There has been great interest in the extent of β-cell regeneration after pancreatic duct ligation (PDL) and whether α- to β-cell conversion might account for β-cell regeneration after near-complete β-cell loss. To assess these questions, we established a PDL-model in adult male rats after almost complete beta-cell depletion achieved by giving a single high dose of streptozocin (STZ) in the fasted state. Because of the resultant severe diabetes, rats were given islet cell transplants to allow long-term follow-up. Although animals were followed up to 10 months, there was no meaningful β-cell regeneration, be it through replication, neogenesis, or α- to β-cell conversion. In contrast, the acinar cell compartment underwent massive changes with first severe acinar degeneration upon PDL injury followed by the appearance of pancreatic adipocytes, and finally near-complete reappearance of acini. We conclude that β-cells and acinar cells, although originating from the same precursors during development, have very distinct regenerative potentials in our PDL model in adult rats.