Gastrin induces ductal cell dedifferentiation and ß-cell neogenesis after 90% pancreatectomy.

ABSTRACT

Induction of ß-cell mass regeneration is a potentially curative treatment for diabetes. We have recently found that long-term gastrin treatment results in improved metabolic control and ß-cell mass expansion in 95% pancreatectomised (Px) rats. In this study, we investigated the underlying mechanisms of gastrin-induced ß-cell mass expansion after Px. After 90%-Px, rats were treated with gastrin (Px+G) or vehicle (Px+V), pancreatic remnants were harvested on days 1, 3, 5, 7, and 14 and used for gene expression, protein immunolocalisation and morphometric analyses. Gastrin- and vehicle-treated Px rats showed similar blood glucose levels throughout the study. Initially, after Px, focal areas of regeneration, showing mesenchymal cells surrounding ductal structures that expressed the cholecystokinin B receptor, were identified. These focal areas of regeneration were similar in size and cell composition in the Px+G and Px+V groups. However, in the Px+G group, the ductal structures showed lower levels of keratin 20 and ß-catenin (indicative of duct dedifferentiation) and higher levels of expression of neurogenin 3 and NKX6-1 (indicative of endocrine progenitor phenotype), as compared with Px+V rats. In Px+G rats, ß-cell mass and the number of scattered ß-cells were significantly increased compared with Px+V rats, whereas ß-cell replication and apoptosis were similar in the two groups. These results indicate that gastrin treatment-enhanced dedifferentiation and reprogramming of regenerative ductal cells in Px rats, increased ß-cell neogenesis and fostered ß-cell mass expansion.