Attenuation of FFA‐Induced Skeletal Muscle Insulin Resistance by Carnosic and Rosmarinic Acid

Abstract

Impaired insulin action in muscle leads to insulin resistance and Type 2 diabetes mellitus, a disease on the rise. Elevated blood free fatty acids (FFAs), as seen in obesity, are associated with insulin resistance and studies have shown increased serine phosphorylation of the insulin receptor substrate (IRS‐1) and reduced insulin‐stimulated glucose uptake in muscle cells exposed to FFA palmitate. A number of serine/threonine kinases including JNK, IKKβ, mTOR and p70 6SK have been implicated in serine phosphorylation of IRS‐1 and insulin resistance. On the other hand, activation of the energy sensor AMP‐activated protein kinase (AMPK) increases glucose uptake and has become an important target to counteract insulin resistance. We reported recently that rosemary extract (RE) increased skeletal muscle cell glucose uptake and activated AMPK. The polyphenols carnosic acid (CA) and rosmarinic acid (RA) are found in high concentration in RE and in the present study we investigated their effect on palmitate‐induced insulin resistant L6 muscle cells. Glucose uptake was measured using [3H]‐2‐deoxy‐D‐glucose and the signaling molecules involved were investigated by immunoblotting.Exposure of L6 myotubes to the FFA palmitate (P) (0.2 mM, 16 hours) resulted in significant reduction of insulin‐stimulated glucose uptake (I: 201±1.21% , P+I: 117±15.6% of control, P<0.001) indicating insulin resistance. Importantly, in the presence of 2 mM CA or 5 mM RA, the insulin‐stimulated glucose uptake was restored (CA+P+I: 185±7.8%, RA+P+I: 181±14.4% of control, P<0.001). Treatment with palmitate increased serine phosphorylation of IRS‐1, increased the phosphorylation/activation of JNK, mTOR and p70 6SK and significantly decreased the insulin‐stimulated phosphorylation of Akt. The effects of CA and RA on these signaling molecules are under investigation. Our data indicate that treatment with CA or RA attenuates the FFA‐induced muscle insulin resistance. These polyphenols may have potent effects against insulin resistance and deserve further study.Support or Funding InformationThe research was funded by the Natural Sciences and Engineering Research Council (NSERC) grant to ET.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.