Oleuropein improves insulin resistance in skeletal muscle by promoting the translocation of GLUT4

Abstract

As the beneficial effects of the Mediterranean diet on human health are well established, the phenolic compounds in olive oil have been gaining interest. Oleuropein, a major phenolic compound in olives, is known to reduce the blood glucose levels in alloxan-induced diabetic rats and rabbits, however, its effect on type 2 diabetes caused by obesity is not clear. The purpose of this study is clarifying the effect of oleuropein on the glucose tolerance in skeletal muscle under the condition of lipotoxicity caused by type 2 diabetes. Oleuropein enhanced glucose uptake in C2C12 cells without insulin. Translocation of glucose transporter 4 (GLUT4) into the cell membrane was promoted by activation of adenosine monophosphate-activated protein kinase (AMPK) but not protein kinase B (Akt). Physiological concentration of oleuropein (10 µM) was sufficient to express beneficial effects on C2C12 cells. Oleuropein prevented palmitic acid-induced myocellular insulin resistance. Furthermore, in gastrocnemius muscles of mice fed a high fat diet, oleuropein also induced the GLUT4 localization into cell membrane. These results suggest the possibility of oleuropein to be effective for type 2 diabetes by reducing insulin resistance in skeletal muscles.

Oleuropein: A natural antioxidant molecule in the treatment of metabolic syndrome

“…In T2D mice fed with OPAICE diet, a phenolic extract containing 35% w/w oleuropein prevented weight gain and significantly reduced nonfasting blood glucose levels and hyperglycemia following glucose loading (Murotomi et al, ). Oleuropein also reduced fasting blood glucose in high‐fat diet‐fed mice (Fujiwara et al, ). Oleuropein has a local action on the intestinal wall where it was observed to inhibit intestinal maltase and sucrase enzymes.…”

“…Oleuropein administered alone improved glucose tolerance (Khalili et al, 2017;Poudyal et al, 2010) and reduced insulin resistance (S.W. Kim et al, 2014) or insulin sensitivity (Lepore et al, 2015) and, on C2C12 myoblast cells, promoted translocation of GLUT4 into the cell membrane via AMPK activation and MAPK's but not PI3 kinase (phosphatidylinositol 3-kinase)/protein kinase B (Akt; Fujiwara et al, 2017, Hadrich, Mahmoudi, et al, 2016. Oleuropein has been implicated to improve postprandial glycemic profile via hampering NOX 2 -derived oxidative stress (R. Carnevale et al, 2018).…”

3,4-DHPEA-EA Peracetylated (3,4-DHPEA-EA(P)) Attenuates H₂O₂-Mediated Cytotoxicity in C2C12 Myocytes <em>via</em> Inactivation of p-JNK/p-c-Jun Signaling Pathway

“…In last years, the importance of the antioxidant activity of 3,4-DHPEA-EA [9][10][11] and its derivatives at the level of skeletal muscle has emerged [12][13][14]. Skeletal muscle is a tissue in which ROS play particular importance: at low concentrations ROS act as signaling molecules in signal transduction pathways; instead at high concentrations they can result in oxidative stress and muscular atrophy [15].…”

“…Among the natural molecules 3,4-DHPEA-EA and its derivatives seem to play an important role in regulation of skeletal muscle homeostasis [12,13]. In particular, it has been demonstrated that oleuropein induces an increase of glucose uptake through the activation of AMP-activated protein kinase (AMPK) and consequent increase in GLUT4 translocation at the cell membrane [13,22].…”

“…In particular, it has been demonstrated that oleuropein induces an increase of glucose uptake through the activation of AMP-activated protein kinase (AMPK) and consequent increase in GLUT4 translocation at the cell membrane [13,22]. Oleuropein also prevents palmitic acid-induced myocellular insulin resistance suggesting the possibility for this molecule to be effective for type 2 diabetes by reducing insulin resistance in skeletal muscles [12]. Moreover, it has been shown that derivatives of oleuropein reduce high fat diet-induced lipid deposits in liver and skeletal muscle, enhance antioxidant enzyme activities, normalize expression of mitochondrial complex subunits and eventually inhibit apoptosis activation [23,24].…”