Here we show that in PDAC elevated levels of heparanase [the predominant mammalian enzyme that degrades HS glycosaminoglycan at the ECM/cell surface (Jayatilleke and Hulett, 2020)], coupled to diabetic conditions typical for PDAC (Stolzenberg-Solomon et al., 2005; Dey et al., 2012; Sah et al., 2013; Andersen et al., 2017; Cheng et al., 2018; Krapf et al., 2020; Deng et al., 2022), promote growth and therapy resistance of pancreatic carcinoma cells by fostering INSR signaling and GLUT4 mediated glucose uptake. Here, HPSE is linked to exocrine pancreatic carcinoma.