M.Sc Thesis

M.Sc StudentHinga Miriam
SubjectRegulation of GLUT1 and GLUT4 activity by arachidonic acid
DepartmentDepartment of Medicine
Supervisor PROFESSOR EMERITUS Eddy Karnieli


Free fatty acids (FFA) play a significant role in the pathophisyology of diabetes mellitus type 2 and especially in insulin resistance (lipotoxicity). We have recently shown that arachidonic acid (AA) down regulates the transcriptional activity of the glucose transporters (GLUT1 and GLUT4) gene promoters. . We studied AA short-term effect on cellular glucose transport and GLUTs translocation in response to insulin. We found that a 4-hour exposure to AA resulted in a 2-fold increase in basal glucose uptake, and a 1.4 fold increase in insulin induced glucose uptake in adipocytes and myoblasts. AA alone induced the translocation of both GLUT1 and GLUT4 in adipocytes, and of GLUT4 in L6-myoblasts. 

Inhibiting Phosphatidyl Inositol 3 Kinase (PI3-K: a key enzyme in the insulin signaling pathway) by wortmannin, reduced [EK1] AA effect on glucose uptake and on GLUT4 translocation and on insulin action.  Thus, AA induces the translocation of GLUT4  in a PI-3-K dependent mechanism.

Inhibiting P38 Mitogen Activated Protein Kinase (p38 MAPK), by SB203580 reduced the effect of AA on basal glucose uptake, suggesting that AA might modulate the GLUT’s intrinsic activity.

We demonstrated that AA has a short-term effect on increasing glucose uptake, through a potential mechanism that involves both translocation and activation of glucose transporters. Exploring these mechanisms may be of value in understanding the lipotoxic effects of FFA at the level of glucose transport.

 [EK1] Which response