Reg is a gene associated with regeneration of pancreatic islets. We have previously shown that nicotinamide induces differentiation of human fetal beta-cells in tissue culture and that hepatocyte growth factor/scatter factor (HGF/SF) is mitogenic for the fetal beta-cells. We now tested whether these conditions, supporting either differentiation or growth, are associated with changes in reg gene expression in human fetal pancreatic cells. Culture for 7 days with 10 mM nicotinamide led to a fourfold decrease in reg mRNA levels (23 +/- 12% of control, n = 5, P < 0.001). In contrast, HGF/SF increased reg expression threefold (302 +/- 68% of control, n = 4, P < 0.05). Nicotinamide, which does not alter the differentiation level of adult beta-cells, did not significantly affect reg expression in adult human islets (84 +/- 4% of control, n = 2, NS). Thus, a higher level of endocrine differentiation is associated with a lower level of reg expression, and a higher rate of beta-cell replication results in increased reg transcription. These results provide the first evidence of a molecular marker, the reg gene, to distinguish between proliferation and differentiation of human beta-cells.