ß-Cell dedifferentiation, reduced duct cell plasticity, and impaired ß-cell mass regeneration in middle-aged rats.

Limitations in ß-cell regeneration potential in middle-aged animals could contribute to the increased risk to develop diabetes associated with aging. We investigated ß-cell regeneration of middle-aged Wistar rats in response to two different regenerative stimuli: partial pancreatectomy (Px + V) and gastrin administration (Px + G). Pancreatic remnants were analyzed 3 and 14 days after surgery. ß-Cell mass increased in young animals after Px and was further increased after gastrin treatment. In contrast, ß-cell mass did not change after Px or after gastrin treatment in middle-aged rats. ß-Cell replication and individual ß-cell size were similarly increased after Px in young and middle-aged animals, and ß-cell apoptosis was not modified. Nuclear immunolocalization of neurog3 or nkx6.1 in regenerative duct cells, markers of duct cell plasticity, was increased in young but not in middle-aged Px rats. The pancreatic progenitor-associated transcription factors neurog3 and sox9 were upregulated in islet ß-cells of middle-aged rats and further increased after Px. The percentage of chromogranin A+/hormone islet cells was significantly increased in the pancreases of middle-aged Px rats. In summary, the potential for compensatory ß-cell hyperplasia and hypertrophy was retained in middle-aged rats, but ß-cell dedifferentiation and impaired duct cell plasticity limited ß-cell regeneration.