While the impact of diabetes mellitus on pancreatic β-cells has been widely explored, its correlation with extracellular matrix (ECM) modification still requires deeper understanding; under chronic hyperglycemic conditions, proteins and other matrix components can undergo non enzymatic glycation, leading to the accumulation of advanced glycation end products and to changes in matrix organization, stiffness and cell interactions. Reproducing these alterations in vitro is therefore important to better understand how β-cells respond to a pathological pancreatic microenvironment. For this reason, biomaterials derived from pancreatic ECM could represent valuable platforms for tissue engineering and diabetes modelling. In this context, the present work focused on the development and preliminary characterization of hydrogels based on pancreatic ECM, obtained from porcine tissue decellularized through supercritical carbon dioxide (scCO2) and chemically modified to reproduce selected aspects of diabetic matrix remodeling.