Muscle Cell Insulin Resistance Is Attenuated by Rosmarinic Acid: Elucidating the Mechanisms Involved

Abstract

Obesity and elevated blood free fatty acid (FFA) levels lead to impaired insulin action causing insulin resistance in skeletal muscle, and contributing to the development of type 2 diabetes mellitus (T2DM). Mechanistically, insulin resistance is associated with increased serine phosphorylation of the insulin receptor substrate (IRS) mediated by serine/threonine kinases including mTOR and p70S6K. Evidence demonstrated that activation of the energy sensor AMP-activated protein kinase (AMPK) may be an attractive target to counteract insulin resistance. We reported previously that rosemary extract (RE) and the RE polyphenol carnosic acid (CA) activated AMPK and counteracted the FFA-induced insulin resistance in muscle cells. The effect of rosmarinic acid (RA), another polyphenolic constituent of RE, on FFA-induced muscle insulin resistance has never been examined and is the focus of the current study. Muscle cell (L6) exposure to FFA palmitate resulted in increased serine phosphorylation of IRS-1 and reduced insulin-mediated (i) Akt activation, (ii) GLUT4 glucose transporter translocation, and (iii) glucose uptake. Notably, RA treatment abolished these effects, and restored the insulin-stimulated glucose uptake. Palmitate treatment increased the phosphorylation/activation of mTOR and p70S6K, kinases known to be involved in insulin resistance and RA significantly reduced these effects. RA increased the phosphorylation of AMPK, even in the presence of palmitate. Our data indicate that RA has the potential to counteract the palmitate-induced insulin resistance in muscle cells, and further studies are required to explore its antidiabetic properties.