In view of the above information and our previous findings demonstrating that NO bioavailability is diminished (Bitar et al., 2005) and fibrovascular invasion is reduced as a function of diabetes (Bitar, 1998; Bitar, 2000), a hypothesis was articulated stating that a signaling axis through PKA, CREB and hypoxia-inducible factor 1α (HIF-1α) (a powerful activator of VEGF-mediated angiogenesis) is altered during the course of diabetes. This evidence concerns the gene CREB1 and diabetes mellitus.