Inhibition of Free fatty acid-Induced Insulin Resistance by Rosemary Extract: Investigation of the Mechanisms Involved
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Excess of plasma free fatty acids (FFA) are highly associated with insulin resistance and are a major risk factor for the development of type 2 diabetes mellitus. This thesis investigates the effect of rosemary extract and rosemary extract polyphenols carnosic acid (CA), rosmarinic acid (RA) and carnosol (COH) on recovering/blunting FFA-induced insulin resistance in skeletal muscle cells and the mechanism(s) involved. Exposure of L6 myotubes with the FFA palmitate significantly reduced the insulin-stimulated glucose uptake. Most importantly, the insulin-stimulated glucose uptake was restored in the presence of RE and its polyphenols CA, RA and COH. Furthermore, treatment with palmitate increased serine phosphorylation of IRS-1 and significantly decreased the insulin-stimulated phosphorylation of Akt. These effects were completely abolished in the presence of rosemary extract. Additionally, we investigated the effect of palmitate and rosemary extract on the phosphorylation and of JNK, mTOR, P70S6K and AMPK kinases. Our results indicate that palmitate treatment increased the phosphorylation of JNK, mTOR, p70S6K whereas rosemary extract completely abolished this effect. Additionally, rosemary extract increased the phosphorylation of AMPK even in the presence of palmitate. The expression levels of these proteins were not affected by any of the treatments. These results indicate that treatment with rosemary extract attenuated the palmitate-induced phosphorylation of the serine residues of IRS-1, mTOR, p70 S6K and JNK while increasing the phosphorylation of AMPK. Additionally, treatment with RE restored the insulin-stimulated glucose uptake in palmitate-induced insulin resistant cells.