Troglitazone Induces GLUT4 Translocation in L6 Myotubes

Abstract

A number of studies have demonstrated that insulin resistance in the skeletal muscle plays a pivotal role in the insulin resistance associated with obesity and type 2 diabetes. A decrease in GLUT4 translocation from the intracellular pool to the plasma membranes in skeletal muscles has been implicated as a possible cause of insulin resistance. Herein, we examined the effects of an insulin-sensitizing drug, troglitazone (TGZ), on glucose uptake and the translocation of GLUT4 in L6 myotubes. The prolonged exposure (24 h) of L6 myotubes to TGZ (10 ؊5 mol/l) caused a substantial increase in the 2-deoxy-[ 3 H]D-glucose (2-DG) uptake without changing the total amount of the glucose transporters GLUT4, GLUT1, and GLUT3. The TGZ-induced 2-DG uptake was completely abolished by cytochalasin-B (10 mol/l). The ability of TGZ to translocate GLUT4 from light microsomes to the crude plasma membranes was greater than that of insulin. Both cycloheximide treatment (3.5 ؋ 10 ؊6 mol/l) and the removal of TGZ by washing reversed the 2-DG uptake to the basal level. Moreover, insulin did not enhance the TGZ-induced 2-DG uptake additively. The TGZ-induced 2-DG uptake was only partially reversed by wortmannin to 80%, and TGZ did not change the expression and the phosphorylation of protein kinase B; the expression of protein kinase C (PKC)-, PKC-␤2, and PKC-; or 5AMP-activated protein kinase activity. ␣-Tocopherol, which has a molecular structure similar to that of TGZ, did not increase 2-DG uptake. We conclude that the glucose transport in L6 myotubes exposed to TGZ for 24 h is the result of an increased translocation of GLUT4. The present results imply that the effects of troglitazone on GLUT4 translocation may include a new mechanism for improving glucose transport in skeletal muscle.

The glucose-lowering agent sodium tungstate increases the levels and translocation of GLUT4 in L6 myotubes through a mechanism associated with ERK1/2 and MEF2D

“…Triplicate measurements of 2-deoxy-D-[1-3 H]glucose (2-DG) uptake were taken after 10 min of incubation as described [26].…”

“…Subcellular fractionation Membrane fractions from myotubes were prepared as described [26,27]. 5′-Nucleotidase and cytochrome c reductase activities were assayed as marker enzymes for plasma membranes and low-density microsomes, respectively [25].…”

Troglitazone Not Only Increases GLUT4 but Also Induces Its Translocation in Rat Adipocytes

“…This suggested that the pathway of the signaling by troglitazone converges with that activated by insulin. We have recently demonstrated that troglitazone also increases translocation of GLUT4 in L6 myotubes (13). In L6 myotubes, it is supposed that troglitazone acts at a step beyond PI3K and PKB in which GLUT4 endocytosis is enhanced or reduces endocytosis of GLUT4.…”

“…In our recent study (13), inhibition of protein synthesis by cycloheximide completely eliminated the increase in translocation of GLUT4 by troglitazone in L6 myotubes. It is tempting to speculate that troglitazone affects the synthesis of some molecules involved in the translocation of GLUT4.…”

“…Furthermore, thiazolidinediones have been suggested to modulate intrinsic activity and translocation of glucose transporters (12). Recently, we have further suggested that the translocation of GLUT4 is stimulated by thiazolidinediones in L6 myocytes (13). However, the direct effects of thiazolidinediones on the translocation of glucose transporters have not yet been verified.…”