engleski

Olive Leaf Polyphenols (OLP) as Stimulators of GLUT4 Expression and Translocation in the Skeletal Muscle in Diabetic Rats

Glucose is the primary source of energy for most cells and an important substrate of many biochemical reactions. Plasma glucose concentration is the result of a balanced state of glucose entering the circulation and its removal from circulation [1]. The entry of glucose into cells is achieved by the activation of glucokinase phosphorylation and the mediation of specific glucose transporters (GLUTs). The impaired glucose homeostasis in insulin resistance is the result of the deregulation of signal pathways PI3K/Akt, mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK). The mechanism by which insulin regulates glucose uptake in peripheral tissues is still not fully clarifying, particularly in the case of intake of hypoglycemic drugs and natural compounds. Damaged functions of Rab proteins and SNARE proteins directly affect GLUT4 translocation and fusion with the PM. Bioactive phenolic compounds can stimulate glucose uptake by inducing GLUT4 expression, affecting on GLUT4 translocation and fusion to PM [2, 3, 4]. The aim of this study is to investigate the improvement of glucose uptake in skeletal muscle through the GLUT4 translocation to maintain glucose homeostasis in vivo. In this study, the streptozotocin (SZT)-induced diabetes mellitus was used as a model for investigation GLUT4 translocation in skeletal muscle in rats. Male Wistar rats (same age, approximately the same weight) were divided into five groups of 6 animals in each group as follows: group 1 – healthy control, group 2 – SZT-induced diabetes, group 3 – insulin-treated diabetic rats, groups 4 and 5 – dose-dependent olive leaves extract treated diabetic rats. Histopathological assessment of changed cell and tissue structure was performed by studying hematoxylin and eosin (H&E)-based preparations. Immunofluorescence labelling was performed on frozen muscle tissue sections. An overlap in fluorescence indicated colocalization of GLUT4 with Rab8A and Rab13 in rat soleus in OLP-treated animals. Results obtained by immunofluorescence were compared and confirmed by Western blot. Increased endomysium was found in the cross-section area in rat muscle soleus in diabetic rats. The used treatments (insulin and dose-dependent OLPs) induced improvements in muscle function in diabetic rats. Higher doses of OLP stimulated expression and translocation of GLUT4 in the soleus of diabetic rats through the expression of Rab8a and Rab13. These findings point out that the OLP-therapy (TOL2 and TOL3) affected the regulatory mechanisms controlling GLUT4 translocation to the membrane surface and glucose uptake in skeletal muscle. This could be one of the mechanisms for the removal of glucose excess from circulation and storage in muscles in diabetes. Our results indicate that OLPs stimulated Rab8a and Rab13 as part of a network to promote induced exocytosis in GLU4 trafficking in insulin-stimulated muscle cells in diabetes. Finally, OLP acts as a stimulator of GLUT4 translocation in rat soleus in a dose-dependent manner.

diabetes ; skeletal muscle ; GLUT4 ; Rab8a ; Rab13

This work has been supported in part by the University of Rijeka under the project code uniri-prirod-18-46, University of Rijeka Foundation