Abstract
Elevated blood free fatty acids (FFAs), as seen in obesity, impair muscle insulin action leading to insulin resistance and Type 2 diabetes mellitus. Serine phosphorylation of the insulin receptor substrate (IRS) is linked to insulin resistance and a number of serine/threonine kinases including JNK, mTOR and p70 S6K have been implicated in this process. Activation of the energy sensor AMP-activated protein kinase (AMPK) increases muscle glucose uptake, and in recent years AMPK has been viewed as an important target to counteract insulin resistance. We reported recently that rosemary extract (RE) increased muscle cell glucose uptake and activated AMPK. However, the effect of RE on FFA-induced muscle insulin resistance has never been examined. In the current study, we investigated the effect of RE in palmitate-induced insulin resistant L6 myotubes. Exposure of myotubes to palmitate reduced the insulin-stimulated glucose uptake, increased serine phosphorylation of IRS-1, and decreased the insulin-stimulated phosphorylation of Akt. Importantly, exposure to RE abolished these effects and the insulin-stimulated glucose uptake was restored. Treatment with palmitate increased the phosphorylation/activation of JNK, mTOR and p70 S6K whereas RE completely abolished these effects. RE increased the phosphorylation of AMPK even in the presence of palmitate. Our data indicate that rosemary extract has the potential to counteract the palmitate-induced muscle cell insulin resistance and further studies are required to explore its antidiabetic properties.
Highlights
Insulin plays a critical role in maintaining blood glucose homeostasis
The action of insulin in muscle cells is initiated by binding to its receptor, leading to tyrosine phosphorylation of the receptor and insulin receptor substrate (IRS-1), activation of the lipid kinase phosphatidylinositol-3 kinase (PI3K) and the serine threonine kinase Akt resulting in GLUT4 glucose transporter translocation from an intracellular pool to the plasma membrane and increase in glucose uptake [3,4]
These data are in agreement with previous studies plasma free fatty acids (FFAs) levels seen in obesity in vivo, significantly decreased the insulin-stimulated glucose showing that exposure of skeletal muscle cells to similar concentrations of palmitate induced insulin uptake indicating the induction of insulin resistance
Summary
The increase in postprandial glucose levels causes the release of insulin by the β cells of the pancreas which is delivered to its target tissues via the bloodstream. In skeletal muscle and adipose tissue, insulin promotes the transport, utilization and storage of glucose [1,2], while in the liver, insulin inhibits endogenous glucose production. The end result of these actions of insulin is to return the plasma glucose levels to a physiological range of 4–7 millimolar (mM). The action of insulin in muscle cells is initiated by binding to its receptor, leading to tyrosine phosphorylation of the receptor and insulin receptor substrate (IRS-1), activation of the lipid kinase phosphatidylinositol-3 kinase (PI3K) and the serine threonine kinase Akt resulting in GLUT4 glucose transporter translocation from an intracellular pool to the plasma membrane and increase in glucose uptake [3,4]. Impairments in the PI3K-Akt cascade leads to insulin resistance and type 2 diabetes mellitus (T2DM) [1,2,5]
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