An in vitro culturing system involving SIECs confirmed that decreased VEGF levels as a function of diabetes appear to be mediated, at least in part, by increasing cAMP to activate PKA, which in turn upregulates CREM/ICER expression to inhibit pCREB-DNA binding and to limit the transcription of VEGF. The functional consequence of this cascade of events was illustrated by a marked reduction in endothelial cell proliferation, migration and tube formation. This evidence concerns the gene CREM and diabetes mellitus.