Glucagon-like peptide 1 induces differentiation of islet duodenal homeobox-1-positive pancreatic ductal cells into insulin-secreting cells

Glucagon-like peptide-1 (GLP-1) is an incretin hormone capable of restoring normal glucose tolerance in aging glucose-intolerant mister rats. Whether the antidiabetic properties of GLP-1 are exclusively due to its insulin sec retory activity remains to be determined. A GLP-1-dependent differentiation of pancreatic precursor cells into mature beta -cells has recently been pr oposed. The aim of this study was to investigate whether pancreatic ductal epithelial cells could be differentiated into insulin-secreting cells by ex posing them to GLP-1. Rat (ARIP) and human (PANC-1) cell lines, both derive d from the pancreatic ductal epithelium, were used to test this hypothesis. A major difference distinguishes these two cell lines: whereas ARIP cells spontaneously express the beta -cell differentiation factor islet duodenal homeobox-1 (IDX-1), PANC-1 cells are characteristically IDX-1 negative. GLP -1 induced the differentiation of ARIP cells into insulin-synthesizing cell s, although it did not affect the phenotype of PANC-1 cells, as determined by fluorescence-activated cell sorting (FACS) analysis. Differentiation of ARIP cells by exposure to human GLP-1 occurs in a time- and dose-dependent manner, and this is associated with an increase in IDX-1 and insulin mRNA l evels. Secretion of insulin was also induced in a parallel manner, and it w as regulated by the concentration of glucose in the culture medium. Interes tingly, PANC-1 cells, when stably transfected with human IDX-1, gained resp onsiveness to GLP-1. and were able to differentiate into beta -cells, as de termined by FAGS analysis, insulin gene expression, intracellular insulin c ontent, and insulin accumulation in the culture medium. Finally, we demonst rated that the receptor for GLP-1 is constitutively expressed by ARIP and P ANC-1 cells and that the mRNA level for this transcript was increased by ce llular transfection with human IDX-1. In summary, our study provides eviden ce that GLP-1 is a differentiation factor for pancreatic ductal cells and t hat its effect requires the expression of IDX-1.