HPSE and diabetes mellitus: Thus, our study not only reveals the mechanism of heparanase upregulation in PDAC, but also implies that the enzyme may contribute to a self-reinforcing sequence of events underlying bi-directional association between diabetes and PDAC (Figure 4): hyperglycemic state, that occurs in the majority of PDAC patients (Figure 4A), leads to heparanase overexpression in carcinoma cells via AGE-dependent mechanism (Figure 4B); increased levels of heparanase, in turn, promote PDAC progression (Figure 4C) through several previously-described mechanisms (13, 15, 25, 26, 74).