INSULIN-LIKE GROWTH FACTOR-II GENE-EXPRESSION IN A RAT INSULIN-PRODUCING BETA-CELL LINE (INS-1) IS REGULATED BY GLUCOSE

A highly differentiated rat glucose-responsive insulin producing cell line INS-1 expresses high levels of insulin-like growth factor-II (IGF-II). Basal levels of IGF-II gene mRNA were expressed in cells cultured at 1-6 mmol/l glucose. At glucose concentrations of 10-20 mmol/l, IGF-II mRNA was increased more than threefold after 44 h of incubation. Levels of IGF-II mRNA in INS-1 cells incubated at 5.6 and 20 mmol/l glucose in the presence of 4 mu g/ml actinomycin D are comparable and are not reduced during 20 h of treatment, indicating the high stability of IGF-II mRNA in this cell line. From the three rat IGF-II promoters, promoter 3 is by far the most active in INS-1 cells. The IGF-II promoter 3 activity and IGF-II mRNA production at high glucose concentrations increased threefold over their respective levels at low glucose concentration, suggesting that the glucose-induced IGF-II gene expression in this beta-cell line might be transcriptionally controlled. The up-regulation of IGF-II mRNA by glucose was not due to the increased intracellular cyclic AMP levels or protein kinase C activation. A protein kinase C activator had no effect on IGF-II gene expression, and an adenylate cyclase;activator (forskolin), suppressed the stimulatory effects of glucose on the IGF-II mRNA. Under all the experimental conditions examined, the IGF-II and insulin genes were differentially regulated in INS-1 cells. The IGF-II gene expression and DNA synthesis, however, were regulated in parallel, suggesting that these two cellular activities are closely associated.