslltsoto2525μMμMcacranronsooslo(l2(4254±5 ±1122.6.6%%oof fcoconntrtorol)l)wwasascocmompparaarbalbeletotommaxaixmimumuminisnusluinlin anadndmmetefotfromrmininrersepsopnosnese(1(9139.34.4±±88.1.1%%,220066±± 66..33%% ooff ccoonnttrrooll, rreessppeeccttiivveellyy))((FFiigguurree11CC))
We examined the effect of the AMPK inhibitor compound C (CC) on the carnosol-stimulated glucose uptake
Summary
Skeletal muscle tissue is a primary insulin target that accounts for approximately 80% of insulin-mediated glucose uptake in the postprandial state and plays a major role in glucose homeostasis [1,2]. The binding of insulin to its receptor increases the receptor’s tyrosine kinase activity, inducing the downstream activation of phosphatidylinositol-3 kinase (PI3-K) and serine/threonine kinase Akt/PKB and GLUT4 glucose transporter translocation from an intracellular storage site to the plasma membrane, allowing glucose entry into muscle cells [1,3]. The AMP-activated protein kinase (AMPK) integrates nutritional and hormonal signals and regulates cell metabolism. It is a serine/threonine kinase that acts as a cellular energy sensor; it consists of three subunits: a catalytic (α) and two regulatory (β and γ) subunits [8,9,10,11]. Skeletal muscle glucose uptake through the stimulation of AMPK is considered a targeted approach to control blood glucose homeostasis
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