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Glucose import down its concentration gradient via the glucose transporter GLUT4 is one of the primary physiologic roles of the insulin-signaling cascade. Insulin sensitivity is therefore highly correlated with the levels of GLUT4 protein in adipose and muscle tissues. GLUT4 expression is known to be regulated by diverse tissue-specific, hormonal, and/or metabolic controls, and a loss of GLUT4 protein in diabetes mellitus has been correlated to a decrease in the transcriptional rate. Elucidating the molecular mechanisms that control the GLUT4 promoter could therefore aid in the search for new interventions for insulin resistance and diabetes. Our work has previously identified two of the cis-acting sites within the smallest functional GLUT4 promoter as well as the transcription factors binding those sites, namely the MEF2-family members MEF2A and MEF2D, and the GLUT4 Enhancer Factor (GEF). We have also recently identified a post-translational modification of MEF2A that correlates with a model of decreased GLUT4 promoter activity. We are examining whether an observed hyperphosphorylation event occurs within insulin-responsive tissues under the streptozotocin-induced diabetic phenotype. Interestingly, hyperphosphorylation correlates with increased cytoplasmic localization of MEF2A in transfected cells, suggesting that hyperphosphorylation regulates nuclear MEF2A concentration. Previously, we observed that MEF2A and GEF function cooperatively to regulate GLUT4 gene expression. Using a biotinylated oligonucleotide corresponding to a truncated GLUT4 promoter that MEF2A and GEF interact with their cognate binding sites cooperatively, thus providing a molecular mechanism to account for the functional cooperativity. Further examination of the regulatory elements governing GLUT4 expression in vivo and in vitro will lead to the development of an system that recapitulates all the essential molecular mechanisms that control GLUT4 promoter activity, aiding in further study of potential therapeutics. ADA-Funded Research [ABSTRACT FROM AUTHOR]