BACKGROUND Transcription factor pancreatic duodenal homeobox-1 (PDX-1) is critical for beta-cell differentiation and insulin gene expression. In this study, we investigated the role of PDX-1 in ductal-to-islet cell transdifferentiation, islet cell apoptosis, and proliferation in addition to other regulators associated with these processes in two developing beta-cell models. MATERIALS AND METHODS CAPAN-1 cells were cultured with the GLP-1 analogue Exendin-4 (Ex-4) to induce transdifferentiation to an insulin-producing phenotype. Expression patterns of PDX-1, somatostatin receptors (SSTR) 1, 2, and 5, p27, and p38 were analyzed. To model pancreatic regeneration in vivo, subtotal pancreatectomies were performed in rats and remnant pancreata were compared to sham laparotomy controls to determine islet size, morphology, apoptosis, and PDX-1 expression. RESULTS In Ex-4-treated cells, PDX-1 expression increased 67% above basal levels within 24 h and was followed by a 10-fold decline in expression by the end of the study. Expression of cell-cycle inhibitor p27 was down-regulated by 81% at 24 h, while levels of the pro-apoptotic modulator p38 significantly increased 4-fold. When compared to controls, SSTR1 expression declined, while SSTR2 and SSTR5 expression were significantly up-regulated in treated cells. Immunofluorescence of pancreatic remnants following subtotal pancreatectomy revealed increased PDX-1 staining at 24 h followed by a significant decline at 72 h post-pancreatectomy. CONCLUSION GLP-1 analogue Ex-4 resulted in up-regulation of PDX-1 in CAPAN-1 cells and PDX-1 was up-regulated in proliferating islets following subtotal pancreatectomy in rats. The increase was seen in the first 24 h. These findings suggest a possible relationship between PDX-1 and the state of islet proliferation, islet-to-ductal transdifferentiation, apoptosis, and the expression of SSTRs.