INS and diabetes mellitus: Additionally, ability of the enzyme to augment insulin/insulin-like growth factor 1 receptor signaling (76, 77), along with the well-documented hyperinsulinemia in PDAC patients [either in the setting of new inset or long-standing diabetes (3, 8, 9)], suggests that in heparanase-rich PDAC microenvironment insulin is expected to induce stronger pro-tumorigenic response.