YM268 INCREASES THE GLUCOSE-UPTAKE, CELL-DIFFERENTIATION, AND MESSENGER-RNA EXPRESSION OF GLUCOSE-TRANSPORTER IN 3T3-L1 ADIPOCYTES

The purpose of this study was to examine the effects of bis[4-[2,4-dio xo-5-thiazolidinyl)methyl] (YM268), a thiazolidinedione derivative, on glucose uptake, adipocyte differentiation through peroxisome prolifer ator-activated receptor gamma (PPAR gamma), and phosphatidylinositol 3 -kinase (PI 3-kinase) activity in cultured cells. YM268 and pioglitazo ne dose-dependently increased the 2-deoxyglucose uptake in 3T3-L1 cell s. YM268 facilitated the insulin-stimulated triglyceride accumulation in 3T3-L1 adipocytes and increased the mRNA expression of fatty acid-b inding protein. YM268, with and without insulin, increased the mRNA ex pression of glucose transporter isoforms such as GLUT1 and GLUT4, indi cating enhancement of adipocyte differentiation. Additionally, YM268 a nd pioglitazone showed activity of the PPAR gamma ligand, a member of the nuclear receptor superfamily responsible for adipogenesis. To exam ine the possible involvement of the increased activity of PI 3-kinase in YM268-stimulated glucose uptake, the enzyme activity was estimated by measuring the phosphatidylinositol-3,4,5-trisphosphate (PI-3,4,5-P- 3) concentration in human monocytic cells. Insulin dose-dependently in creased the PI-3,4,5-P-3 production but YM268 had no significant effec t on the insulin-dependent and -independent PI 3-kinase activation. Th ese results indicate that the mechanism by which YM268 increased gluco se uptake. may be accounted for in part by the enhancement of GLUT1 an d GLUT4 expression through PPAR gamma activation.