Abstract

Induction of β-cell mass regeneration is a potentially curative treatment of diabetes. We have recently found that long-term gastrin treatment results in improved metabolic control and β-cell mass expansion in 95% pancreatectomised (Px) rats. In the present study, we investigated the underlying mechanisms of gastrin-induced β-cell mass expansion after pancreatectomy. After 90%-Px, rats were treated with gastrin (Px+G) or vehicle (Px+V) and pancreatic remnants were harvested on days 1, 3, 5, 7 and 14 and used for gene expression, protein immunolocalization and morphometric analysis. 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 (CCKBR) were identified. These focal areas of regeneration were similar in size and cell composition in Px+G and Px+V groups. However, in Px+G group the ductal structures showed lower levels of keratin 20 (KRT20) and β-catenin (indicative of duct dedifferentiation), and higher Neurog3 and NKX6.1 expression (indicative of endocrine progenitor phenotype) than in Px+V rats. In Px+G rats, β-cell mass and the number of scattered β-cells were significantly increased compared with Px+V rats, whereas β-cell replication and apoptosis were similar in both groups. These results indicate that gastrin treatment enhanced the dedifferentiation and reprogramming of regenerative ductal cells in Px rats, increased beta cell neogenesis and fostered beta cell mass expansion.