Understanding the Mechanism Underlie the Antidiabetic Activity of Oleuropein Using Ex-Vivo Approach

Background: Oleuropein, the main constituent of olive fruit and leaves, has been reported to protect against insulin resistance and diabetes. While many experimental investigations have examined the mechanisms by which oleuropein improves insulin resistance and diabetes, much of these investigations have been carried out in either muscle cell lines or in vivo models two scenarios with many drawbacks. Accordingly, to simplify identification of  mechanisms by which oleuropein regulates specific cellular processes, we resort, in the present study, to isolated muscle preparation which enables better metabolic milieu control and permit more detailed analyses. Methods: For this purpose, soleus muscles were incubated for ۱۲ h without or with palmitate (۱.۵ mM) in the presence or absence of oleuropein (۱.۵ mM), and compound C. Insulin-stimulated glucose transport, glucose transporter type ۴ (GLUT۴) translocation, Akt substrate of ۱۶۰ kDa (AS۱۶۰) hosphorylation and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation were examined. Results: Palmitate treatment reduced insulin-stimulated glucose transport, GLUT۴ translocation and AS۱۶۰ phosphorylation, but AMPK phosphorylation was not changed. Oleuropein administration (۱۲ h) fully rescued insulin-stimulated glucose transport, but partially restored GLUT۴ translocation. However, it fully restored AS۱۶۰ phosphorylation, raising the possibility that oleuropein may also have contributed to the restoration of glucose transport by increased GLUT۴ intrinsic activity. Inhibition of AMPK phosphorylation with compound C (۵۰ μM) prevented oleuropein -induced improvements in insulin-stimulated glucose transport, GLUT۴ translocation, and AS۱۶۰ phosphorylation. Conclusions: Our results clearly indicate that oleuropein alleviates palmitate-induced insulin resistance appears to occur via an AMPK-dependent mechanism involving improvements in the functionality of the AS۱۶۰-GLUT۴ signaling system.

Keywords:

AMPK , GLUT۴ , Muscle , Insulin resistance , Oleuropein.