English: Diagram showing a pancreatic islet and four stages of T1D disease driven by heparanase and loss of intra-islet HS. HS (intense blue color) is shown in normal beta cells and in intact peri-islet BM. In Stage 1 of the disease process, non-destructive insulitis mononuclear cells produce heparanase (red dots). Onset of destructive insulitis occurs when heparanase becomes catalytically active and degrades HS in the islet BM (Stage 2). Damage to the islet BM barrier allows activated autoreactive T cells to enter the islet cell mass where the local production of heparanase leads to degradation of intracellular HS in islet beta cells (paling blue color; Stage 3). Progression of HS depletion throughout the islet beta cell population results in increased beta cell death (palest blue color in “shriveled” beta cells; Stage 4), loss of insulin production and ultimately the development of T1D. MNC, mononuclear cell; BM, basement membrane; Hpse, heparanase.