Abstract
Skeletal muscle is a major insulin-target tissue and plays an important role in glucose homeostasis. Insulin action in muscle activates the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway causing the translocation of intracellularly stored GLUT4 glucose transporters to the plasma membrane and increased glucose uptake. Impaired insulin action in muscle results in insulin resistance and type 2 diabetes mellitus (T2DM). Activation of the energy sensor AMP-activated kinase (AMPK) increases muscle glucose uptake and the use of AMPK activators is viewed as an effective strategy to combat insulin resistance. Rosemary extract (RE) has been shown to stimulate muscle AMPK and glucose uptake, but the exact components responsible for these effects are unknown. In the current study, we investigated the effect of carnosol, a RE polyphenol, in L6 rat muscle cells. Carnosol stimulated glucose uptake in L6 myotubes in a dose- and time-dependent manner, did not affect Akt, increased AMPK phosphorylation and plasma membrane GLUT4 levels. The carnosol-stimulated glucose uptake and GLUT4 translocation was significantly reduced by the AMPK inhibitor compound C (CC). Our study is the first to show an AMPK-dependent increase in muscle glucose uptake by carnosol. Carnosol has potential as a glucose homeostasis regulating agent and deserves further study.
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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