THE ANTIDIABETIC AGENT PIOGLITAZONE INCREASES EXPRESSION OF GLUCOSE TRANSPORTERS IN 3T3-F442A CELLS BY INCREASING MESSENGER-RIBONUCLEIC-ACID TRANSCRIPT STABILITY

Whereas adipocytes normally play an important role as a major site for systemic energy homeostasis, adipocyte function is markedly altered i n disorders such as diabetes. In this study, we investigated the effec t of pioglitazone, a novel antidiabetic agent known to lower plasma gl ucose in animal models of diabetes mellitus, on expression of glucose transporters GLUT1 and GLUT4 in 3T3-F442A cells. Treatment of confluen t 3T3-F442A preadipocyte cultures for 7 days with pioglitazone (1 muM) and insulin (1 mug/ml) resulted in nearly 100% differentiation of cel ls to lipid-accumulating adipocytes, and such adipocytes showed a mark edly increased capacity for glucose uptake. Analysis of messenger RNA transcripts encoding GLUT1 and GLUT4 glucose transporters over the 7-d ay differentiation period indicated time-dependent increases in abunda nce of each type that were maximal at more than 5-fold with the combin ed presence of insulin and pioglitazone. In accord, GLUT1 and GLUT4 pr otein levels also increased to maximal levels of 10-fold and 7-fold, r espectively, over those in undifferentiated preadipocytes. Increased m essenger RNA half-lives from 2.2 to greater than 24 h for GLUT1 and fr om 1.2 to greater than 24 h for GLUT4 correlated with this induced adi pocyte differentiation. Taken together, these findings indicated that pioglitazone markedly enhanced expression of cellular glucose transpor ters, and the mechanism for this action was mainly stabilization of tr ansporter messenger RNA transcripts. Such increased expression of gluc ose transporters in adipocytes establishes the cells in a state active for glucose uptake, thus ultimately facilitating storage and metaboli sm as well.