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 Wistar rats. Whether the antidiabetic properties of GLP-1 are exclusively due to its insulin secretory activity remains to be determined. A GLP-1-dependent differentiation of pancreatic precursor cells into mature beta-cells has recently been proposed. The aim of this study was to investigate whether pancreatic ductal epithelial cells could be differentiated into insulin-secreting cells by exposing them to GLP-1. Rat (ARIP) and human (PANC-1) cell lines, both derived 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 cells, 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 levels. Secretion of insulin was also induced in a parallel manner, and it was regulated by the concentration of glucose in the culture medium. Interestingly, PANC-1 cells, when stably transfected with human IDX-1, gained responsiveness to GLP-1 and were able to differentiate into beta-cells, as determined by FACS analysis, insulin gene expression, intracellular insulin content, and insulin accumulation in the culture medium. Finally, we demonstrated that the receptor for GLP-1 is constitutively expressed by ARIP and PANC-1 cells and that the mRNA level for this transcript was increased by cellular transfection with human IDX-1. In summary, our study provides evidence that GLP-1 is a differentiation factor for pancreatic ductal cells and that its effect requires the expression of IDX-1.
Hui
H
H
Division of Diabetes, Endocrinology and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Wright
C
C
Perfetti
R
R
D000199:Actins / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003470:Culture Media / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D018398:Homeodomain Proteins; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology* / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D011498:Protein Precursors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D003470:Culture Media; D018398:Homeodomain Proteins; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D012333:RNA, Messenger; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D052216:Glucagon-Like Peptide 1; D005934:Glucagon