INSR and carcinoma: Based on these findings, the inducibility of heparanase expression in PDAC by diabetic milieu components (Goldberg et al., 2019), and impairment of insulin-triggered insulin receptor (INSR) activation under conditions of heparanase deficiency/enzymatic inhibition (Cassinelli et al., 2018; Hermano et al., 2021), we hypothesized that the overexpression of the enzyme can contribute to PDAC pathogenesis by increasing insulin sensitivity of the carcinoma cells, thus mechanistically linking systemic diabetic state to the intracellular metabolic rewiring.