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 in disorders such as diabetes. In this study, we investigated the effect of pioglitazone, a novel antidiabetic agent known to lower plasma glucose in animal models of diabetes mellitus, on expression of glucose transporters GLUT1 and GLUT4 in 3T3-F442A cells. Treatment of confluent 3T3-F442A preadipocyte cultures for 7 days with pioglitazone (1 microM) and insulin (1 microgram/ml) resulted in nearly 100% differentiation of cells to lipid-accumulating adipocytes, and such adipocytes showed a markedly increased capacity for glucose uptake. Analysis of messenger RNA transcripts encoding GLUT1 and GLUT4 glucose transporters over the 7-day differentiation period indicated time-dependent increases in abundance of each type that were maximal at more than 5-fold with the combined presence of insulin and pioglitazone. In accord, GLUT1 and GLUT4 protein levels also increased to maximal levels of 10-fold and 7-fold, respectively, over those in undifferentiated preadipocytes. Increased messenger RNA half-lives from 2.2 to greater than 24 h for GLUT1 and from 1.2 to greater than 24 h for GLUT4 correlated with this induced adipocyte differentiation. Taken together, these findings indicated that pioglitazone markedly enhanced expression of cellular glucose transporters, and the mechanism for this action was mainly stabilization of transporter messenger RNA transcripts. Such increased expression of glucose transporters in adipocytes establishes the cells in a state active for glucose uptake, thus ultimately facilitating storage and metabolism as well.
Sandouk
T
T
Department of Molecular and Cellular Biochemistry, Loyola University Stritch School of Medicine, Maywood, Illinois 60153.
Reda
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D
Hofmann
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C
D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004355:Drug Stability; D015870:Gene Expression / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D009124:Muscle Proteins; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014158:Transcription, Genetic / Q000187:drug effects*
D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D013844:Thiazoles; D045162:Thiazolidinediones; D005947:Glucose; D000077205:Pioglitazone